The assembly of mature cell–matrix junctional complexes depends on the recruitment of dozens of different scaffolding and signaling proteins. Talin is a major component of many cell–matrix complexes, but numerous other proteins also make important contributions. These include the integrin-linked kinase (ILK) and its binding partners pinch and parvin, which together form a trimeric complex that serves as an organizing hub at many junctions. Cell–matrix junctions also employ several actin-binding proteins, such as vinculin, zyxin, VASP, and α-actinin, to promote the assembly and organization of actin filaments. Another critical component of many cell–matrix junctions is the focal adhesion kinase (FAK), which interacts with multiple components in the junction and serves an important function in signaling, as we describe next.
Extracellular Matrix attachments act through Integrins to Control Cell proliferation and Survival
Like other transmembrane cell adhesion proteins, integrins do more than just create attachments. They also activate intracellular signaling pathways and thereby allow control of almost any aspect of the cell’s behavior according to the nature of the surrounding matrix and the state of the cell’s attachments to it.
Many cells will not grow or proliferate in culture unless they are attached to extracellular matrix; nutrients and soluble growth factors in the culture medium are not enough. For some cell types, including epithelial, endothelial, and muscle cells, even cell survival depends on such attachments. When these cells lose contact with the extracellular matrix, they undergo apoptosis. This dependence of cell growth, proliferation, and survival on attachment to a substratum is known as anchorage dependence, and it is mediated mainly by integrins and the intracellular signals they generate. Mutations that disrupt or override this form of control, allowing cells to escape from anchorage dependence, occur in cancer cells and play a major part in their invasive behavior.
Our understanding of anchorage dependence has come mainly from studies of cells living on the surface of matrix-coated culture dishes. For connective-tissue cells that are normally surrounded by matrix on all sides, this is a far cry from the natural environment. Walking over a two-dimensional plain is very different from clambering through a three-dimensional jungle. The types of contacts that cells make with a rigid substratum are not the same as those, much less well studied, that they make with the deformable web of fibers of the extracellular matrix, and there are substantial differences in cell behavior in the two contexts. Nevertheless, it is likely that the same basic principles apply. Both in vitro and in vivo, intracellular signals generated at cell–matrix adhesion sites are crucial for cell proliferation and survival.
Integrins recruit Intracellular Signaling proteins at Sites of  Cell–Matrix adhesion
The mechanisms by which integrins signal into the cell interior are complex, involving several pathways, and integrins and conventional signaling receptors often influence one another and work together to regulate cell behavior, as we have already emphasized. The Ras/MAP kinase pathway (see Figure 15–49), for
Figure 19–59 Tyrosine phosphorylation at focal adhesions. a fibroblast cultured on a fibronectin-coated substratum and stained with fluorescent antibodies: actin filaments are stained green and activated proteins that contain phosphotyrosine are red, giving orange where the two components overlap. the actin filaments terminate at focal adhesions, where the cell attaches to the substratum by means of integrins. proteins containing phosphotyrosine are also concentrated at these sites, reflecting the local activation of FaK and other protein kinases. Signals generated at such adhesion sites help regulate cell division, growth, and survival. (Courtesy of Keith Burridge.) example, can be activated both by conventional signaling receptors and by integrins, but cells often need both kinds of stimulation of this pathway at the same time to give sufficient activation to induce cell proliferation. Integrins and conventional signaling receptors also cooperate to promote cell survival (discussed in Chapters 15 and 18).