Medicine › Immunology and Allergy

Cell Adhesion Molecules Research

Works Count: 98256

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Description

This cluster of papers explores the role of integrins in cell adhesion, inflammation, and cancer. It covers topics such as leukocyte migration, focal adhesion kinase, extracellular matrix interactions, and the impact of integrin signaling on angiogenesis. The research also delves into the molecular mechanisms underlying integrin activation and its implications for various biological processes.

Keywords

Integrins; Cell Adhesion; Inflammation; Cancer; Focal Adhesion Kinase; Extracellular Matrix; Leukocyte Migration; Tetraspanins; Ligand Binding; Angiogenesis

Leukocyte-endothelial adhesion molecules

1994-10-01

TM Carlos , JM Harlan

Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix.

1986-03-01

Ronald A. Ignotz , Joan Massagué

We have examined whether the extracellular matrix is a biochemical target for transforming growth factor-beta (TGFbeta). We find that TGFbeta increases the expression of the major extracellular matrix proteins, fibronectin … We have examined whether the extracellular matrix is a biochemical target for transforming growth factor-beta (TGFbeta). We find that TGFbeta increases the expression of the major extracellular matrix proteins, fibronectin and collagen. This effect is a general response to TGFbeta seen in primary cultures and established lines of cells from various types, normal and transformed. The relative incorporation of fibronectin and collagen into the matrix also increases in response to TGFbeta. The effect of TGFbeta on fibronectin levels as characterized in chick embryo fibroblasts is rapid, selective, persistent, and specific, and involves transcriptional events; it is not mimicked by other growth factors tested. The induction of anchorage-independent growth of normal fibroblasts by TGFbeta is mimicked by fibronectin and is specifically blocked by inhibitors of fibronectin binding to its cell surface receptor. The results demonstrate a functional involvement of fibronectin in mediating cellular responses to TGFbeta, and suggest a model for TGFbeta action based on the control of the extracellular matrix in target cells.

CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells

1998-02-01

Volker Henn , Joseph R. Slupsky , Michael Gräfe +4 more

Integrins

2002-09-01

Richard O. Hynes

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Laminin–a glycoprotein from basement membranes.

1979-10-01

Rupert Timpl , H. Rohde , Pamela Gehron Robey +3 more

We have isolated a large noncollagenous glycoprotein, laminin, from a mouse tumor that produces basement membrane. The protein consists of at least two polypeptide chains (Mr = 220,000 and Mr … We have isolated a large noncollagenous glycoprotein, laminin, from a mouse tumor that produces basement membrane. The protein consists of at least two polypeptide chains (Mr = 220,000 and Mr = 440,000) joined to each other by disulfide bonds. Laminin and type IV collagen are major constituents of the tumor. Laminin is distinctly different from fibronectin, another component of basement membranes, in amino acid composition and immunological reactivity. Pepsin digestion of laminin releases a large, cystine-rich fragment which retains most of the antigenicity of the original protein. Immunological studies using purified antibody against laminin show that it is produced by a variety of cultured cells. In addition, these antibodies react with the basement membranes of normal tissues, suggesting that this protein or an immunologically related protein is a constituent of the basement membranes of these tissues.

The microenvironment of the tumour–host interface

2001-05-01

Lance A. Liotta , Elise C. Kohn

Interleukin-8 and related chemotactic cytokines--CXC and CC chemokines.

1994-01-01

Marco Baggiolini , Béatrice Dewald , Bernhard Moser

Publisher Summary This chapter focuses on interleukin-8 (IL-8) and related chemotactic cytokines—namely, CXC and CC chemokines. IL-8 is the best known member of a new class of cytokines that are … Publisher Summary This chapter focuses on interleukin-8 (IL-8) and related chemotactic cytokines—namely, CXC and CC chemokines. IL-8 is the best known member of a new class of cytokines that are widely studied because of their ability to attract and activate leukocytes, and their potential role as mediators of inflammation. IL-8 was originally isolated from the culture supernatants of stimulated human blood monocytes and was identified as a protein of 72 amino acids with a molecular weight of 8383. The three-dimensional structure of IL-8 has been studied by nuclear magnetic resonance spectroscopy and X-ray crystallography. In concentrated solution, and on crystallization, IL-8 is present as a dimer. The first CC chemokine was identified after cloning by differential hybridization from human tonsillar lymphocytes and was termed LD78. The CC and CXC chemokines are similar in size and have an overall structure that is characterized by the two intrachain disulfide bonds, short N-terminal and long C-terminal sequences. It discusses the role of chemokines in pathology with skin inflammation because psoriasis was the first disease to be linked to overproduction of IL-8. Several independent studies document the occurrence of high levels of IL-8 in the synovial fluid of inflamed joints of patients with different forms of rheumatic diseases, osteoarthritis, and gout.

Adhesion receptors of the immune system

1990-08-01

Timothy A. Springer

Monitoring of Blood Vessels and Tissues by a Population of Monocytes with Patrolling Behavior

2007-08-02

Cédric Auffray , Darin K. Fogg , Meriem Garfa-Traoré +7 more

The cellular immune response to tissue damage and infection requires the recruitment of blood leukocytes. This process is mediated through a classical multistep mechanism, which involves transient rolling on the … The cellular immune response to tissue damage and infection requires the recruitment of blood leukocytes. This process is mediated through a classical multistep mechanism, which involves transient rolling on the endothelium and recognition of inflammation followed by extravasation. We have shown, by direct examination of blood monocyte functions in vivo, that a subset of monocytes patrols healthy tissues through long-range crawling on the resting endothelium. This patrolling behavior depended on the integrin LFA-1 and the chemokine receptor CX(3)CR1 and was required for rapid tissue invasion at the site of an infection by this "resident" monocyte population, which initiated an early immune response and differentiated into macrophages.

New Perspectives in Cell Adhesion: RGD and Integrins

1987-10-23

Erkki Ruoslahti , Michael D. Pierschbacher

Rapid progress has been made in the understanding of the molecular interactions that result in cell adhesion. Many adhesive proteins present in extracellular matrices and in the blood contain the … Rapid progress has been made in the understanding of the molecular interactions that result in cell adhesion. Many adhesive proteins present in extracellular matrices and in the blood contain the tripeptide arginine-glycine-aspartic acid (RGD) as their cell recognition site. These proteins include fibronectin, vitronectin, osteopontin, collagens, thrombospondin, fibrinogen, and von Willebrand factor. The RGD sequences of each of the adhesive proteins are recognized by at least one member of a family of structurally related receptors, integrins, which are heterodimeric proteins with two membrane-spanning subunits. Some of these receptors bind to the RGD sequence of a single adhesion protein only, whereas others recognize groups of them. The conformation of the RGD sequence in the individual proteins may be critical to this recognition specificity. On the cytoplasmic side of the plasma membrane, the receptors connect the extracellular matrix to the cytoskeleton. More than ten proved or suspected RGD-containing adhesion-promoting proteins have already been identified, and the integrin family includes at least as many receptors recognizing these proteins. Together, the adhesion proteins and their receptors constitute a versatile recognition system providing cells with anchorage, traction for migration, and signals for polarity, position, differentiation, and possibly growth.

Fibronectin at a glance

2002-10-15

Roumen Pankov , Kenneth M. Yamada

Fibronectin (FN) mediates a wide variety of cellular interactions with the extracellular matrix (ECM) and plays important roles in cell adhesion,migration, growth and differentiation(Mosher, 1989;Carsons, 1989;Hynes, 1990;Yamada and Clark, 1996). … Fibronectin (FN) mediates a wide variety of cellular interactions with the extracellular matrix (ECM) and plays important roles in cell adhesion,migration, growth and differentiation(Mosher, 1989;Carsons, 1989;Hynes, 1990;Yamada and Clark, 1996). FN is widely expressed by multiple cell types and is critically important in vertebrate development, as demonstrated by the early embryonic lethality of mice with targeted inactivation of the FN gene(George et al., 1993). Although FN has been studied for more than two decades, this remarkably complex molecule is still the subject of exciting discoveries, such as finding new integrin- and heparin-binding sites(Mostafavi-Pour et al., 2001;Liao et al., 2002) or even a new form of the molecule (Zhao et al.,2001) that mediates a particular viral infection(Liu and Collodi, 2002).FIG1FN usually exists as a dimer composed of two nearly identical ∼250 kDa subunits linked covalently near their C-termini by a pair of disulfide bonds(see poster). Each monomer consists of three types of repeating units (termed FN repeats): type I (purple rectangles), type II (green octagons) and type III(red ovals). FN contains 12 type I repeats, two type II repeats and 15-17 type III repeats, which together account for approximately 90% of the FN sequence. Type I repeats are about 40 amino-acid residues in length and contain two disulfide bonds; type II repeats comprise a stretch of approximately 60 amino acids and two intrachain disulfide bonds; and type III repeats are about 90 residues long without any disulfide bonds. All three types of FN repeat are also found in other molecules, suggesting that FN evolved through exon shuffling (Patel et al.,1987).Although FN molecules are the product of a single gene, the resulting protein can exist in multiple forms that arise from alternative splicing of a single pre-mRNA that can generate as many as 20 variants in human FN (for reviews, see ffrench-Constant,1995; Kosmehl et al.,1996) (left panel, Plasma and Cellular fibronectin). A major type of splicing occurs within the central set of type III repeats (left panel, FN III7 to FN III15). Exon usage or skipping leads to inclusion or exclusion of either of two type III repeats — EDB (also termed EIIIB or EDII and located between FN repeats III7 and III8) and EDA (also called EIIIA or EDI and located between FN repeats III11 and III12). This `yes or no' type of splicing of FN ED domains is found in many vertebrates, including Xenopus, chickens, rats and humans.A third region of alternative splicing is localized to a non-homologous stretch called the V (variable in length) or IIICS (type III connecting segment) region. The structural variations in this region are more complex and species dependent (left panel, lower four gray boxes). In most species studied to date, except chicken, this region can be either partially or completely included or excluded; for example, in human FN, there can be five different V region variants.1 A fourth type of splicing is found in cartilage, where the predominant form of FN [termed (V+C)-] lacks the entire V region along with the FN III15 and FN I10 repeats. Interestingly, this FN isoform exists not only as a homodimer but also in an unusual monomeric configuration(left panel, Single-chain fibronectins). Recently, another single-chain FN(termed FN2) has been described in zebrafish, together with a FN1 form that is very similar to FNs identified in other vertebrates. The truncated FN2 form results from a fifth type of splicing in zebrafish (left panel, Single-chain fibronectins).1In chicken, the whole 120 amino acid residues of the V region can be included or a 44 amino acid segment from the 5′ end can be excluded(creating V76), but the whole V region is never missing. A similar mechanism leads to exclusion of a 25 amino acid fragment in rat, generating V95 that can be detected together with V0 and V120 forms. Splicing of the V region is even more complicated in human where segments from both 5′ (25aa) and 3′ (31aa) ends can be omitted independently (creating V95 and V89 correspondingly) or together (V64) producing five different V regions.FN is an abundant soluble constituent of plasma (300 μg/ml) and other body fluids and also part of the insoluble extracellular matrix. On the basis of its solubility, FN can be subdivided into two forms — soluble plasma FN (pFN) and less-soluble cellular (cFN) FN. Plasma FN is synthesized predominantly in the liver by hepatocytes and shows a relatively simple splicing pattern. The alternatively spliced EDA and EDB domains are almost always absent from plasma FN, although both V0 and V+ are present (left panel,Plasma fibronectin). Cellular FN consists of a much larger and more heterogeneous group of FN isoforms that result from cell-type-specific and species-specific splicing patterns (left panel, Cellular fibronectin). Thus,alternative splicing of precursor mRNA from the single FN gene has the capacity to produce a large number of variants, generating FNs with different cell-adhesive, ligand-binding, and solubility properties that provide a mechanism for cells to precisely alter the composition of the ECM in a developmental and tissue-specific manner.FN can be a ligand for a dozen members of the integrin receptor family (for a recent review, see Plow et al.,2000). Integrins are structurally and functionally related cell-surface heterodimeric receptors that link the ECM with the intracellular cytoskeleton. A large number of different integrins bind to FN, including the classic FN receptor α5β1 (middle panel,Integrin interaction sites). Extensive analyses have narrowed down the regions involved in cell adhesion along the lengthy FN molecule to several minimal integrin-recognition sequences (middle panel, single amino-acid sequences in red). The best known of these — RGD — is located in FN repeat III10. The recognition of this simple tripeptide sequence is complex and depends on flanking residues, its three-dimensional presentation and individual features of the integrin-binding pockets. For example, a second site in FN repeat III9 (the `synergy site' PHSRN, green) promotes specific α5β1 integrin binding to FN,apparently via interactions with the α5 subunit. However,binding of the FN receptor α5β1 to FN is not restricted only to repeats III9 and III10. It can also interact with an N-terminal fragment containing repeats I1-9 and II1,2, which also promotesα 5β1-integrin-mediated cell adhesion. Interestingly, interaction with this N-terminal region can trigger integrin-mediated intracellular signals that are distinct from those generated in response to ligation with the RGD sequence.A second set of FN sequences, which are bound by theα 4β1 integrin, has also received considerable attention. Two cell-recognition sequences (LDV and REDV) were originally identified in the alternatively spliced V region. Both of them are recognized by α4β1 andα 4β7. Additional sites recognized by theα 4β1 integrin — IDAPS and KLDAPT— are also present in repeats III14 and III5,respectively (the latter also binds to theα 4β7 integrin). Recently, binding ofα 4β1 as well asα 9β1 to an EDGIHEL sequence located within the alternatively spliced EDA segment has been reported, suggesting a possible adhesive function for the increased EDA-containing FN species observed during wound healing (Liao et al.,2002).Elucidation of the sites of integrin binding as well as other functionally important domains within the FN molecule was greatly facilitated by the early discovery that all FNs are cleaved only in specific regions when subjected to limited proteolytic digestion (reviewed byMosher, 1989;Hynes, 1990). Even a protease capable of cleaving proteins at many sites (such as pronase) will initially cleave FN, and it will only do this at highly specific, probably non-folded,unprotected locations. A simplified scheme of the major proteolytic cleavage sites is shown in the middle panel (see Major proteolytic digestion sites). The binding activities of FN are often preserved after such proteolysis and can be identified within particular fragments.FN has a remarkably wide variety of functional activities besides binding to cell surfaces through integrins. It binds to a number of biologically important molecules that include heparin, collagen/gelatin, and fibrin. These interactions are mediated by several distinct structural and functional domains, which have been defined by proteolytic fragmentation or recombinant DNA analyses (see Mosher,1989; Hynes, 1990;Yamada and Clark, 1996; and the website http://www.gwumc.edu/biochem/ingham/fnpage.htm).FN contains two major heparin-binding domains that interact with heparan sulfate proteoglycans (right panel, Ligand interaction sites). The strongest heparin-binding site is located in the C-terminal part (Heparin II) and a weaker binding domain is situated at the N-terminal end of the protein(Heparin I). The high-affinity heparin II domain can also bind to a widely distributed glycosaminoglycan, chondroitin sulfate, whereas the weaker heparin-binding domain contains a Staphylococus-aureus-binding site that mediates FN interactions with bacteria. Recently, a novel glycosaminoglycan-binding site has been identified within the V region of FN(Mostafavi-Pour et al., 2001)(marked as `Heparin' at the V domain). In at least some cell types, the heparin-binding domains of FN potentiate cell adhesion.The collagen-binding domain includes repeats I6-9 and II1,2, and it binds far more effectively to denatured collagen(gelatin) than to native collagen. Thus, FN interactions with collagens in general may be due to its binding to unfolded regions of the collagen triple helix. It has been suggested that the physiological function of the collagen/gelatin-binding domain is related more to binding and clearance of denatured collagenous materials from blood and tissue than to mediating cell adhesion to collagen. Interestingly, however, a recent analysis of the physiological state of collagen indicates that the triple helix is likely to unfold locally at body temperature (Leikina et al., 2002), which suggests that this FN domain could be involved in interactions with native collagen in vivo.FN also contains two major fibrin-binding sites (Fibrin I and Fibrin II). The major site is in the N-terminal domain and is formed by type I repeats 4 and 5. The interaction of FN with fibrin is thought to be important for cell adhesion or cell migration into fibrin clots. In both cases, cross-linking between FN and fibrin mediated by factor XIII transglutaminase is proposed to mediate the effect (the cross-linking site on the FN molecule is marked by factor XIIIa and an arrow). The interaction of FN with fibrin may also be involved in macrophage clearance of fibrin from circulation after trauma or in inflammation.FNs are glycoproteins that contain 4-9% carbohydrate, depending on the cell source. Glycosylation sites that are either N-linked (red stars) or O-linked(green star) reside predominantly within type III repeats and the collagen-binding domain. The physiological role of the carbohydrates is not certain, although they appear to stabilize FN against hydrolysis and modulate its affinity to some substrates.Although the plasma FN that circulates in blood is in a closed, reportedly non-active form, most of the FN activities in the body have been ascribed to the insoluble form of FN that exists as part of the extracellular matrix (see the immunofluorescence image obtained with anti-FN antibodies at the bottom of the middle panel labeled Fibronectin-based matrix). The creation and deposition of insoluble FN fibrils into the ECM is a tightly regulated,cell-mediated process termed FN fibrillogenesis or FN matrix assembly (for a review, see Geiger et al.,2001). A critical step in this process is self-association of FN into aggregates and fibrils, which is directed by multiple binding sites that have been identified along the molecule (right panel, Sites involved in fibronectin fibrillogenesis). Some of these self-interaction sites are exposed and available for binding (marked in yellow), while others are cryptic (marked in light brown) and become accessible only after conformational changes, for example, by cell-driven mechanical stretching of the FN molecule.FN is one of the largest multi-domain proteins for which domain organization, molecular interactions, and key functions have been established in great detail. Exploration of the cell-type-specific splicing variants,glycosylation patterns and their relationship to health and disease will be further challenges in the study of this fascinating molecule.

RGD modified polymers: biomaterials for stimulated cell adhesion and beyond

2003-08-12

Ulrich Hersel , Claudia Dahmen , Horst Kessler

A Mechanism for Regulating Pulmonary Inflammation and Fibrosis: The Integrin αvβ6 Binds and Activates Latent TGF β1

1999-02-01

John S. Munger , Xiaozhu Huang , Hisaaki Kawakatsu +7 more

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Integrin αvβ3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels

1994-12-01

Peter C. Brooks , Anthony M.P. Montgomery , Mauricio Rosenfeld +4 more

Integrins: A family of cell surface receptors

1987-02-01

R HYNES

Sox9 Modulates Proliferation and Expression of Osteogenic Markers of Adipose-Derived Stem Cells (ASC)

2013-01-01

Sabine Stöckl , Claudia Göttl , Joachim Grifka +1 more

Integrins are cell adhesion receptors that are evolutionary old and that play important roles during developmental and pathological processes. The integrin family is composed of 24 alphabeta heterodimeric members that … Integrins are cell adhesion receptors that are evolutionary old and that play important roles during developmental and pathological processes. The integrin family is composed of 24 alphabeta heterodimeric members that mediate the attachment of cells to the extracellular matrix (ECM) but that also take part in specialized cell-cell interactions. Only a subset of integrins (8 out of 24) recognizes the RGD sequence in the native ligands. In some ECM molecules, such as collagen and certain laminin isoforms, the RGD sequences are exposed upon denaturation or proteolytic cleavage, allowing cells to bind these ligands by using RGD-binding receptors. Proteolytic cleavage of ECM proteins might also generate fragments with novel biological activity such as endostatin, tumstatin, and endorepellin. Nine integrin chains contain an alphaI domain, including the collagen-binding integrins alpha1beta1, alpha2beta1, alpha10beta1, and alpha11beta1. The collagen-binding integrins recognize the triple-helical GFOGER sequence in the major collagens, but their ability to recognize these sequences in vivo is dependent on the fibrillar status and accessibility of the interactive domains in the fibrillar collagens. The current review summarizes some basic facts about the integrin family including a historical perspective, their structure, and their ligand-binding properties.

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Binding of soluble form of fibroblast surface protein, fibronectin, to collagen

1977-07-15

Eva Engvall , Erkki Ruoslahti

Abstract Fibronectin, a plasma protein immunologically identical with a major surface protein of normal fibroblasts, was found to bind to collagen and gelatin. A solid phase enzyme immunoassay was used … Abstract Fibronectin, a plasma protein immunologically identical with a major surface protein of normal fibroblasts, was found to bind to collagen and gelatin. A solid phase enzyme immunoassay was used for the binding tests. Collagen, gelatin or various control proteins were adsorbed to a plastic surface. Binding of fibronectin was detected using purified fibronectin antibodies conjugated to alkaline phosphatase. Circulating fibronectin and fibronectin obtained from fibroblast cultures both showed specific binding to collagen and gelatin. Preparative affinity chromatography of plasma on gelatin coupled to Sepharose gave electrophoretically and immunologically pure fibronectin in high yields. Malignantly transformed fibroblasts lack surface fibronectin. Our findings suggest the possibility that this results in a lack of anchorage to the surrounding intercellular matrix, which could contribute to the malignant growth behavior.

Endothelial Leukocyte Adhesion Molecule 1: an Inducible Receptor for Neutrophils Related to Complement Regulatory Proteins and Lectins

1989-03-03

M P Bevilacqua , Siegfried Stengelin , Michael A. Gimbrone +1 more

Focal adhesion of leukocytes to the blood vessel lining is a key step in inflammation and certain vascular disease processes. Endothelial leukocyte adhesion molecule-1 (ELAM-1), a cell surface glycoprotein expressed … Focal adhesion of leukocytes to the blood vessel lining is a key step in inflammation and certain vascular disease processes. Endothelial leukocyte adhesion molecule-1 (ELAM-1), a cell surface glycoprotein expressed by cytokine-activated endothelium, mediates the adhesion of blood neutrophils. A full-length complementary DNA (cDNA) for ELAM-1 has now been isolated by transient expression in COS cells. Cells transfected with the ELAM-1 clone express a surface structure recognized by two ELAM-1 specific monoclonal antibodies (H4/18 and H18/7) and support the adhesion of isolated human neutrophils and the promyelocytic cell line HL-60. Expression of ELAM-1 transcripts in cultured human endothelial cells is induced by cytokines, reaching a maximum at 2 to 4 hours and decaying by 24 hours; cell surface expression of ELAM-1 protein parallels that of the mRNA. The primary sequence of ELAM-1 predicts an amino-terminal lectin-like domain, an EGF domain, and six tandem repetitive motifs (about 60 amino acids each) related to those found in complement regulatory proteins. A similar domain structure is also found in the MEL-14 lymphocyte cell surface homing receptor, and in granule-membrane protein 140, a membrane glycoprotein of platelet and endothelial secretory granules that can be rapidly mobilized (<5 minutes) to the cell surface by thrombin and other stimuli. Thus, ELAM-1 may be a member of a nascent gene family of cell surface molecules involved in the regulation of inflammatory and immunological events at the interface of vessel wall and blood.

Taking Cell-Matrix Adhesions to the Third Dimension

2001-11-23

Edna Cukierman , Roumen Pankov , Daron R. Stevens +1 more

Adhesions between fibroblastic cells and extracellular matrix have been studied extensively in vitro, but little is known about their in vivo counterparts. Here, we characterized the composition and function of … Adhesions between fibroblastic cells and extracellular matrix have been studied extensively in vitro, but little is known about their in vivo counterparts. Here, we characterized the composition and function of adhesions in three-dimensional (3D) matrices derived from tissues or cell culture. "3D-matrix adhesions" differ from focal and fibrillar adhesions characterized on 2D substrates in their content of alpha5beta1 and alphavbeta3 integrins, paxillin, other cytoskeletal components, and tyrosine phosphorylation of focal adhesion kinase (FAK). Relative to 2D substrates, 3D-matrix interactions also display enhanced cell biological activities and narrowed integrin usage. These distinctive in vivo 3D-matrix adhesions differ in structure, localization, and function from classically described in vitro adhesions, and as such they may be more biologically relevant to living organisms.

Integrins: Versatility, modulation, and signaling in cell adhesion

1992-04-01

Richard O. Hynes

Requirement of Vascular Integrin α v β 3 for Angiogenesis

1994-04-22

Peter C. Brooks , Richard A.F. Clark , David A. Cheresh

Angiogenesis depends on the adhesive interactions of vascular cells. The adhesion receptor integrin α v β 3 was identified as a marker of angiogenic vascular tissue. Integrin α v β … Angiogenesis depends on the adhesive interactions of vascular cells. The adhesion receptor integrin α v β 3 was identified as a marker of angiogenic vascular tissue. Integrin α v β 3 was expressed on blood vessels in human wound granulation tissue but not in normal skin, and it showed a fourfold increase in expression during angiogenesis on the chick chorioallantoic membrane. In the latter assay, a monoclonal antibody to α v β 3 blocked angiogenesis induced by basic fibroblast growth factor, tumor necrosis factor-α, and human melanoma fragments but had no effect on preexisting vessels. These findings suggest that α v β 3 may be a useful therapeutic target for diseases characterized by neovascularization.

Interleukin-8 as a Macrophage-Derived Mediator of Angiogenesis

1992-12-11

Alisa E. Koch , Peter J. Polverini , Steven L. Kunkel +4 more

Angiogenic factors produced by monocytes-macrophages are involved in the pathogenesis of chronic inflammatory disorders characterized by persistent angiogenesis. The possibility was tested that interleukin-8 (IL-8), which is a cytokine that … Angiogenic factors produced by monocytes-macrophages are involved in the pathogenesis of chronic inflammatory disorders characterized by persistent angiogenesis. The possibility was tested that interleukin-8 (IL-8), which is a cytokine that is chemotactic for lymphocytes and neutrophils, is also angiogenic. Human recombinant IL-8 was potently angiogenic when implanted in the rat cornea and induced proliferation and chemotaxis of human umbilical vein endothelial cells. Angiogenic activity present in the conditioned media of inflamed human rheumatoid synovial tissue macrophages or lipopolysaccharide-stimulated blood monocytes was equally blocked by antibodies to either IL-8 or tumor necrosis factor-α. An IL-8 antisense oligonucleotide specifically blocked the production of monocyte-induced angiogenic activity. These data suggest a function for macrophage-derived IL-8 in angiogenesis-dependent disorders such as rheumatoid arthritis, tumor growth, and wound repair.

The Immunoglobulin Superfamily—Domains for Cell Surface Recognition

1988-04-01

Alan F. Williams , A. Neil Barclay

Leukocytes roll on a selectin at physiologic flow rates: Distinction from and prerequisite for adhesion through integrins

1991-05-01

Michael B. Lawrence , Timothy A. Springer

Leukocyte-endothelial cell recognition: Three (or more) steps to specificity and diversity

1991-12-01

Eugene C. Butcher

Getting to the site of inflammation: the leukocyte adhesion cascade updated

2007-08-24

Klaus Ley , Carlo Laudanna , Myron I. Cybulsky +1 more

Focal adhesion kinase: in command and control of cell motility

2005-01-01

Satyajit K. Mitra , Daniel Hanson , David D. Schlaepfer

Cell Migration: Integrating Signals from Front to Back

2003-12-04

Anne J. Ridley , Martin A. Schwartz , Keith Burridge +5 more

Cell migration is a highly integrated multistep process that orchestrates embryonic morphogenesis; contributes to tissue repair and regeneration; and drives disease progression in cancer, mental retardation, atherosclerosis, and arthritis. The … Cell migration is a highly integrated multistep process that orchestrates embryonic morphogenesis; contributes to tissue repair and regeneration; and drives disease progression in cancer, mental retardation, atherosclerosis, and arthritis. The migrating cell is highly polarized with complex regulatory pathways that spatially and temporally integrate its component processes. This review describes the mechanisms underlying the major steps of migration and the signaling pathways that regulate them, and outlines recent advances investigating the nature of polarity in migrating cells and the pathways that establish it.

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The Extracellular Matrix: Not Just Pretty Fibrils

2009-11-27

Richard O. Hynes

The extracellular matrix (ECM) and ECM proteins are important in phenomena as diverse as developmental patterning, stem cell niches, cancer, and genetic diseases. The ECM has many effects beyond providing … The extracellular matrix (ECM) and ECM proteins are important in phenomena as diverse as developmental patterning, stem cell niches, cancer, and genetic diseases. The ECM has many effects beyond providing structural support. ECM proteins typically include multiple, independently folded domains whose sequences and arrangement are highly conserved. Some of these domains bind adhesion receptors such as integrins that mediate cell-matrix adhesion and also transduce signals into cells. However, ECM proteins also bind soluble growth factors and regulate their distribution, activation, and presentation to cells. As organized, solid-phase ligands, ECM proteins can integrate complex, multivalent signals to cells in a spatially patterned and regulated fashion. These properties need to be incorporated into considerations of the functions of the ECM.

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Integrins and Signal Transduction Pathways: the Road Taken

1995-04-14

Edwin Clark , Joan S. Brugge

Adhesive interactions play critical roles in directing the migration, proliferation, and differentiation of cells; aberrations in such interactions can lead to pathological disorders. These adhesive interactions, mediated by cell surface … Adhesive interactions play critical roles in directing the migration, proliferation, and differentiation of cells; aberrations in such interactions can lead to pathological disorders. These adhesive interactions, mediated by cell surface receptors that bind to ligands on adjacent cells or in the extracellular matrix, also regulate intracellular signal transduction pathways that control adhesion-induced changes in cell physiology. Though the extracellular molecular interactions involving many adhesion receptors have been well characterized, the adhesion-dependent intracellular signaling events that regulate these physiological alterations have only begun to be elucidated. This article will focus on recent advances in our understanding of intracellular signal transduction pathways regulated by the integrin family of adhesion receptors.

A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells

1997-02-01

Roy A. Black , Charles T. Rauch , Carl J. Kozlosky +7 more

VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/Fibronectin binding site

1990-02-01

Mariano J. Elices , Laurelee Osborn , Yoshikazu Takada +4 more

Tumour-cell invasion and migration: diversity and escape mechanisms

2003-05-01

Peter Friedl , Katarina Wolf

Multiple nuclear factors interact with the immunoglobulin enhancer sequences

1986-08-01

Ranjan Sen , David Baltimore

Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm

1994-01-01

Timothy A. Springer

Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling

2009-11-01

Kandice R. Levental , Hongmei Yu , Laura Kass +7 more

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Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule

1984-05-01

Michael D. Pierschbacher , Erkki Ruoslahti

Focal Adhesions: Transmembrane Junctions Between the Extracellular Matrix and the Cytoskeleton

1988-11-01

Keith Burridge , Karl R. Fath , Thomas J. Kelly +2 more

INTRODUCTION 487 MORPHOLOGY AND OBSERVATION OF FOCAL ADHESIONS 488 FORMATION OF FOCAL ADHESIONS 490 DYNAMICS OF FOCAL ADHESION COMPONENTS ...... 491 INTRODUCTION 487 MORPHOLOGY AND OBSERVATION OF FOCAL ADHESIONS 488 FORMATION OF FOCAL ADHESIONS 490 DYNAMICS OF FOCAL ADHESION COMPONENTS ...... 491

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RGD AND OTHER RECOGNITION SEQUENCES FOR INTEGRINS

1996-11-01

Erkki Ruoslahti

▪ Abstract Proteins that contain the Arg-Gly-Asp (RGD) attachment site, together with the integrins that serve as receptors for them, constitute a major recognition system for cell adhesion. The RGD … ▪ Abstract Proteins that contain the Arg-Gly-Asp (RGD) attachment site, together with the integrins that serve as receptors for them, constitute a major recognition system for cell adhesion. The RGD sequence is the cell attachment site of a large number of adhesive extracellular matrix, blood, and cell surface proteins, and nearly half of the over 20 known integrins recognize this sequence in their adhesion protein ligands. Some other integrins bind to related sequences in their ligands. The integrin-binding activity of adhesion proteins can be reproduced by short synthetic peptides containing the RGD sequence. Such peptides promote cell adhesion when insolubilized onto a surface, and inhibit it when presented to cells in solution. Reagents that bind selectively to only one or a few of the RGD-directed integrins can be designed by cyclizing peptides with selected sequences around the RGD and by synthesizing RGD mimics. As the integrin-mediated cell attachment influences and regulates cell migration, growth, differentiation, and apoptosis, the RGD peptides and mimics can be used to probe integrin functions in various biological systems. Drug design based on the RGD structure may provide new treatments for diseases such as thrombosis, osteoporosis, and cancer.

Integrins αvβ3 and αvβ5 promote adenovirus internalization but not virus attachment

1993-04-01

Thomas J. Wickham , Patricia Mathias , David A. Cheresh +1 more

Structural design and molecular evolution of a cytokine receptor superfamily.

1990-09-01

J. Fernando Bazán

A family of cytokine receptors comprising molecules specific for a diverse group of hematopoietic factors and growth hormones has been principally defined by a striking homology of binding domains. This … A family of cytokine receptors comprising molecules specific for a diverse group of hematopoietic factors and growth hormones has been principally defined by a striking homology of binding domains. This work proposes that the approximately 200-residue binding segment of the canonical cytokine receptor is composed of two discrete folding domains that share a significant sequence and structural resemblance. Analogous motifs are found in tandem approximately 100-amino acid domains in the extracellular segments of a receptor family formed by the interferon-alpha/beta and -gamma receptors and tissue factor, a membrane tether for a coagulation protease. Domains from the receptor supergroup reveal clear evolutionary links to fibronectin type III structures, approximately 90-amino acid modules that are typically found in cell surface molecules with adhesive functions. Predictive structural analysis of the shared receptor and fibronectin domains locates seven beta-strands in conserved regions of the chain; these strands are modeled to fold into antiparallel beta-sandwiches with a topology that is similar to immunoglobulin constant domains. These findings have strong implications for understanding the evolutionary emergence of an important class of regulatory molecules from primitive adhesive modules. In addition, the resulting double-barrel design of the receptors and the spatial clustering of conserved residues suggest a likely binding site for cytokine ligands.

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The extracellular matrix: A dynamic niche in cancer progression

2012-02-20

Pengfei Lu , Valerie M. Weaver , Zena Werb

The local microenvironment, or niche, of a cancer cell plays important roles in cancer development. A major component of the niche is the extracellular matrix (ECM), a complex network of … The local microenvironment, or niche, of a cancer cell plays important roles in cancer development. A major component of the niche is the extracellular matrix (ECM), a complex network of macromolecules with distinctive physical, biochemical, and biomechanical properties. Although tightly controlled during embryonic development and organ homeostasis, the ECM is commonly deregulated and becomes disorganized in diseases such as cancer. Abnormal ECM affects cancer progression by directly promoting cellular transformation and metastasis. Importantly, however, ECM anomalies also deregulate behavior of stromal cells, facilitate tumor-associated angiogenesis and inflammation, and thus lead to generation of a tumorigenic microenvironment. Understanding how ECM composition and topography are maintained and how their deregulation influences cancer progression may help develop new therapeutic interventions by targeting the tumor niche.

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Novel Modulator for Endothelial Adhesion Molecules

1999-12-21

Noriyuki Ouchi , Shinji Kihara , Yukio Arita +7 more

Among the many adipocyte-derived endocrine factors, we recently found an adipocyte-specific secretory protein, adiponectin, which was decreased in obesity. Although obesity is associated with increased cardiovascular mortality and morbidity, the … Among the many adipocyte-derived endocrine factors, we recently found an adipocyte-specific secretory protein, adiponectin, which was decreased in obesity. Although obesity is associated with increased cardiovascular mortality and morbidity, the molecular basis for the link between obesity and vascular disease has not been fully clarified. The present study investigated whether adiponectin could modulate endothelial function and relate to coronary disease.For the in vitro study, human aortic endothelial cells (HAECs) were preincubated for 18 hours with the indicated amount of adiponectin, then exposed to tumor necrosis factor-alpha (TNF-alpha) (10 U/mL) or vehicle for the times indicated. The adhesion of human monocytic cell line THP-1 cells to HAECs was determined by adhesion assay. The surface expression of vascular cell adhesion molecule-1 (VCAM-1), endothelial-leukocyte adhesion molecule-1 (E-selectin), and intracellular adhesion molecule-1 (ICAM-1) was measured by cell ELISA. Physiological concentrations of adiponectin dose-dependently inhibited TNF-alpha-induced THP-1 adhesion and expression of VCAM-1, E-selectin, and ICAM-1 on HAECs. For the in vivo study, the concentrations of adiponectin in human plasma were determined by a sandwich ELISA system that we recently developed. Plasma adiponectin concentrations were significantly lower in patients with coronary artery disease than those in age- and body mass index-adjusted control subjects.These observations suggest that adiponectin modulates endothelial inflammatory response and that the measurement of plasma adiponectin levels may be helpful in assessment of CAD risk.

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Integrins and other cell adhesion molecules

1990-08-01

Steven Μ. Albelda , Clayton A. Buck

Cell-cell and cell-substratum interactions are mediated through several different families of receptors. In addition to targeting cell adhesion to specific extracellular matrix proteins and ligands on adjacent cells, these receptors … Cell-cell and cell-substratum interactions are mediated through several different families of receptors. In addition to targeting cell adhesion to specific extracellular matrix proteins and ligands on adjacent cells, these receptors influence many diverse processes including cellular growth, differentiation, junction formation, and polarity. Several families of adhesion receptors have been identified. These include: 1) the integrins, heterodimeric molecules that function both as cell-substratum and cell-cell adhesion receptors; 2) the adhesion molecules of the immunoglobulin superfamily, which are involved in cell-cell adhesion and especially important during embryo-genesis, wound healing, and the inflammatory response; 3) the cadherins, developmentally regulated, calcium-dependent homophilic cell-cell adhesion proteins; 4) the LEC-CAMs, cell adhesion molecules with lectin-like domains that mediate white blood cell/endothelial cell adhesion; and 5) homing receptors that target lymphocytes to specific lymphoid tissue. In this review we summarize recent data describing the structure and function of some of these cell adhesion molecules (with special emphasis on the integrin family) and discuss the possible role of these molecules in development, inflammation, wound healing, coagulation, and tumor metastasis.

Integrins in cancer: biological implications and therapeutic opportunities

2009-12-23

Jay S. Desgrosellier , David A. Cheresh

Vascular Channel Formation by Human Melanoma Cells in Vivo and in Vitro: Vasculogenic Mimicry

1999-09-01

Andrew J. Maniotis , Robert Folberg , Angela R. Hess +6 more

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PERIODATE-LYSINE-PARAFORMALDEHYDE FIXATIVE A NEW FIXATIVE FOR IMMUNOELECTRON MICROSCOPY

1974-12-01

Ian W. McLean , Paul K. Nakane

A new fixative which primarily stabilizes carbohydrate moieties was developed for immunoelectron microscopy. It contains periodate, lysine and paraformaldehyde. Theoretically, the carbohydrates are oxidized by periodate and cross-linked by lysine. … A new fixative which primarily stabilizes carbohydrate moieties was developed for immunoelectron microscopy. It contains periodate, lysine and paraformaldehyde. Theoretically, the carbohydrates are oxidized by periodate and cross-linked by lysine. The fixative can preserve antigenicity as well as paraformaldehyde and ultrastructure as well as glutaraldehyde. Using this fixative and the peroxidase-labeled antibody technique, basement membrane antigen was localized within the cisternae of endoplasmic reticulum of parietal yolk sac cells and in extracellular basement membranes with adequate tissue preservation, a task which has not been successfully accomplished by conventional fixatives.

FOCAL ADHESIONS, CONTRACTILITY, AND SIGNALING

1996-11-01

Keith Burridge , Magdalena Chrzanowska‐Wodnicka

▪ Abstract Focal adhesions are sites of tight adhesion to the underlying extracellular matrix developed by cells in culture. They provide a structural link between the actin cytoskeleton and the … ▪ Abstract Focal adhesions are sites of tight adhesion to the underlying extracellular matrix developed by cells in culture. They provide a structural link between the actin cytoskeleton and the extracellular matrix and are regions of signal transduction that relate to growth control. The assembly of focal adhesions is regulated by the GTP-binding protein Rho. Rho stimulates contractility which, in cells that are tightly adherent to the substrate, generates isometric tension. In turn, this leads to the bundling of actin filaments and the aggregation of integrins (extracellular matrix receptors) in the plane of the membrane. The aggregation of integrins activates the focal adhesion kinase and leads to the assembly of a multicomponent signaling complex.

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Integrin Signaling

1999-08-13

Filippo G. Giancotti , Erkki Ruoslahti

Cells reside in a protein network, the extracellular matrix (ECM), which they secrete and mold into the intercellular space. The ECM exerts profound control over cells. The effects of the … Cells reside in a protein network, the extracellular matrix (ECM), which they secrete and mold into the intercellular space. The ECM exerts profound control over cells. The effects of the matrix are primarily mediated by integrins, a family of cell surface receptors that attach cells to the matrix and mediate mechanical and chemical signals from it. These signals regulate the activities of cytoplasmic kinases, growth factor receptors, and ion channels and control the organization of the intracellular actin cytoskeleton. Many integrin signals converge on cell cycle regulation, directing cells to live or die, to proliferate, or to exit the cell cycle and differentiate.

Leukocyte-endothelial adhesion molecules

1994-10-01

TM Carlos , JM Harlan

Regulation of Adult Zebrafish Retinal Regeneration by Lamβ1b-Chain-Containing Laminins

2025-06-25

Dmitri Serjanov , James F. Twist , Haoyuan Jiang +1 more | bioRxiv (Cold Spring Harbor Laboratory)

Retinal degenerative diseases are a major cause of blindness in humans that often result in permanent and progressive loss of vision. Unlike humans, zebrafish possess the remarkable ability to regenerate … Retinal degenerative diseases are a major cause of blindness in humans that often result in permanent and progressive loss of vision. Unlike humans, zebrafish possess the remarkable ability to regenerate lost retinal neurons through Müller glia (MG) reprogramming and asymmetric cell division to produce multipotent retinal progenitor cells (RPCs). While most studies on the molecular mechanisms underlying this regeneration process have focused on intracellular mechanisms, the role of the microenvironment surrounding retinal cells, the extracellular matrix (ECM), has been understudied. Laminins are heterotrimeric glycoproteins, are principal components of the ECM basement membrane, and play important roles in vertebrate retinal development. Here, we examine the role of β1b chain-containing laminins in the regenerative response of the zebrafish retina. We found that the zebrafish lamb1b gene is differentially expressed during MG reprogramming and MG and NPC proliferation during retinal regeneration. Further, we found that β1b-containing laminins play important roles in regulating MG and NPC proliferation and neuroprotection of photoreceptors in light-damaged zebrafish retinas. Finally, Lamβ1b plays an important role in regulating the expression of integrin receptors and other laminin genes during the regeneration response. Taken together, Lamβ1b, and likely other ECM components, play a critical role in the MG-dependent neuronal regeneration response in the zebrafish retina.

Alport syndrome complicated with steroid-sensitive nephrotic syndrome: a case report

2025-06-24

Fu Qian , Yuling Luo , Xingfeng Yao +1 more | Pediatric Nephrology

Enhancing the Potency of Growth Factor‐Mimicking Peptides via Cross‐Presentation With Integrin Ligands

2025-06-24

Sydney Neal , Xiaohong Tan , Era Jain +4 more | Journal of Biomedical Materials Research Part A

Growth factors enhance survival and integration of transplanted Mesenchymal Stromal Cells (MSC), but successful supplementation often requires supraphysiological growth factor doses, risking off-target effects. Short peptide mimics like the knuckle … Growth factors enhance survival and integration of transplanted Mesenchymal Stromal Cells (MSC), but successful supplementation often requires supraphysiological growth factor doses, risking off-target effects. Short peptide mimics like the knuckle epitope (KE) of Bone Morphogenetic Protein 2 (BMP-2) can be covalently immobilized to biomaterials, localizing bioactivity at the delivery site. However, these short peptides often lack the potency of full-length growth factors. We sought to improve the potency of alginate-grafted KE to encourage MSC osteogenic differentiation. When alginate gels co-presented KE and integrin-binding cyclo-RGD (cRGD) peptides, MSC expressed early markers of osteogenesis (Runt-related Transcription Factor2, RUNX2, Alkaline Phosphatase, ALP, and osteocalcin, OCN) in a KE-dose dependent manner. When co-presented with cRGD, high concentrations of KE partially mimicked the osteogenic potential (ALP induction) of full-length BMP-2. Proximity between KE and cRGD may be the mechanism through which high dose KE induces osteogenesis in the presence of cRGD. To investigate this possibility, we used orthogonal strain-promoted azide-alkyne cycloaddition (SPAAC) and maleimide-thiol chemistries to graft KE and cRGD in a bivalent (same alginate chain) and a monovalent (different alginate chain) manner, at constant bulk peptide concentration. Bivalent presentation of peptides (separation distance of 5.5 ± 0.5 nm verified by FRET) ultimately increased RUNX2 and ALP expression compared to monovalent presentation. This platform technology can be used in future studies to control peptide nanopatterning to enhance potency, in the context of MSC-based therapies and beyond.

Persistent microscopic haematuria in a female associated with COL4A1 gene mutation: A case report

2025-06-23

Heba Ali Aldarawsha , Md. Saimul Islam , Tetyana L. Vasylyeva | International Journal of Integrative Pediatrics and Environmental Medicine

Background: Hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is an autosomal dominant syndrome caused by mutations in COL4A1. COL4A1 gene mutation leads to a rare, multi-system disorder characterized … Background: Hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is an autosomal dominant syndrome caused by mutations in COL4A1. COL4A1 gene mutation leads to a rare, multi-system disorder characterized by abnormal brain, eyes, kidneys, and muscle blood vessels. Case Presentation: We are presenting a 7-year-old child with this rare medical condition, who presented with persistent microscopic hematuria and was diagnosed through genetic screening early in life. Although she had limited clinical presentation due to her early age, the genetic testing revealed a pathogenic mutation in the COL4A1 gene, which is a known cause of HANAC syndrome. Conclusion: COL4A1 gene mutation should be suspected in patients with unexplained persistent hematuria, especially with a strong family history of the same complaint without a clear underlying reason. Early in-life diagnosis is important for prognosis, health monitoring, and management. Key Words: HANAC syndrome; Pediatric; Clinical Management

Tracing a Rare Genetic Disease: Familial Congenital CD59 Deficiency and Carrier Cases Identified through Village Screening: Erratum

2025-06-23

Şefika İlknur Kökçü Karadağ , Medine Karadağ Alparslan , Hüseyin Karadağ +3 more | Journal of Pediatric Hematology/Oncology

Expression and Biological Activity Analysis of Recombinant Fibronectin3 Protein in Bacillus subtilis

2025-06-23

Chaozheng Lu , Guangxin Xu , Tian Yin +2 more | BioTech

Fibronectin (FN), a primary component of the extracellular matrix (ECM), features multiple structural domains closely linked to various cellular behaviors, including migration, spreading, adhesion, and proliferation. The FN3 domain, which … Fibronectin (FN), a primary component of the extracellular matrix (ECM), features multiple structural domains closely linked to various cellular behaviors, including migration, spreading, adhesion, and proliferation. The FN3 domain, which contains the RGD sequence, is critical in tissue repair because it enables interaction with integrin receptors on the cell surface. However, the large molecular weight of wild-type FN presents challenges for its large-scale production through heterologous expression. Therefore, this study focused on cloning the FN3 functional domain of full-length FN for expression and validation. This study selected Bacillus subtilis as the expression host due to its prominent advantages, including efficient protein secretion, absence of endotoxins, and minimal codon bias. The recombinant vector pHT43-FN3 was successfully constructed through homologous recombination technology and transformed into Bacillus subtilis WB800N. The FN3 protein was successfully expressed after induction with IPTG. Following purification of the recombinant FN protein using a His-tag nickel column, SDS-PAGE analysis showed that the molecular weight of FN3 was approximately 27.3 kDa. Western blot analysis confirmed the correct expression of FN3, and the BCA protein assay kit determined a protein yield of 5.4 mg/L. CCK8 testing demonstrated the good biocompatibility of FN3. In vitro cell experiments showed that FN3 significantly promoted cell migration at a 20 μg/mL concentration and enhanced cell adhesion at 10 μg/mL. In summary, this study successfully utilized Bacillus subtilis to express the FN3 functional domain peptide from FN protein and has validated its ability to promote cell migration and adhesion. These findings not only provide a strategy for the expression of FN protein in B. subtilis, but also establish an experimental foundation for the potential application of FN3 protein in tissue repair fields such as cutaneous wound healing and cartilage regeneration.

A novel bispecific integrin α5β1/αv antibody reprograms the Myc-regulated basal phenotype of prostate cancer with natural killer cell–mediated tumor elimination

2025-06-23

Raghav Joshi , Ming Zhou , Jeffrey H. Lin +6 more | Molecular Cancer Research

Integrin α5β1 and αv crosstalk in chemotaxis and clonogenic survival of prostate cancer cells is abrogated by a bispecific α5β1/αv antibody (BsAbα5β1/αv), which uniquely induces internalization and lysosomal degradation of … Integrin α5β1 and αv crosstalk in chemotaxis and clonogenic survival of prostate cancer cells is abrogated by a bispecific α5β1/αv antibody (BsAbα5β1/αv), which uniquely induces internalization and lysosomal degradation of target integrins. We hypothesized that the BsAbα5β1/αv inactivates pathological mechanosignaling pathways that correlate with integrin expression from patient samples. Mechanistic studies indicate that the BsAbα5β1/αv uniquely reverses YAP, beta-catenin and FAK nuclear localization compared to monospecific integrin α5β1 and αv antibody controls in basal-type androgen-receptor negative prostate cancer cells. Dual integrin αv and α5 knockdown alone phenocopied the BsAbα5β1/αv effect. Following BsAbα5β1/αv treatment, ATAC-seq studies indicated the chromatin accessibility to TEAD and AP-1 family members was markedly reduced. In vitro and in vivo RNA-seq indicated down-regulation of Myc/E2F, TGF-beta and epithelial mesenchymal transition (EMT) and upregulation of Type I and II interferon transcriptomic pathways. The BsAbα5β1/αv induced CXCL10 and CCL5 cytokine secretion, immune-infiltration of tumors, and natural-killer cell-mediated elimination of the basal-type prostate cancer xenografts in nude mice. αv integrin was highly expressed and principally correlated with the Myc signaling pathway in rapid autopsy tissue microarrays, consistent with correlative data from the SU2C metastatic castration-resistant prostate cancer and DKFZ early-onset prostate cancer cohorts. These studies connect integrin signaling with the central biology of basal-type and castration-resistant prostate cancer and define a novel therapeutic strategy that controls critical immunosuppressive pathways. Implications: Dual integrin α5β1/αv targeting with a bispecific antibody represents a novel therapeutic strategy that reprograms the epigenetic and transcriptomic signature of basal-type prostate cancer with induction of immunological tumor control.

Prostaglandin E2 dependent migration of human brain endothelial cells is mediated through Rho-Kinase-II

2025-06-23

Gausal A. Khan , Arjun K. Ghosh | PLoS ONE

Prostaglandin E2 (PGE2), that plays a crucial role in angiogenesis as well as in ischemic and inflammatory disorders of the brain, is associated with breakdown of the blood-brain barrier (BBB). … Prostaglandin E2 (PGE2), that plays a crucial role in angiogenesis as well as in ischemic and inflammatory disorders of the brain, is associated with breakdown of the blood-brain barrier (BBB). Previously, we had shown that PGE2-induced human brain endothelial cells (HBECs) migration, and works in a cooperative manner through its three receptors (EP2, EP3 & EP4). However, the detailed signaling mechanism of PGE2-induced HBECs migration remains obscure. In this present study, we investigated the signaling pathway of actin dynamics/polymerization and migration of HBECs by PGE2 in vitro. Expression of ROCK was analyzed by ELISA and RT-PCR. Actin polymerization was evaluated by NBD-phallacidin immunofluorescence staining. HBECs expressed only ROCK II. PGE2 (100 pM) induced ROCK II expression occurs in dose-and-time-dependent manner. ROCK II inhibition by Y27632 (150nM), as well as ROCK II silencing significantly attenuated PGE2-induced migration of HBECs. We further showed that pretreatment of PKA inhibitor (H-89; 0.5 μM) or adenylate cyclase inhibitor (ddA; 1μM) completely inhibited PGE2-induced ROCK II activity. Furthermore, PGE2-induced MLC phosphorylation also occurs in a time-dependent manner. However, pretreatment of ROCK II inhibitor or silencing of ROCK II significantly abrogated PGE2-induced MLC phosphorylation as well as F-actin polymerization. Our ex-vivo aortic ring angiogenesis study also showed that pretreatment of ROCK II inhibitor significantly inhibited ECs sprouting. These results suggest that PGE2-induced HBECs migration is mediated through PKA, ROCK II and MLC phosphorylation as well as F-actin polymerization, indicating that modulation of these pathways may aid in the future treatment of dysregulated angiogenesis in cerebrovascular diseases.

A genetic modifier links integrin α5 to the phenotypic variation in fibronectin 1a mutant zebrafish

2025-06-23

Samuel J. Capon , Anastasia Maroufidou , McKenna Feltes +6 more | PLoS Genetics

Phenotypic variation is often observed in individuals with the same mutation. However, the mechanisms that contribute to this variation remain largely unknown. Fibronectin mutants in both mouse and zebrafish fail … Phenotypic variation is often observed in individuals with the same mutation. However, the mechanisms that contribute to this variation remain largely unknown. Fibronectin mutants in both mouse and zebrafish fail to form a functional cardiovascular system, although the penetrance and expressivity of this phenotype vary depending on the genetic background. Here we investigate the variation of the zebrafish natter phenotype, which is caused by a nonsense mutation in fibronectin 1a (fn1a). natter/fn1a mutants exhibit incompletely penetrant cardia bifida, a phenotype caused by the failure of cardiac progenitors to migrate to the midline. To examine whether this variation is related to the nonsense mutation, we first generated a large deletion in fn1a that removes the proximal promoter and first 17 exons. Characterisation of this allele found that mutants display variable cardiac phenotypes indistinguishable from those observed in natter/fn1a mutants. As phenotypic variation is often associated with changes in paralogous gene expression, we next examined the expression of the fn1a paralogue, fn1b, and observed its upregulation specifically in the natter/fn1a mutants that exhibit a severe phenotype. However, overexpression and double mutant analyses suggest that fn1b expression levels do not modulate the natter/fn1a mutant phenotype. During these studies, we observed a small proportion of natter/fn1a mutants with a wild-type (WT)-like phenotype. Selectively raising WT looking mutant larvae increased the proportion of natter/fn1a mutants displaying the WT-like phenotype from 1.7% to 38.6% in just three generations, indicating the selection of a genetic modifier of the mutant phenotype. We mapped this modifier to the integrin alpha 5 (itgα5) locus through whole-genome sequencing. Furthermore, we found that manipulating itgα5 expression influenced the severity of the fn1a mutant phenotype, and that the variance in itgα5 expression was increased in fn1a mutants exhibiting a severe phenotype. Taken together, these results indicate that itgα5 modifies the fn1a mutant phenotype.

In Silico Prediction of Tetrastatin-Derived Peptide Interactions with αvβ3 and α5β1 Integrins

2025-06-21

Vivien Paturel , Stéphanie Baud , Christophe Schneider +1 more | Pharmaceuticals

Background/Objectives: Tetrastatin, the globular non collagenous (NC1) domain of the α4 chain of collagen IV, was previously demonstrated to inhibit melanoma progression. We identified the minimal active sequence (QKISRCQVCVKYS: QS-13) … Background/Objectives: Tetrastatin, the globular non collagenous (NC1) domain of the α4 chain of collagen IV, was previously demonstrated to inhibit melanoma progression. We identified the minimal active sequence (QKISRCQVCVKYS: QS-13) that reproduced the anti-tumor effects of whole Tetrastatin and demonstrated its anti-angiogenic activity mediated through αvβ3 and α5β1 binding. As QS-13 peptide was not fully soluble in aqueous solution, we designed new peptides with better water solubility. The present work aimed to investigate the interactions of ten QS-13-derived peptides, exhibiting improved hydro-solubility, with αvβ3 and α5β1 integrins. Methods: Using bioinformatics tools such as GROMACS, VMD, and the Autodock4 suite, we investigated the ability of the substituted peptides to bind αvβ3 and α5β1 integrins in silico. Results: We demonstrated in silico that all substituted peptides were able to bind both integrins at the RGD-binding site and determined their theoretical binding energy. Conclusions: The new soluble peptides should be able to compete with natural integrin ligands such as fibronectin, but also FGF1, FGF2, IGF1, and IGF2. Taken together, these findings suggest that the QS-13-derived peptides are reliable anti-angiogenic and anti-tumor agents.

[PSGL-1: A Universal Selectin Ligand or a Signaling Molecule? (Review of the Literature)].

2025-06-21

Nataliy V. Korotkova , R.Е. Kalinin , I.А. Suchkov +2 more | PubMed

Interactions of intercellular adhesion molecules of the selectin family with glycoconjugates of cell membranes mediate the initial stage of the adhesion cascade, which recruits leukocytes circulating in the bloodstream to … Interactions of intercellular adhesion molecules of the selectin family with glycoconjugates of cell membranes mediate the initial stage of the adhesion cascade, which recruits leukocytes circulating in the bloodstream to sites of infection or damage. The formation of heterotypic cell aggregates between individual cells of hematopoietic and non-hematopoietic origin may be involved in processes leading to inflammation, thrombosis, and metastasis. A key protein, the dimeric glycoprotein PSGL-1, a P-selectin glycoprotein ligand, plays an important role in the binding of selectins, serving as a ligand for all three selectins. PSGL-1 combines signals activating various biochemical pathways during binding and rolling of leukocytes. The integration of these signals leads to activation of leukocytes, integrin-mediated arrest, restructuring of the cyto- skeleton of interacting cells, polarization, and subsequent diapedesis of leukocytes into surrounding tissues. The multilevel effect of PSGL-1 on cellular traffic in the physiological and inflammatory states is largely determined by posttranslational modifications, among which an important place is given to specific O- and N-glycosylation and sulfation. In this review, we discuss modifications of PSGL-1 associated with the initiation of biochemical pathways, as well as its interactions, which make it possible to classify this molecule as signaling, paying special attention to the mechanisms leading to pathology, including cardiovascular.

PET/CT imaging of esophageal cancer targeting tumor cell specific αvβ6-integrin expression

2025-06-20

Kateřina Bendová , Tanja Groll , Barbora Neužilová +7 more | European Journal of Nuclear Medicine and Molecular Imaging

Abstract Purpose To assess the potential of αvβ6-integrin as a theranostic target in esophageal cancer. Methods Membranous β6-integrin (ITGB6) expression was analyzed in 306 specimens of human esophageal squamous cell … Abstract Purpose To assess the potential of αvβ6-integrin as a theranostic target in esophageal cancer. Methods Membranous β6-integrin (ITGB6) expression was analyzed in 306 specimens of human esophageal squamous cell carcinoma (ESCC) obtained by immunohistochemistry (IHC) from 100 patient cases (1, 37, 58, and 4 of grade G1, G2, G3, and G4, respectively). Ga-68 labeling of D0103 was done manually for preclinical experiments and fully automated for clinical application. Preclinical characterization of Ga-68-D0103 was performed in SCID mice bearing subcutaneous xenografts of H2009 (αvβ6-positive) or MDA-MB-231 (αvβ6-negative) carcinoma cell lines, by ex vivo biodistribution (10, 30, 90, and 180 min p.i) and PET imaging (30, 90, and 180 min p.i.)., without and with co-injection of gelofusine (4% succinylated gelatin). A patient with type-II diabetes (f, 68y, 115 kg) with proximal G2 ESCC was investigated by Ga-68-D0103 PET/CT (193 MBq) at 15, 45, 90, and 104 min p.i.. Results 99% of ESCC cases were found β6-integrin positive by IHC, of which 48%, 31%, and 20% showed strong, moderate, and low ITGB6 expression, respectively, with no correlation to tumor grade. Ex vivo biodistribution of Ga-68-D0103 in H2009 xenografted mice after 30, 90, and 180 min showed tumor-to-blood ratios of 6.8, 37, and 124, respectively; tumor-to-muscle ratios of 12, 14, and 36, respectively; tumor-to-liver ratios of 10, 17, and 14, respectively; and tumor-to-pancreas ratios of 20, 47, and 56, respectively. Co-administration of gelofusine did not change the tumor uptake but reduced the kidney uptake by 89% (from 178%iA/g to 19.1%iA/g, 90 min p.i.), resulting in an 8.7-fold higher tumor/kidney ratio. µPET imaging in H2009 xenografted mice confirmed a high tumor uptake and low background already 30 min p.i.. Blockade biodistribution and µPET in αvβ6-(–) MDA-MB-231 mice demonstrated target specificity. Clinical PET/CT of a patient with ESCC showed increasing tracer uptake over time in the primary tumor (SUVmax 9.0 and 11.3 at 15 and 104 min p.i., respectively) and in a lymph node metastasis (SUVmax 19.5 and 28.3, respectively), and a decreasing blood pool activity (SUVmean 2.75 and 0.98, respectively). Conclusions High (99%) membranous expression frequency and density on tumor cells underscores the potential of αvβ6-integrin as a theranostic target in ESCC, suggesting that αvβ6-integrin PET/CT imaging may adopt a role in re-staging and therapy guidance in this cancer type. The prolonged tumor retention furthermore indicates a therapeutic potential of αvβ6-integrin targeted radiopharmaceuticals when labeled with radionuclides such as lutetium-177, terbium-161, or actinium-225.

VPS45 promotes the progression of hepatocellular carcinoma by recycling β1 integrin to the cell membrane via the endocytic pathway

2025-06-20

Takashi Ofuchi , Hajime Otsu , Kiyotaka Hosoda +7 more | Journal of Gastroenterology

Proteomic characterization of type I collagen N-terminal crosslinked peptides

2025-06-19

Zsuzsanna Darula , Maxwell C. McCabe , Alex Barrett +7 more | Matrix Biology Plus

The phosphatase PPM1F, a negative regulator of integrin activity, is essential for embryonic development and controls tumor cell invasion

2025-06-19

Tanja Grimm , Nina I. Dierdorf , Marleen Herbinger +5 more | BMC Biology

Epac (RAPGEF3) promotes betaglycan expression to mediate ciprofloxacin-induced suppression of cancer cell migration and metastasis: Mechanistic insights and drug repurposing potential

2025-06-18

Hui-Pu Liu , Shun-Ban Tai , Jun‐Lin Jiang +6 more | Biomedicine & Pharmacotherapy

Insights into the structural features of a feline CD8αα homodimer

2025-06-18

Rui Liang , Yu Cao , Yan Gao +7 more | Developmental & Comparative Immunology

Author Correction: Collagenolysis-dependent DDR1 signalling dictates pancreatic cancer outcome

2025-06-18

Hua Su , Fei Yang , Rao Fu +7 more | Nature

A Novel <scp>COL12A1</scp> Mutation Causes Oral Tissue Abnormalities by Regulating Gingival Fibroblast Function

2025-06-18

Shi Yu , Yuanyuan Wang , Xiaojing Yuan +3 more | Oral Diseases

ABSTRACT Objective This study aimed to identify a novel COL12A1 mutation in a patient with Ullrich congenital muscular dystrophy‐2 (UCMD2) presenting with gingival hyperplasia and skeletal anomalies and to characterize … ABSTRACT Objective This study aimed to identify a novel COL12A1 mutation in a patient with Ullrich congenital muscular dystrophy‐2 (UCMD2) presenting with gingival hyperplasia and skeletal anomalies and to characterize its functional impact on gingival fibroblasts (GFs) behavior. Methods Whole‐exome sequencing identified COL12A1 mutations in a consanguineous family. GFs isolated from the patient and healthy controls underwent functional assays to assess proliferation, apoptosis, and osteogenic differentiation. Lentiviral COL12A1 knockdown in GFs validated phenotypic changes. RNA sequencing elucidated altered molecular pathways. Results A homozygous COL12A1 frameshift mutation (NM_004370: c.6747del, p.Thr2249Thrfs*44) caused collagen XII deficiency. Patient‐derived GFs exhibited hyperproliferation (elevated cyclin D1/PCNA, S‐phase accumulation), reduced apoptosis (increased Bcl2/Bax ratio), and impaired osteogenic differentiation (downregulated RUNX2 , OCN, OPN; reduced mineralization). COL12A1 knockdown recapitulated these defects. Transcriptomics revealed upregulated interferon‐alpha/beta response and apoptotic signaling pathways, alongside downregulated extracellular matrix (ECM) organization, cell adhesion, and skeletal development genes in COL12A1 ‐deficient GFs. Conclusion COL12A1 deficiency disrupts gingival homeostasis by driving fibroblast hyperproliferation, inhibiting fibroblast apoptosis, and suppressing osteogenic differentiation via dysregulated ECM remodeling. These findings establish collagen XII as a critical regulator of neural crest‐derived oral connective tissues, providing mechanistic insights into gingival hyperplasia and skeletal anomalies in COL12A1 ‐related disorders.

The role of FAK signaling in early placental development and trophoblast lineage specification in human pregnancy

2025-06-18

Hong-Xiu Liang , Cen Yi , Shilin He +7 more | Cellular Signalling

Conformational dynamics and multimodal interaction of Paxillin with the focal adhesion targeting domain

2025-06-18

S. Bhattacharya , Yanan He , Yihong Chen +5 more | Science Advances

Paxillin (PXN) and focal adhesion kinase (FAK) are two major components of the focal adhesion complex, a multiprotein structure linking the intracellular cytoskeleton to the cell exterior. The interaction between … Paxillin (PXN) and focal adhesion kinase (FAK) are two major components of the focal adhesion complex, a multiprotein structure linking the intracellular cytoskeleton to the cell exterior. The interaction between the disordered amino-terminal domain of PXN and the carboxyl-terminal targeting domain of FAK (FAT) is necessary and sufficient for localizing FAK to focal adhesions. Furthermore, PXN serves as a platform for recruiting other proteins that together control the dynamic changes needed for cell migration and survival. Here, we show that the PXN N-domain undergoes significant compaction upon FAT binding, forming a 48-kilodalton multimodal complex with four major interconverting states. Although the complex is flexible, each state has unique sets of contacts involving disordered regions that are both highly represented in ensembles and conserved. PXN being a hub protein, the results provide a structural basis for understanding how shifts in the multistate equilibrium (e.g., through ligand binding and phosphorylation) may rewire cellular networks leading to phenotypic changes.

Pro-inflammatory granzyme K contributes extracellularly to disease

2025-06-18

Christopher T. Turner | Frontiers in Immunology

Granzyme K (GzmK) is an immune-secreted serine protease typically expressed at low levels but elevated in response to tissue injury and disease. Known as an orphan granzyme due to limited … Granzyme K (GzmK) is an immune-secreted serine protease typically expressed at low levels but elevated in response to tissue injury and disease. Known as an orphan granzyme due to limited scientific investigation, this tryptase is being redefined as having important roles in inflammation and disease pathogenesis. Multiple GzmK expressing CD8 + T cell subsets are being identified with augmented expression and important roles in disease. Traditionally recognized as a mediator of cytotoxic lymphocyte-mediated cell death, GzmK’s role is being recharacterized through multiple recently released studies focused on newly identified extracellular mechanisms of action. These studies identify GzmK to be inflammatory, being able to trigger pro-inflammatory cytokine release, enhance immune cell recruitment, exacerbate the immune response to bacterial infections, and activate complement. In multiple disease states, dysregulated GzmK expression and potential accumulation in the extracellular space directly contributes to impaired health outcomes, thereby suggesting downregulation may prevent disease severity. GzmK is therefore emerging as a therapeutic target, potentially valuable in sepsis, pulmonary disease, inflammatory skin disease, rheumatoid arthritis and even aging.

Abstract P2-06-15: DCIS-associated myoepithelial cells drive transcriptional alterations in macrophages through up-regulation of integrin αvβ6

2025-06-13

Michael D. Allen , M. Reza Roozitalab , Stephen Murtough +2 more | Clinical Cancer Research

Abstract Ductal carcinoma in-situ (DCIS) is a non-obligate precursor of invasive breast cancer, however, less than 50% of DCIS will ever progress to invasive cancer. There is therefore a need … Abstract Ductal carcinoma in-situ (DCIS) is a non-obligate precursor of invasive breast cancer, however, less than 50% of DCIS will ever progress to invasive cancer. There is therefore a need to understand how we can predict those DCIS cases that will progress. A key component in promoting tumour invasion is the immune microenvironment, though its role in DCIS is unclear. We previously have shown that up-regulation of integrin αvβ6 on DCIS-associated myoepithelial cells switches the tumour-suppressor properties of myoepithelial cells to tumour-promoter properties, leading to enhanced tumour cell invasion. We found that macrophages surrounding ducts positive for αvβ6; exhibited a more M2 tumour-promoter phenotype compared to DCIS ducts with myoepithelial cells negative for αvβ6. We therefore hypothesised that the altered phenotype of myoepithelial cells in DCIS may directly influence the peri-ductal immune infiltrate which could influence disease progression. Macrophages were isolated from fresh tissue from patients with DCIS. These were confirmed as either positive or negative for myoepithelial αvβ6. The macrophages were subjected to RNA sequencing. In parallel, primary myoepithelial cells were isolated from cosmetic mammoplasty samples and used to overexpress αvβ6 using a lentiviral inducible system. Conditioned Medium (CM) was collected and this was applied to macrophages which then underwent RNA seq. RNA-seq analysis demonstrated novel transcriptomic profiles revealing upregulation of genes, e.g. AREG and FOSL2, with potential prognostic significance in DCIS. Utilising conditioned medium generated from primary myoepithelial cells with inducible expression of αvβ6, we demonstrate induction of immune checkpoint inhibitor - CD274 (PD-L1) in monocyte-derived macrophages in vitro. We identified a novel macrophage gene signature, outside of the usual M1/M2 dichotomy, pointing towards a macrophage spectrum which is driven by an in vivo αvβ6-dependent tumour progressive ME. This work thus suggest a panel of microenvironmental markers could be used to predict progressive DCIS cases and may represent novel therapeutic targets to influence a tumour suppressive immune response. Citation Format: Michael Allen, M. Reza Roozitalab, Stephen Murtough, Eleni Maniati, J. Louise Jones. DCIS-associated myoepithelial cells drive transcriptional alterations in macrophages through up-regulation of integrin αvβ6 [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-06-15.

Single-cell Analysis of Intracellular Transport and Expression of Cell Surface Proteins

2025-06-12

Rekha Mudappathi , Vaishali Bhardwaj , Li Liu | bioRxiv (Cold Spring Harbor Laboratory)

Abstract Intracellular protein transport (ICT) is a tightly regulated process that orchestrates protein localization and expression, ensuring proper cellular function. Dysregulated ICT can lead to aberrant expression of surface proteins … Abstract Intracellular protein transport (ICT) is a tightly regulated process that orchestrates protein localization and expression, ensuring proper cellular function. Dysregulated ICT can lead to aberrant expression of surface proteins involved in cell-cell communication, adhesion, and immune responses, contributing to disease progression and therapeutic resistance. Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) enables the simultaneous measurement of mRNA and surface protein levels in the same cell, providing a powerful opportunity to investigate the molecular mechanisms underlying surface protein regulation. In this study, we introduce a novel computational frame for Modeling Protein Expression and Transport (MPET) that evaluates the contribution of ICT activity to differential surface protein expression using CITE-seq data. MPET comprises three modules for identification of ICT– surface protein regulatory circuits across biological scales and their contributions to phenotypic variation. We applied MPET to analyze single-cell data from COVID-19 patients with varying disease severity. Our analysis revealed context-dependent recruitment of ICT genes and pervasive rewiring of ICT pathways throughout the course of disease progression. Notably, we found that even when the transcriptional levels of key immune response proteins remained stable, their expression on cell surface were significantly altered due to dysregulated ICT. MPET provides a valuable new tool for dissecting complex regulatory networks and offers mechanistic insight into post-transcriptional regulation of cell surface proteins in diseases.

Therapeutic splice modulation of COL4A5 reinstates collagen IV assembly in an organoid model of X-linked Alport syndrome

2025-06-12

Hassan Saei , Bruno Estèbe , Nicolas Gaudin +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Abstract Kidney organoids are an emerging tool for disease modeling, especially genetic diseases. Among them, X-linked Alport syndrome (XLAS) is a hematuric nephropathy affecting the glomerular basement membrane (GBM) secondary … Abstract Kidney organoids are an emerging tool for disease modeling, especially genetic diseases. Among them, X-linked Alport syndrome (XLAS) is a hematuric nephropathy affecting the glomerular basement membrane (GBM) secondary to pathogenic variations in the COL4A5 gene encoding the α5 subunit of type IV collagen [α5(IV)]. In patients carrying pathogenic variations affecting splicing, the use of antisense oligonucleotides (ASOs) offers immense therapeutic hope. In this study, we develop a framework combining the use of patient-derived cells and kidney organoids to provide evidence of the therapeutic efficacy of ASOs in XLAS patients. Using multiomics analysis, we describe the development of GBM in wild-type and mutated human kidney organoids. We show that GBM maturation is a dynamic process, which requires long organoid culture. Then, using semi-automated quantification of α5(IV) at basement membranes in organoids carrying the splicing variants identified in patients, we demonstrate the efficacy of ASO treatment for α5(IV) restoration. These data contribute to our understanding of the development of GBM and pave the way for a therapeutic screening platform for patients.

Proteomic landscape of decellularized breast carcinomas identifies C-type lectin domain family 3 member A as a driver of cancer aggressiveness

2025-06-06

Tiziana Triulzi , Marta Giussani , Elisa Maffioli +7 more | npj Breast Cancer

An extracellular matrix (ECM) gene expression pattern (ECM3) distinguished truly aggressive grade III breast carcinomas (BCs). Here, we examined the biomechanical characteristics of the ECM in human BCs to identify … An extracellular matrix (ECM) gene expression pattern (ECM3) distinguished truly aggressive grade III breast carcinomas (BCs). Here, we examined the biomechanical characteristics of the ECM in human BCs to identify the molecules that mediate the aggressiveness of ECM3/grade III (E3G3) tumors. By shotgun proteomics of decellularized human BCs, we found a significant enrichment in proteins involved in tumor-ECM interaction in E3G3 tumors. These tumors were characterized by high dense collagen deposition, a fibrillary cytoskeleton network and the highest stiffness. CLEC3A, a secreted C-type lectin domain family 3 member, was found unique of E3G3 tumors and was validated to be more expressed in these tumors by immunohistochemistry in 2 human BC cohorts, associating significantly with worse prognosis. Ectopic CLEC3A overexpression in MDA-MB-231, MDA-MB-361, and MDA-MB-468 BC cells increased intracellular mediators of tumor adhesion to the ECM, actin-stress fibers and YAP activation, and tumor migration. Accordingly, levels of the YAP/TAZ gene signature were higher in CLEC3A-positive ECM3-enriched tumors and correlated with tumor stiffness. These results implicate CLEC3A in mediating the ability of E3G3 BCs to sense cues in the surrounding ECM, accelerating tumor progression.

Annular Migratory Rash In a Newborn Related to Prostaglandin E1 Infusion: A Case Report

2025-06-06

Buse Önen Ocak , Refika SİRMA DOKUZBOY , Hayriye Gözde Kanmaz Kutman | Zeitschrift für Geburtshilfe und Neonatologie

Abstract Prostaglandin E1 (PGE1, alprostadil) is essential in managing ductus-dependent congenital heart defects (CHD) in neonates. Although its common adverse effects are well documented, dermatologic manifestations remain rare and underrecognized. … Abstract Prostaglandin E1 (PGE1, alprostadil) is essential in managing ductus-dependent congenital heart defects (CHD) in neonates. Although its common adverse effects are well documented, dermatologic manifestations remain rare and underrecognized. We report a term male neonate with a prenatal diagnosis of complex critical CHD who required PGE1 infusion and subsequently developed an annular migratory rash on the third postnatal day. The rash resolved within minutes of PGE1 dose reduction but recurred upon dose escalation, strongly suggesting a causal link. Following surgical palliation and discontinuation of PGE1, the skin findings resolved completely and did not recur. This case underscores a rare but distinctive cutaneous reaction to PGE1 therapy and highlights the importance of early recognition to avoid unnecessary diagnostic testing and interruption of life-saving treatment.

Characterization of Sex-Based Differences in Integrin-Mediated Endothelial Cel Adhesion to Bioactive Hydrogels

2025-06-05

Abbey Nkansah , Aashee Budhwani , Nicholas Grammer +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Endothelialization promotes thromboresistance in blood-contacting devices, but biomaterial designs often overlook sex differences in endothelialization processes. In this study, we elucidated sex differences in endothelial cell-material interactions through investigation of … Endothelialization promotes thromboresistance in blood-contacting devices, but biomaterial designs often overlook sex differences in endothelialization processes. In this study, we elucidated sex differences in endothelial cell-material interactions through investigation of the integrin-ligand interplay with biomaterial substrates and the corollary effects on cell adhesion and spreading. First, integrin expression of human coronary artery endothelial cells (HCAECs) was characterized for age-matched donors (3 male, 3 female). Sex-based differences in integrin expression were identified, with notably higher α2β1, α5β1, and αVβ3 expression in female cells and higher α1β1 expression in male cells. On polyethylene glycol (PEG)-based hydrogel incorporating collagen or gelatin, female cells showed increased attachment on stiff substrates as compared to male HCAECs, likely driven by increased α2β1, α5β1, and αVβ3 expression in female cells. Collectively, these results demonstrate sex-biased endothelial cell responses to bioactive hydrogels mediated by integrin interactions and highlight the importance of incorporating biological sex as a design variable in the development of blood-contacting biomaterials.

CD151 interacts with integrin beta 2 in B cell lymphomas

2025-06-04

Philipp M. Hagemann , Angelique N. Kenyon , Alfredo Cabrera‐Orefice +7 more | Cellular and Molecular Life Sciences

Abstract CD151 is a broadly expressed four-transmembrane protein (tetraspanin) that interacts with laminin‐binding integrins like integrin alpha 3 (ITGA3). CD151 drives tumor development and expression correlates with poor prognosis in … Abstract CD151 is a broadly expressed four-transmembrane protein (tetraspanin) that interacts with laminin‐binding integrins like integrin alpha 3 (ITGA3). CD151 drives tumor development and expression correlates with poor prognosis in solid cancers, but CD151 has not been studied in B cell malignancies. We investigated CD151 expression on normal human B cells and B cell lymphomas using highly sensitive flow cytometry and immunohistochemistry. Expression of CD151 increased during B cell differentiation from naïve to memory B cells to plasma cells. B lymphoma cell lines and human lymphoma biopsy samples expressed higher levels of CD151 compared to normal B cells, but CD151‐deficient lymphomas were identified as well. To investigate the function of CD151 in B cells, CD151‐deficient and stably transduced CD151 expressing B lymphoma cell lines were generated. Immunoprecipitation-mass spectrometry analysis of CD151 protein complexes identified integrin beta 2 (ITGB2) as new interaction partner in lymphoma cells. Deficiency of CD151 decreased cell surface expression of alpha integrin subunits L (ITGAL) and M (ITGAM), and impaired ICAM-1-mediated cell spreading. Interestingly, B cells and lymphomas did not express ITGA3‐bound CD151 compared to T cells that expressed two different populations of integrin‐bound and integrin‐free CD151. Despite CD151 expression not being related to clinical outcome of patients with diffuse large B cell lymphoma (DLBCL), CD151 expression was predominantly detected in the activated (ABC) subset of DLBCL. Taken together, we identified a new molecular association of CD151 with ITGB2, and targeting integrin-free CD151 in DLBCL may represent a new target for immunotherapy.