Integrins and other cell adhesion molecules

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.     

The echinoderm adhesome

Although the development of sea urchin embryos has been studied extensively and clearly involves both cell adhesion and cell migration, rather little is known about the adhesion receptors and extracellular matrix molecules involved. The completion of the genome of Strongylocentrotus purpuratus allows a comprehensive survey of the complement of cell-cell and cell-matrix adhesion molecules in this organism. Furthermore, the phylogenetic position of echinoderms offers the opportunity to compare the complement of adhesion proteins between protostome and deuterostome invertebrates and between invertebrate and vertebrate deuterostomes. Many aspects of development and cell interactions differ among these different taxa and it is likely that analysis of the spectrum of adhesion receptors and extracellular matrix proteins can open up new insights into which molecules have evolved to suit particular developmental processes. In this paper, we report the results of an initial analysis along these lines. The echinoderm adhesome (complement of adhesion-related genes/proteins) is similar overall to that of other invertebrates although there are significant deuterostome-specific innovations and some interesting features previously thought to be chordate or vertebrate specific.     

Integrin functions play a key role in the differentiation of thymocytes in vivo

T cells express a variety of surface proteins as they develop to maturity in the thymus. In addition to the TCR-CD3 complex and the two major coreceptors, CD4 and CD8, other surface proteins expressed include receptors for cytokines, growth factors, counterreceptors, and extracellular matrix molecules. To determine the role of integrin adhesion receptors in T cell development, we have expressed a trans-dominant inhibitor of integrin function in the thymus. This inhibitor leads to a block of adhesion to fibronectin due to reduced activation of integrin receptors. This reduced adhesion leads to a partial block in differentiation from CD4-CD8- cells to CD4+CD8+ cells, after the CD25+ stage, suggesting that integrins are important during Lck-mediated differentiation. Furthermore, the overall production of CD4+ cells is reduced compared with that of CD8+ cells without changes in negative selection, suggesting that integrins may be involved in the determination of the fate of the cell as well. These results demonstrate that integrin receptor function is required for proper thymocyte development in vivo.     

Platelets with wings: the maturation of Drosophila integrin biology

The integrin family of cell surface receptors is strongly conserved in metazoans, making simple invertebrate genetic systems valuable contributors to understanding integrin function. The Drosophila integrins have long served as a paradigm for genetic studies of adhesion proteins during development. Currently, Drosophila experiments are exploring more general aspects of integrin biology. Genetic screens are identifying proteins involved in integrin adhesion complexes and signaling, and structures such as embryonic muscle attachments can be manipulated experimentally to dissect the functions of cytoplasmic components of integrin adhesion sites in whole animals. Drosophila also is beginning to yield some insights into integrin heterodimer structure and function.     

T cell adhesion molecules

Cell adhesion or conjugate formation between T lymphocytes and other cells is an important early step in the generation of the immune response. Although the antigen-specific T cell receptor confers antigen recognition and specificity, a number of other molecules expressed on the T cell surface are involved in the regulation of lymphocyte adhesion. T cell molecules that function to strengthen adhesion include lymphocyte function-associated antigen (LFA)-1, CD2, CD4, and CD8. Their ligands have recently been identified. LFA-1 is a member of the integrin family of adhesion receptors and one of its ligands is intercellular adhesion molecule-1 (ICAM-1); a ligand for CD2 is LFA-3; and ligands for CD4 and CD8 appear to be major histocompatibility complex class II and class I molecules, respectively. In addition, T cells express a number of receptors thought to be involved in cell matrix adhesion. The function and significance of these T cell adhesion receptors and their ligands are reviewed.     

Epithelial cell shape: cadherins and small GTPases

Cadherins are cell-cell adhesion receptors that are essential for the establishment of the epithelial cell shape and maintenance of the differentiated epithelial phenotype. In order to show efficient adhesion, cadherin receptors require an association with actin filaments and the activity of RHO proteins. The RHO family of small GTPases is primarily involved in the reorganization of the cytoskeleton. In different cell types, each member of the family can induce specific types of organization of actin filaments: stress fibers (Rho), lamellae/ruffles (Rac), or filopodia (Cdc42). This review focuses on how the function of small GTPases may impinge on the regulation of cadherin-dependent adhesion. In particular, it discusses the impact that the above cytoskeletal structures induced by RHO proteins have on the development of epithelial morphology. Finally, the participation of small GTPase-interacting proteins is considered during the remodeling of cell shape that follows cell-cell contact formation.     

The “A Disintegrin And Metalloprotease” (ADAM) family of sheddases: Physiological and cellular functions

There is an exciting increase of evidence that members of the disintegrin and metalloprotease (ADAM) family critically regulate cell adhesion, migration, development and signalling. ADAMs are involved in “ectodomain shedding” of various cell surface proteins such as growth factors, receptors and their ligands, cytokines, and cell adhesion molecules. The regulation of these proteases is complex and still poorly understood. Studies in ADAM knockout mice revealed their partially redundant roles in angiogenesis, neurogenesis, tissue development and cancer. ADAMs usually trigger the first step in regulated intramembrane proteolysis leading to activation of intracellular signalling pathways and the release of functional soluble ectodomains.     

The Adaptor Protein Paxillin Is Essential for Normal Development in the Mouse and Is a Critical Transducer of Fibronectin Signaling

The integrin family of cell adhesion receptors are important for a diverse set of biological responses during development. Although many integrins have been shown to engage a similar set of cytoplasmic effector proteins in vitro, the importance of these proteins in the biological events mediated by different integrin receptors and ligands is uncertain. We have examined the role of one of the best-characterized integrin effectors, the focal adhesion protein paxillin, by disruption of the paxillin gene in mice. Paxillin was found to be critically involved in regulating the development of mesodermally derived structures such as heart and somites. The phenotype of the paxillin(-/-) mice closely resembles that of fibronectin(-/-) mice, suggesting that paxillin is a critical transducer of signals from fibronectin receptors during early development. Paxillin was also found to play a critical role in fibronectin receptor biology ex vivo since cultured paxillin-null fibroblasts display abnormal focal adhesions, reduced cell migration, inefficient localization of focal adhesion kinase (FAK), and reduced fibronectin-induced phosphorylation of FAK, Cas, and mitogen-activated protein kinase. In addition, we found that paxillin-null fibroblasts show some defects in the cortical cytoskeleton and cell spreading on fibronectin, raising the possibility that paxillin could play a role in structures distinct from focal adhesions. Thus, paxillin and fibronectin regulate some common embryonic developmental events, possibly due to paxillin modulation of fibronectin-regulated focal adhesion dynamics and organization of the membrane cytoskeletal structures that regulate cell migration and spreading.     

黏着斑激酶与肿瘤侵袭转移

黏着斑激酶（focal adhesion kinase,FAK）是一种非受体型蛋白酪氨酸激酶,在肿瘤细胞的侵袭和转移中起着重要的作用。FAK是整合素介导的或生长因子受体诱导的调节细胞迁移的信号通路的关键组分。FAK通过与相关分子作用可以调节细胞骨架重构、胞外基质降解、细胞黏附更新以及质膜突出,进而参与肿瘤细胞的运动等多个过程,所以FAK与肿瘤发展的关系已经越来越受到重视。     

Synergistic control of keratinocyte adhesion through muscarinic and nicotinic acetylcholine receptor subtypes

The biological mechanisms involved in initiating, coordinating, and ultimately terminating cell-cell adhesion in the stratified epithelium are not well understood at present. This study was designed to elucidate the roles of the muscarinic M3, the nicotinic alpha3, and the mixed muscarinic-nicotinic alpha9 acetylcholine receptors in physiologic control of keratinocyte adhesion. Both muscarinic and nicotinic antagonists caused keratinocyte detachment and reversibly increased the permeability of keratinocyte monolayers, indicative of the involvement of both muscarinic and nicotinic pathways in the cholinergic control of keratinocyte adhesion. Since phosphorylation of adhesion proteins plays an important role in rapid assembly and disassembly of intercellular junctions, we measured muscarinic and nicotinic effects on phosphorylation of keratinocyte adhesion molecules. The phosphorylation levels of E-cadherin, beta-catenin, and gamma-catenin increased following pharmacological blockage of muscarinic receptors. Long-term blocking of alpha3, alpha9, and M3 receptor signaling pathways with antisense oligonucleotides resulted in cell-cell detachment and changes in the expression levels of E-cadherin, beta-catenin, and gamma-catenin in cultured human keratinocytes. Simultaneous inhibition of several receptor subtypes with a mixture of antisense oligonucleotides produced intensified abnormalities with cell adhesion. Moreover, altered cell-cell adhesion was found in the stratified epithelium of alpha3, alpha9, and M3 receptor knockout mice. Keratinocytes from these mice exhibited abnormal expression of adhesion molecules at both the protein and the mRNA levels. Thus, our data indicate that the alpha3, alpha9, and M3 acetylcholine receptors play key roles in regulating in a synergistic mode keratinocyte adhesion, most probably by modulating cadherin and catenin levels and activities. These findings may aid in the development of novel methods useful for the treatment of skin adhesion diseases and tumor metastasis.     

T-cell activation: a multidimensional signaling network

Na?ve T cell activation requires the interactions of antigen receptors, adhesion molecules and co-stimulatory molecules. Antigen receptors and adhesion molecules are involved in spatio-temporal movement to form a stable immunological synapse. This stable junction interrupts T cell migration, and provides a platform for temporally regulated co-stimulatory receptor signaling spanning a period of days.     

Phagocytosis, an alternative model system for the study of cell adhesion

Cell adhesion encompasses a variety of cell-cell and cell-matrix adhesive interactions. Whereas ligation of most adhesion receptors activate Rho-family GTP-binding proteins and the subsequent reorganization of the actin cytoskeleton, the molecular mechanisms involved remain poorly understood. Because phagocytosis is a spatially restricted adhesion process, it represents a simplified model system to investigate the spatio-temporal regulation of the signalling pathways that link surface adhesion receptors, small GTPases and the actin cytoskeleton. This review highlights some of the similarities between the formation and maintenance of adhesive contacts and phagocytic uptake and discusses why the study of phagocytosis can help understand more complex adhesion processes.     

The effect of cell-ECM adhesion on signalling via the ErbB family of growth factor receptors

Integrins and growth factor receptors of the ErbB family are involved in the regulation of cellular interactions with the extracellular microenvironment. Cross-talk between these two groups of transmembrane receptors is essential for cellular responses and can be regulated through the formation of multimolecular complexes. Tetraspanins as facilitators and building blocks of specialized microdomains may be involved in this process. In the present study, we demonstrated that, in contrast with previous reports, integrin-mediated adhesion did not stimulate ligand-independent activation of ErbB receptors in epithelial cells. However, integrin-dependent adhesion potentiated ligand-induced activation of EGFR (epidermal growth factor receptor) and ErbB2 and facilitated receptor homo- and hetero-dimerization. The actin cytoskeleton appeared to play a critical role in this phenomenon.     

Multiple carbohydrate receptors on lymphocytes revealed by adhesion to immobilized polysaccharides

Phosphomannan polysaccharides and fucoidan, a polymer of fucose 4-sulfate, have been demonstrated to inhibit adhesion of lymphocytes to tissue sections that contain high endothelial venules (Stoolman, L. M., T. S. Tenforde, and S. D. Rosen, 1984, J. Cell Biol., 99:1535-1540). We have investigated the potential cell surface carbohydrate receptors involved by quantitating adhesion of rat cervical lymph node lymphocytes to purified polysaccharides immobilized on otherwise inert polyacrylamide gels. One-sixth of the lymphocytes adhered specifically to surfaces derivatized with PPME (a phosphomannan polysaccharide prepared from Hansenula holstii yeast), whereas up to half of the cells adhered to surfaces derivatized with fucoidan. Several lines of evidence demonstrated that two distinct receptors were involved. Adhesion to PPME-derivatized gels was labile at 37 degrees C (decreasing to background levels within 120 min) whereas adhesion to fucoidan-derivatized gels was stable. Soluble PPME and other phosphomannans blocked adhesion only to PPME-derivatized gels; fucoidan and a structurally related fucan blocked adhesion to fucoidan-derivatized gels. Other highly charged anionic polysaccharides, such as heparin, did not block adhesion to either polysaccharide-derivatized gel. Adhesion to PPME-derivatized gels was dependent on divalent cations, whereas that to fucoidan-derivatized gels was not. The PPME-adherent lymphocytes were shown to be a subpopulation of the fucoidan-adhesive lymphocytes which contained both saccharide receptors. These data reveal that at least two distinct carbohydrate receptors can be found on peripheral lymphocytes.     

Plasticity of cadherin-catenin expression in the melanocyte lineage

Cadherins are calcium-dependent cell adhesion receptors with strong morphoregulatory functions. To mediate functional adhesion, cadherins must interact with actin cytoskeleton. Catenins are cytoplasmic proteins that mediate the interactions between cadherins and the cytoskeleton. In addition to their role in cell-cell adhesion, catenins also participate in signaling pathways that regulate cell growth and differentiation. Cadherins and catenins appear to be involved in melanocyte development and transformation. Here, we investigated the function of cadherin-catenin complexes in the normal development and transformation of melanocytes by studying the patterns of expression of the cell-cell adhesion molecules, E-, N- and P-cadherin, and the expression of their cytoplasmic partners, alpha-, beta- and gamma-catenin during murine development. Similar analyses were performed in vitro using murine melanoblast, melanocyte, and melanoma cell lines in the presence and absence of keratinocytes, the cells with which melanocytes interact in vivo. Overall, the results suggest that the expression of cadherins and catenins is very plastic and depends on their environment as well as the transformation status of the cells. This plasticity is important in fundamental cellular mechanisms associated with normal and pathological ontogenesis, as well as with tumorigenesis.     

The Role of Cellular and Extracellular Matrix Adhesion Proteins in Organ Transplantation

The specific adhesion of cells to other cells or to particular tissue microenvirorvments is a basic function of cell migration and recognition, and underlines many biologic processes including embryogenesis, repair and immunity. Leukocytes express an array of surface receptors broadly known as “accessory adhesion molecules.” which mediate most cell -cell interactions, direct lymphocyte traffic between anatomical compartments, and facilitate cellular adhesion to the inflammation or alloantigenic sites (Springer 1990). In addition, adhesion molecules are involved in the process of antigen recognition, and may costimulate cell activation and transformation. These proteins are thought to affect the very early antigen independent events between host leukocytes and vascular endothelium. Because of these activities, the subject of adhesion molecules is gaining interest in the field of organ transplantation, in both conceptualization and development of novel therapeutic strategies (de Sousa et al. 1991, Kupiec-Weglinski et al. 1993a, Heemann et al. 1993).     

Cell adhesion receptors, tyrosine kinases and actin modulators: a complex three-way circuitry

The interaction of cells with surrounding matrix and neighbouring cells governs many aspects of cell behaviour. Aside from transmitting signals from the external environment, adhesion receptors also receive signals from the cell interior. Here we review the interrelationship between adhesion receptors, tyrosine kinases (both growth factor receptor and non-receptor) and modulators of the actin cytoskeletal network. Deregulation of many aspects of these signalling pathways in cancer highlights the need for a better understanding of the complexities involved.     

Regulation of chondrocyte differentiation by the actin cytoskeleton and adhesive interactions

Chondrocyte differentiation is a multi-step process characterized by successive changes in cell morphology and gene expression. In addition to tight regulation by numerous soluble factors, these processes are controlled by adhesive events. During the early phase of the chondrocyte life cycle, cell-cell adhesion through molecules such as N-cadherin and neural cell adhesion molecule (N-CAM) is required for differentiation of mesenchymal precursor cells to chondrocytes. At later stages, for example in growth plate chondrocytes, adhesion signaling from extracellular matrix (ECM) proteins through integrins and other ECM receptors such as the discoidin domain receptor (DDR) 2 (a collagen receptor) and Annexin V is necessary for normal chondrocyte proliferation and hypertrophy. Cell-matrix interactions are also important for chondrogenesis, for example through the activity of CD44, a receptor for Hyaluronan and collagens. The roles of several signaling molecules involved in adhesive signaling, such as integrin-linked kinase (ILK) and Rho GTPases, during chondrocyte differentiation are beginning to be understood, and the actin cytoskeleton has been identified as a common target of these adhesive pathways. Complete elucidation of the pathways connecting adhesion receptors to downstream effectors and the mechanisms integrating adhesion signaling with growth factor- and hormone-induced pathways is required for a better understanding of physiological and pathological skeletal development.     

Dullard promotes degradation and dephosphorylation of BMP receptors and is required for neural induction

Bone morphogenetic proteins (BMPs) regulate multiple biological processes, including cellular proliferation, adhesion, differentiation, and early development. In Xenopus development, inhibition of the BMP pathway is essential for neural induction. Here, we report that dullard, a gene involved in neural development, functions as a negative regulator of BMP signaling. We show that Dullard promotes the ubiquitin-mediated proteosomal degradation of BMP receptors (BMPRs). Dullard preferentially complexes with the BMP type II receptor (BMPRII) and partially colocalizes with the caveolin-1-positive compartment, suggesting that Dullard promotes BMPR degradation via the lipid raft-caveolar pathway. Dullard also associates with BMP type I receptors and represses the BMP-dependent phosphorylation of the BMP type I receptor. The phosphatase activity of Dullard is essential for the degradation of BMP receptors and neural induction in Xenopus. Together, these observations suggest that Dullard is an essential inhibitor of BMP receptor activation during Xenopus neuralization.