The integrin family of cell adheson receptors mediates many of the interactions between cells and the extracellular matrix. Because the extracellular matrix has profound Influences on cell behavior, it seems llkely that t S transduce biochemical signals across the cell membrane. The nature ofthese putative signals has, thus far, rem elusive.Antibody-mediated clustering of integrin receptors was used to mimic the integrin clustering process that occurs during formation of adhesive contacts. Human epidermal carcinoma (KB) cells were incubated with an anti-lI integrin monocional antibody for 30 min on ice followed by incubation at 37C with anti-rat IgG. This treatment, which induced integrin clustering, stimulated the phosphorylation on tyrosine residues of a 115-to 130-kDa complex of proteins termed ppl3O. When integrins were clustered in the presence of the phosphatase inhibitor sodium orthovanadate, ppl3O showed a substantial increase in phosphorylation compared to the case in which integrins were clustered in the absence of vanadate. Maximal ppl3O phosphorylation was observed 10-20 min after initiation of integrin clustering in the absence of vanadate or after 5-10 min in its presence. These time courses roughly parallel the formation of integrin clusters on the cell surface as observed by fluorescence microscopy. ppl30 phosphorylation depended on the amount of anti-inte antibody present. Additionally, the tyrosine phosphorylation of ppl30 showed specificity since it was stmulated by antibodies to the integrin a3 and 3 subunits but not by antibodies to other integrin a subunits or to nonintgrin cell surface proteins. Immunoprecipitation experiments clearly demonstrated that ppl30 is not itself a PI integrin. It is postulated, therefore, that the integrinstimulated tyrosine phosphorylation of ppl30 may reflect part of an important signal transduction process between the extracellular matrix and the cell interior.Cell interactions with the extracellular matrix are important determinants of cellular morphology, growth, and differentiation (1-4). Contacts between cells and the extracellular matrix are mediated in part by members of the integrin superfamily of adhesive receptors (5-10). Integrins are heterodimeric cell surface glycoproteins consisting of noncovalently linked a and ( chains. The large extracellular amino-terminal domains of both chains associate to form an extracellular binding site for matrix proteins; each chain has a single a-helical transmembrane region and a short cytoplasmic domain (11,12). The abbreviated intracellular domains of integrins interact with a-actinin, talin, and probably other as yet to be discovered proteins to link integrins to the actin-containing cytoskeleton (9,13,14). Interference reflection microscopy in concert with fluorescence microscopy has shown that integrins can be clustered on the ventral surfaces of adherent cells in structures known as focal contacts (14-17). These structures provide a link (mediated through integrins) between extracellular matrix proteins...

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Background Integrins are cell surface receptors which, in part, mediate the adhesion of cells to the extracelluar matrix. In addition to providing a molecular “glue” essential for tissue organization and survival, integrins are dynamic signaling molecules. Integrins allow normal, nontransformed cells to sense that they are adhered to the extracellular matrix, thus providing a cell survival signal. This signal allows cells to proliferate in the presence of growth factors and in some instances prevents apoptosis. Integrins also mediate cell migration as it occurs in normal processes such as angiogenesis, wound healing, immune system function, and development. Aberrances in the expression and function of integrins contribute to many disease states including cancer. Results Focal adhesion kinase (FAK) becomes phosphorylated and activated during integrin‐mediated cell adhesion. Focal adhesion kinase is a signal transducer of integrins (and certain soluble growth factors). Cells derived from FAK −/− mouse embryos exhibit reduced migration relative to wild‐type cells. Cells which overexpress FAK show increased migration relative to wild‐type cells. Focal adhesion kinase promotes cell survival under certain in vitro conditions. Focal adhesion kinase is overexpressed in invasive and metastatic colon, breast, thyroid, and prostate cancers. Enhanced FAK immunostaining is detected in small populations of preinvasive (carcinoma in situ) oral cancers and in large populations of cells in invasive oral cancers. Conclusions Focal adhesion kinase is probably not a classical oncogene but may be involved in the progression of cancer to invasion and metastasis. It is hypothesized that overexpression of FAK in subpopulations of tumor cells leads to populations of cells with a high propensity toward invasion and metastasis. Focal adhesion kinase would have a dual role in this regard: Overexpression of FAK leads to (1) increased cell migration and (2) increased cell survival under anchorage‐independent conditions. Further work is needed to test this model and to determine whether FAK represents a viable target for anticancer therapy. © 1998 John Wiley & Sons, Inc. Head Neck 20: 745–752, 1998.