Role of the β3 Integrin Subunit in Human Primary Melanoma Progression
1998; Elsevier BV; Volume: 153; Issue: 5 Linguagem: Inglês
10.1016/s0002-9440(10)65719-7
ISSN1525-2191
Autores Tópico(s)Immunotherapy and Immune Responses
ResumoRecent research into how cells interact with and function within their different (and sometimes dynamically changing) environments has become a primary focus of cell biology, centering on the examination of cell surface adhesion receptors, most notably the integrins.1Hynes RO Integrins: versatility, modulation, and signaling in cell adhesion.Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (8966) Google Scholar, 2Gille J Swerlick RA Integrins: role in cell adhesion and communication.Ann New York Acad Sci. 1996; 797: 93-107Crossref PubMed Scopus (42) Google Scholar Integrins form one family of cell adhesion receptors, which also include the immunoglobulin gene superfamily, selectins, cadherins, cartilage-link proteins, and cell mucins (which act as ligands for the selectins). All integrins are heterodimers composed of noncovalently linked α and β subunit transmembrane glycoproteins containing large extracellular domains, short transmembrane domains, and carboxy-terminal cytoplasmic domains of variable length.1Hynes RO Integrins: versatility, modulation, and signaling in cell adhesion.Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (8966) Google Scholar, 2Gille J Swerlick RA Integrins: role in cell adhesion and communication.Ann New York Acad Sci. 1996; 797: 93-107Crossref PubMed Scopus (42) Google Scholar, 3Ruoslahti E Pierschbacher MD New perspectives in cell adhesion: RGD and integrins.Science. 1987; 238: 491-497Crossref PubMed Scopus (3841) Google Scholar, 4Loftus JC Smith JW Ginsberg MH Integrin-mediated cell adhesion: the extracellular face.J Biol Chem. 1994; : 25235-25238PubMed Google Scholar, 5Hynes RO Integrins: a family of cell surface receptors.Cell. 1987; 48: 459-552Google Scholar There are presently 17 α subunits and eight β subunits known, which occur in just over 20 integrins identified so far. However, these numbers may belie the added complexity introduced by the alternately spliced cytoplasmic domains observed in some variants of these subunits.1Hynes RO Integrins: versatility, modulation, and signaling in cell adhesion.Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (8966) Google Scholar, 6Fornaro M Languino LR Alternatively spliced variants: a new view of the integrin cytoplasmic domain.Matrix Biol. 1997; 16: 185-193Crossref PubMed Scopus (59) Google Scholar The eight β subunits share approximately 40 to 80% amino acid sequence homology and are similar in size (90 to 110 kd) except for the β4 chain, which is almost twice as big because of its large intracytoplasmic domain. The β chains contain a fourfold repeat of cystein-rich segments and a highly conserved cytoplasmic domain with an Asp-X-Ser-X-Ser sequence (where X is any amino acid) associated with cation-dependent ligand binding and with the metal ion-dependent adhesion site motif.2Gille J Swerlick RA Integrins: role in cell adhesion and communication.Ann New York Acad Sci. 1996; 797: 93-107Crossref PubMed Scopus (42) Google Scholar, 7Humphries MJ Integrin activation: the link between ligand binding and signal transduction.Curr Opin Cell Biol. 1996; : 632-640Crossref PubMed Scopus (203) Google Scholar This cytoplasmic tail region of the β subunits has been implicated both in cytoskeletal interactions and with signaling complexes. The α subunits, with molecular weights ranging between 120 and 180 kd, tend to be more heterogeneous than the β subunits. Furthermore, some α units contain light and heavy chains linked by a disulfide bridge in the extracellular domain, whereas other α subunits contain an extra segment of approximately 180 amino acids called the αA-domain7Humphries MJ Integrin activation: the link between ligand binding and signal transduction.Curr Opin Cell Biol. 1996; : 632-640Crossref PubMed Scopus (203) Google Scholar (or I domain)1Hynes RO Integrins: versatility, modulation, and signaling in cell adhesion.Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (8966) Google Scholar, 2Gille J Swerlick RA Integrins: role in cell adhesion and communication.Ann New York Acad Sci. 1996; 797: 93-107Crossref PubMed Scopus (42) Google Scholar inserted before the last five homologous repeats, which contain a cation-binding domain. This αA-domain contains a sequence homologous to the collagen-binding domains of von Willebrand factor, cartilage matrix protein, and complement proteins. Only recently has functional activity in recombinant versions of this domain permitted the opportunity to study ligand binding; the fragment αL A-domain has been shown to bind the intercellular cell adhesion molecule-2 (ICAM-2) and the fragment α1/α2 A-domain has been shown to bind to laminins.7Humphries MJ Integrin activation: the link between ligand binding and signal transduction.Curr Opin Cell Biol. 1996; : 632-640Crossref PubMed Scopus (203) Google Scholar All α subunits contain a sevenfold repeat of a homologous segment with the last three or four repeats containing the sequence Asp-X-Asp-X-Asp-Gly-X-X-Asp1Hynes RO Integrins: versatility, modulation, and signaling in cell adhesion.Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (8966) Google Scholar (or related sequence)2Gille J Swerlick RA Integrins: role in cell adhesion and communication.Ann New York Acad Sci. 1996; 797: 93-107Crossref PubMed Scopus (42) Google Scholar motif. This motif is associated with the divalent cation-binding EF-handlike domains2Gille J Swerlick RA Integrins: role in cell adhesion and communication.Ann New York Acad Sci. 1996; 797: 93-107Crossref PubMed Scopus (42) Google Scholar, 7Humphries MJ Integrin activation: the link between ligand binding and signal transduction.Curr Opin Cell Biol. 1996; : 632-640Crossref PubMed Scopus (203) Google Scholar and contributes to cation-dependent ligand binding to the integrin receptor. While divalent cations are required for receptor function they can also, depending on the nature of the cation, affect both the integrin's affinity and specificity for ligands.1Hynes RO Integrins: versatility, modulation, and signaling in cell adhesion.Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (8966) Google Scholar, 2Gille J Swerlick RA Integrins: role in cell adhesion and communication.Ann New York Acad Sci. 1996; 797: 93-107Crossref PubMed Scopus (42) Google Scholar, 3Ruoslahti E Pierschbacher MD New perspectives in cell adhesion: RGD and integrins.Science. 1987; 238: 491-497Crossref PubMed Scopus (3841) Google Scholar, 4Loftus JC Smith JW Ginsberg MH Integrin-mediated cell adhesion: the extracellular face.J Biol Chem. 1994; : 25235-25238PubMed Google Scholar, 5Hynes RO Integrins: a family of cell surface receptors.Cell. 1987; 48: 459-552Google Scholar, 7Humphries MJ Integrin activation: the link between ligand binding and signal transduction.Curr Opin Cell Biol. 1996; : 632-640Crossref PubMed Scopus (203) Google Scholar Some integrins also require divalent cations for their αβ subunit association.1Hynes RO Integrins: versatility, modulation, and signaling in cell adhesion.Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (8966) Google Scholar, 8Gailit J Ruoslahti E Regulation of the fibronectin receptor affinity by divalent cations.J Biol Chem. 1988; 263: 12927-12933Abstract Full Text PDF PubMed Google Scholar, 9Kirchhofer D Gailit J Ruoslahti E Grzesiak J Pierschbacher MD Cation-dependent changes in the binding specificity of the platelet receptor GPIIb/IIIa.J Biol Chem. 1990; 265: 18525-18530Abstract Full Text PDF PubMed Google Scholar In general, whereas the theoretical number of integrin heterodimers exceeds 100, the 20-plus observed integrins fall into three basic groups based on similar chain structures and/or the ability to recognize similar protein or adhesion motifs. These three groups include integrins which contain the β1, β2, and β3 or αv subunits; three αβ integrins do not fall within these groups.1Hynes RO Integrins: versatility, modulation, and signaling in cell adhesion.Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (8966) Google Scholar, 2Gille J Swerlick RA Integrins: role in cell adhesion and communication.Ann New York Acad Sci. 1996; 797: 93-107Crossref PubMed Scopus (42) Google Scholar Many α subunits can associate with just one of the β subunits, although some α subunits can associate with more than one β subunit. In particular, the αv subunit appears to be one of the most promiscuous of the α subunits and can associate with at least five different β subunits, including the β1 chain (see below). Although originally identified as cell adhesion molecules (both cell-extracellular matrix and cell-cell), integrins have most recently been shown to play significant roles in signal transduction events,1Hynes RO Integrins: versatility, modulation, and signaling in cell adhesion.Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (8966) Google Scholar, 2Gille J Swerlick RA Integrins: role in cell adhesion and communication.Ann New York Acad Sci. 1996; 797: 93-107Crossref PubMed Scopus (42) Google Scholar, 3Ruoslahti E Pierschbacher MD New perspectives in cell adhesion: RGD and integrins.Science. 1987; 238: 491-497Crossref PubMed Scopus (3841) Google Scholar, 4Loftus JC Smith JW Ginsberg MH Integrin-mediated cell adhesion: the extracellular face.J Biol Chem. 1994; : 25235-25238PubMed Google Scholar, 5Hynes RO Integrins: a family of cell surface receptors.Cell. 1987; 48: 459-552Google Scholar, 6Fornaro M Languino LR Alternatively spliced variants: a new view of the integrin cytoplasmic domain.Matrix Biol. 1997; 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95: 7074-7079Crossref PubMed Scopus (332) Google Scholar and Lyme disease spirochetes, whose attachment to human cells is mediated by the αvβ3 and α5β1integrins.50Coburn J Magoun L Bodary SC Leong LM Integrins α(v)β(3), and apha(5)β(1) mediate attachment of lyme disease spirochetes to human cells.Infection Immunity. 1998; 66 (1952): 1946PubMed Google ScholarIntegrin function in normal and pathological processes in terms of ligand and adhesive specificity was initially determined using cell adhesion assays, monoclonal antibodies, and affinity chromatography.1Hynes RO Integrins: versatility, modulation, and signaling in cell adhesion.Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (8966) Google Scholar, 2Gille J Swerlick RA Integrins: role in cell adhesion and communication.Ann New York Acad Sci. 1996; 797: 93-107Crossref PubMed Scopus (42) Google Scholar It became apparent that individual integrins can often bind to different ligands and that different ligands are recognized by more than one integrin. Integrins bind to extracellular matrix proteins and facilitate cell-substratum adhesion and, in the case of the ligand fibrinogen, can facilitate cell-cell aggregation. Some integrins can also recognize integral membrane proteins of the immunoglobulin superfamily (ICAM-1, ICAM-2, and VCAM-1) and thereby mediate direct cell-cell adhesion (ie, recognize and bind to a counterreceptor on other cells). The first defined integrin recognition site was the sequence Arg-Gly-Asp (RGD),1Hynes RO Integrins: versatility, modulation, and signaling in cell adhesion.Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (8966) Google Scholar, 2Gille J Swerlick RA Integrins: role in cell adhesion and communication.Ann New York Acad Sci. 1996; 797: 93-107Crossref PubMed Scopus (42) Google Scholar, 3Ruoslahti E Pierschbacher MD New perspectives in cell adhesion: RGD and integrins.Science. 1987; 238: 491-497Crossref PubMed Scopus (3841) Google Scholar, 4Loftus JC Smith JW Ginsberg MH Integrin-mediated cell adhesion: the extracellular face.J Biol Chem. 1994; : 25235-25238PubMed Google Scholar, 5Hynes RO Integrins: a family of cell surface receptors.Cell. 1987; 48: 459-552Google Scholar found in fibronectin, vitronectin, and other adhesive proteins. Subsequent binding motifs identified include Lys-Gln-Ala-Gly-Asp-Val (KQAGDV) in fibrinogen, Asp-Gly-Glu-Ala (DGEA) in type I collagen, Glu-Ile-Leu-Asp-Val (EILDV) in an alternatively spliced segment of fibronectin, and Gly-Pro-Arg-Pro (GPRP) in fibrinogen. Whereas the integrins that bind laminin appear to recognize specific parts of the laminin molecule, integrins that bind counterreceptors appear to recognize specific immunoglobulin-like domains.1Hynes RO Integrins: versatility, modulation, and signaling in cell adhesion.Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (8966) Google Scholar, 2Gille J Swerlick RA Integrins: role in cell adhesion and communication.Ann New York Acad Sci. 1996; 797: 93-107Crossref PubMed Scopus (42) Google ScholarAt present, integrins are described structurally as heterodimeric glycoproteins that contain an extracellular ligand-binding site composed of the N-terminal domains of the α and β subunits. This region is connected by two stalks, one from each subunit, to the membrane-spanning segments and ends at the α and β subunit cytoplasmic domains. All current evidence indicates that these cytoplasmic domains interact with cytoskeletal proteins and components. The cytoplasmic tail of some β subunits appears to direct integrin receptors in a ligand-independent manner to focal adhesion sites where the integrins become organized at the ends of actin filaments. These focal contacts also contain the proteins vinculin, talin, and α-actinin, which are thought to mediate interactions between the ligand-integrin structure outside the cell and the actin microfilaments inside the cell.1Hynes RO Integrins: versatility, modulation, and signaling in cell adhesion.Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (8966) Google Scholar, 2Gille J Swerlick RA Integrins: role in cell adhesion and communication.Ann New York Acad Sci. 1996; 797: 93-107Crossref PubMed Scopus (42) Google Scholar, 7Humphries MJ Integrin activation: the link between ligand binding and signal transduction.Curr Opin Cell Biol. 1996; : 632-640Crossref PubMed Scopus (203) Google Scholar The cytoplasmic tail of some α subunits appear to convey ligand-specific signals to the cells in response to the integrin binding its ligand.51Blystone SD Lindberg FP Williams MP McHugh KP Brown EJ Inducible tyrosine phosphorylation of the β3 integrin requires the alphav integrin cytoplasmic tail.J Biol Chem. 1996; 271: 31458-31462Crossref PubMed Scopus (62) Google Scholar In contrast, the α6β4integrin is unique in that it becomes concentrated in epithelial cells specifically at hemidesmosomes and is thought to interact with the intermediate filaments characteristic of hemidesmosome structure.1Hynes RO Integrins: versatility, modulation, and signaling in cell adhesion.Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (8966) Google ScholarWe now know that individual cells can vary their adhesive properties by selectively expressing different integrins and by modulating their integrin specificity and affinity for ligands through a process known as integrin activation and deactivation. The change in integrins' activation/deactivation state as a conformation change in the receptors' extracellular domains has been detected using both immunohistochemical and biophysical techniques and could relate to the degree of phosphorylation of the β subunit (see below)51Blystone SD Lindberg FP Williams MP McHugh KP Brown EJ Inducible tyrosine phosphorylation of the β3 integrin requires the alphav integrin cytoplasmic tail.J Biol Chem. 1996; 271: 31458-31462Crossref PubMed Scopus (62) Google Scholar or result from interactions of the integrins with lipid-derived mediators.1Hynes RO Integrins: versatility, modulation, and signaling in cell adhesion.Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (8966) Google Scholar Recently, it has been shown that integrin function is also subject to modulation by interaction with other membrane proteins, including other integrins.52Wei Y Lukashev M Simon DI Bodary SC Rosenberg S Doyle MV Chapman HA Regulation of integrin function by the urokinase receptor.Science. 1996; 273: 1551-1555Crossref PubMed Scopus (696) Google Scholar, 53Chapman HA Plasminogen activators, integrins, and coordinated regulation of cell adhesion and migration.Curr Opin Cell Biol. 1997; 9: 714-724Crossref PubMed Scopus (421) Google Scholar, 54Schwartz MA Integrins, oncogenes, and anchorage independence.J Cell Biol. 1997; 139: 575-578Crossref PubMed Scopus (303) Google Scholar, 55Bauer JS Schreiner CL Giancotti FG Ruoslahti E Juliano RL Motility of fibronectin receptor-deficient cells on fibronectin and vitronectin: collaborative interactions among integrins.J Cell Biol. 1992; 116: 477-487Crossref PubMed Scopus (116) Google Scholar, 56Simon KO Nutt EM Abraham DG Rodan GA Duong LT The αvβ3 integrins regulates α5β1-mediated cell migration toward fibronectin.J Biol Chem. 1997; 272: 29380-29389Crossref PubMed Scopus (84) Google Scholar The glycosyl-phosphatidylinositol (GPI)-linked cell surface protein urokinase receptor (uPAR), which can function as an adhesion receptor for vitronectin with distinct sites for binding both vitronectin and urokinase,52Wei Y Lukashev M Simon DI Bodary SC Rosenberg S Doyle MV Chapman HA Regulation of integrin function by the urokinase receptor.Science. 1996; 273: 1551-1555Crossref PubMed Scopus (696) Google Scholar, 53Chapman HA Plasminogen activators, integrins, and coordinated regulation of cell adhesion and migration.Curr Opin Cell Biol. 1997; 9: 714-724Crossref PubMed Scop
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