Integrins: versatility, modulation, and signaling in cell adhesion.

Matrix metalloproteinases (MMPs) are a family of nine or more highly homologous Zn(++)-endopeptidases that collectively cleave most if not all of the constituents of the extracellular matrix. The present review discusses in detail the primary structures and the overlapping yet distinct substrate specificities of MMPs as well as the mode of activation of the unique MMP precursors. The regulation of MMP activity at the transcriptional level and at the extracellular level (precursor activation, inhibition of activated, mature enzymes) is also discussed. A final segment of the review details the current knowledge of the involvement of MMP in specific developmental or pathological conditions, including human periodontal diseases.

Matrix Metalloproteinases: A Review

The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis.

Adhesive interactions between cells and the insoluble meshwork of extracellular matrix proteins play a vital role in embryonic morphogenesis (33, 36, 94, 109, 135, 145), and in the regulation of gene expression in cells of the adult organism (1, 6, 105, 124). While the overall phenomenology ofextracellular matrix (ECM) 1 effects on cell differentiation is well known, the biochemical and molecular bases for these effects have remained elusive. It is clear that many of the interactions between cells and the ECM are mediated by the integrin family of cell surface receptors (2, 3, 13, 72). However, the precise mechanism(s) whereby signals from ECM proteins are transduced via integfins to the intraceUular machinery that controls cell growth, behavior, and differentiation, remains poorly defined. There are many compelling examples of control of cell differentiation and gene expression through adhesive interactions with extracellular matrix. In fibroblasts, cell attachment has been reported to rapidly increase expression of c-los and pro al(I) collagen messages (26, 27). Adhesion to fibronectin fragments, or cross-linking of the integfin oe5/~l fibronectin receptor with antibody, induced the expression of metalloprotease genes in fibroblastic cells; interestingly, intact fibronectin did not provoke this response nor did fibronectin fragments in solution (137). In a somewhat similar vein, stimulation of the C~v//~3 integrin in melanoma cells induced the expression of type IV collagenase and increased the invasive ability of these cells (115). The capacity of breast epithelial cells to express milk proteins in response to hormonal stimuli is quite dependent on the presence of an appropriate ECM (124). Studies in this system have led to the preliminary identification of matrix-dependent elements in the promoter region of the ~ casein gene (111). In the immune system, activation of T-lymphocytes through the T-cell antigen receptor is markedly enhanced by integrin-mediated adhesion to fibronectin or laminin (85, 97, 119). This process is part of a complex dialogue involving adhesive receptors occurring between mature T-cells and antigen presenting cells, as well as during lymphocyte differentiation (40, 132, 133). There is extensive signaling \"cross talk\" between

/pdf/signal-transduction-from-the-extracellular-matrix-2h1bqsi6x6.pdf

Signal transduction from the extracellular matrix.

Rheumatoid arthritis (RA) remains a significant unmet medical need despite significant therapeutic advances. The pathogenesis of RA is complex and includes many cell types, including T cells, B cells, and macrophages. Fibroblast-like synoviocytes (FLS) in the synovial intimal lining also play a key role by producing cytokines that perpetuate inflammation and proteases that contribute to cartilage destruction. Rheumatoid FLS develop a unique aggressive phenotype that increases invasiveness into the extracellular matrix and further exacerbates joint damage. Recent advances in understanding the biology of FLS, including their regulation regulate innate immune responses and activation of intracellular signaling mechanisms that control their behavior, provide novel insights into disease mechanisms. New agents that target FLS could potentially complement the current therapies without major deleterious effect on adaptive immune responses.

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Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis

We have investigated the effects of ligation of the fibronectin receptor (FnR) on gene expression in rabbit synovial fibroblasts. Monoclonal antibodies to the FnR that block initial adhesion of fibroblasts to fibronectin induced the expression of genes encoding the secreted extracellular matrix-degrading metalloproteinases collagenase and stromelysin. That induction was a direct consequence of interaction with the FnR was shown by the accumulation of mRNA for stromelysin and collagenase. Monoclonal antibodies to several other membrane glycoprotein receptors had no effect on metalloproteinase gene expression. Less than 2 h of treatment of the fibroblasts with anti-FnR in solution was sufficient to trigger the change in gene expression, and induction was blocked by dexamethasone. Unlike other inducers of metalloproteinase expression, including phorbol diesters and growth factors, addition of the anti-FnR in solution to cells adherent to serum-derived adhesion proteins or collagen produced no detectable change in cell shape or actin microfilament organization. Inductive effects were potentiated by cross-linking of the ligand. Fab fragments of anti-FnR were ineffective unless cross-linked or immobilized on the substrate. Adhesion of fibroblasts to native fibronectin did not induce metallo-proteinases. However, adhesion to covalently immobilized peptides containing the arg-gly-asp sequence that were derived from fibronectin, varying in size from hexapeptides up to 120 kD, induced collagenase and stromelysin gene expression. This suggests that degradation products of fibronectin are the natural inductive ligands for the FnR. These data demonstrate that signals leading to changes in gene expression are transduced by the FnR, a member of the integrin family of extracellular matrix receptors. The signaling of changes in gene expression by the FnR is distinct from signaling involving cell shape and actin cytoarchitecture. At least two distinct signals are generated: the binding of fibronectin-derived fragments and adhesion-blocking antibodies to the FnR triggers events different from those triggered by binding of the native fibronectin ligand. Because the genes regulated by this integrin are for enzymes that degrade the extracellular matrix, these results suggest that information transduced by the binding of various ligands to integrins may orchestrate the expression of genes regulating cell behavior in the extracellular environment.

https://rupress.org/jcb/article-pdf/109/2/877/1058190/877.pdf

Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression.

This study was undertaken to determine the roles of individual alpha/beta 1 integrin heterodimers in promoting cellular interactions with the different attachment-promoting domains of laminin (LN). To do this, antibodies to the integrin beta 1 subunit or to specific integrin alpha subunits were tested for effects on cell attachment to LN, to elastase fragments E1-4 and E1, derived from the short arms and core of LN's cruciform structure, and to fragment E8 derived from the long arm of this structure. The human JAR choriocarcinoma cells used in this study attached to LN and to fragments E1 and E8. Attachment to E1-4 required a much higher substrate coating concentration, suggesting that it is a poor substrate for JAR cell attachment. The ability of cells to attach to different LN domains suggested the presence of more than one LN receptor. These multiple LN receptors were shown to be beta 1 integrin heterodimers because antibodies to the integrin beta 1 subunit inhibited attachment of JAR cells to LN and its three fragments. To identify the individual integrin alpha/beta 1 heterodimers that mediate interactions with these LN domains, mAbs specific for individual beta 1 heterodimers in human cells were used to study JAR cell interactions with LN and its fragments. An anti-alpha 6/beta 1-specific mAb, GoH3, virtually eliminated cell attachment to E8 and partially inhibited attachment to E1 and intact LN. Thus the major alpha 6/beta 1 attachment domain is present in fragment E8. An alpha 1/beta 1-specific mAb (S2G3) strongly inhibited cell attachment to collagen IV and partially inhibited JAR attachment to LN fragment E1. Thus, the alpha 1/beta 1 heterodimer is a dual receptor for collagen IV and LN, interacting with LN at a site in fragment E1. In combination, the anti-alpha 1- and anti-alpha 6-specific antibodies completely inhibited JAR cell attachment to LN and fragment E1. Thus, the alpha 1/beta 1 and alpha 6/beta 1 integrin heterodimers each function as LN receptors and act together to mediate the interactions of human JAR choriocarcinoma cells with LN.

/pdf/the-alpha-1-beta-1-and-alpha-6-beta-1-integrin-heterodimers-19y4w2cxmi.pdf

The alpha 1/beta 1 and alpha 6/beta 1 integrin heterodimers mediate cell attachment to distinct sites on laminin.

This study was undertaken to determine the roles of individual a//3, integrin heterodimers in promoting cellular interactions with the different attachment-promoting domains of laminin (LN). To do this, antibodies to the integrin ~) subunit or to specific integrin c~ subunits were tested for effects on cell at- tachment to LN, to elastase fragments El-4 and El, de- rived from the short arms and core of LN's cruciform structure, and to fragment E8 derived from the long arm of this structure. The human JAR choriocarci- noma cells used in this study attached to LN and to fragments E1 and E8. Attachment to El-4 required a much higher substrate coating concentration, suggest- ing that it is a poor substrate for JAR cell attachment. The ability of cells to attach to different LN domains suggested the presence of more than one LN receptor. These multiple LN receptors were shown to be ~ integrin heterodimers because antibodies to the inte- grin/3, subunit inhibited attachment of JAR cells to LN and its three fragments. To identify the individual integrin ot/~) heterodimers that mediate interactions with these LN domains, mAbs specific for individual ~ heterodimers in human cells were used to study JAR cell interactions with LN and its fragments. An anti-c~6//3rspecific mAb, GoH3, virtually eliminated cell attachment to E8 and partially inhibited attach- ment to E1 and intact LN. Thus the major ot6//3t attachment domain is present in fragment E8. An a,/ /3,-specific mAb ($2G3) strongly inhibited cell attach- ment to collagen IV and partially inhibited JAR attachment to LN fragment El. Thus, the ot~/~, hetero- dimer is a dual receptor for collagen IV and LN, interacting with LN at a site in fragment El. In com- bination, the anti-at and anti-~6-specific antibodies completely inhibited JAR cell attachment to LN and fragment El. Thus, the ot~/~3, and ol6/~, integrin het- erodimers each function as LN receptors and act to- gether to mediate the interactions of human JAR choriocarcinoma cells with LN.

E Crowley

Papers

Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression.

The alpha 1/beta 1 and alpha 6/beta 1 integrin heterodimers mediate cell attachment to distinct sites on laminin.

The 1//31 and c 6/ 1 Integrin Heterodimers Mediate Cell Attachment to Distinct Sites on Laminin