One of the best-studied modes of integrin signaling depends on a cytoplasmic protein tyrosine kinase called focal adhesion kinase (FAK). In studies of cells cultured on plastic dishes, focal adhesions are often prominent sites of tyrosine phosphorylation (Figure 19–59), and FAK is one of the major tyrosine-phosphorylated proteins found at these sites. When integrins cluster at cell–matrix contacts, FAK is recruited to the integrin β subunit by intracellular adaptor proteins such as talin or paxillin (which binds to one type of integrin α subunit). The clustered FAK molecules phosphorylate each other on a specific tyrosine, creating a phosphotyrosine docking site for members of the Src family of cytoplasmic tyrosine kinases. In addition to phosphorylating other proteins at the adhesion sites, these kinases then phosphorylate FAK on additional tyrosines, creating docking sites for a variety of additional intracellular signaling proteins. In this way, outside-in signaling from integrins, via FAK and Src family kinases, is relayed into the cell in much the same way as receptor tyrosine kinases generate signals (as discussed in Chapter 15).
Cell–Matrix adhesions respond to Mechanical Forces
Like the cell–cell junctions we described earlier, cell–matrix junctions can sense and respond to the mechanical forces that act on them. Most cell–matrix junctions, for example, are connected to a contractile actin network that tends to pull the junctions inward, away from the matrix. When cells are attached to a rigid matrix that strongly resists such pulling forces, the cell–matrix junction is able to sense the resulting high tension and trigger a response in which it recruits additional integrins and other proteins to increase the junction’s ability to withstand that tension. Cell attachment to a relatively soft matrix generates less tension and therefore a less robust response. These mechanisms allow cells to sense and respond to differences in the rigidity of extracellular matrices in different tissues.
We saw earlier that mechanotransduction at cadherin-based cell–cell junctions likely depends on junctional proteins that change their structure when the junction is stretched by tension (see Figure 19–12). The same is true for cell– matrix junctions. The long C-terminal tail domain of talin, for example, includes a large number of binding sites for the actin-regulatory protein vinculin. Many of these sites are hidden inside folded protein domains but are exposed when those folded talin helices 1 to 12 vinculin as talin unfolds, helix 12 is exposed and can bind to vinculin domains are unfolded by stretching the protein (Figure 19–60). The N-terminal end of talin binds integrin and the C-terminal end binds actin (see Figure 19–55); thus, when actin filaments are pulled by myosin motors inside the cell, the resulting tension stretches the talin rod, thereby exposing vinculin-binding sites. The vinculin molecules then recruit and organize additional actin filaments. Tension thereby increases the strength of the junction.