Integrin signal transduction

A cell resting on the extracellular matrix (ECM) doesn't just sit there like a football fan in a La-Z-Boy. It develops a deep connection with its substrate. Contact between matrix proteins and integrin receptors in the membrane adjusts the cell's cytoskeleton and shape (Haimovich, et al., 1993), galvanizes survival-promoting pathways, and causes numerous other changes. A 1992 paper by Keith Burridge, Christopher Turner, and Lewis Romer (Burridge et al., 1992) implicated the focal adhesion kinase (FAK) as a key relay for ECM signals. As later studies showed, FAK is a well-connected protein that gets involved in everything from the cell cycle to apoptosis.

By 1992, evidence indicated that ECM proteins pass their messages to the cell by tweaking integrins (see “ECM signals ECM degradation” JCB 172:642), but cell biologists had worked out only a few of the following steps. Integrins gather at focal adhesions, specialized portions of the membrane where the cell meets the matrix. Researchers had identified several possible relay molecules at these junctions, including FAK (Schaller et al., 1992).

To probe FAK's activity, Burridge and colleagues grew cells on different substrates and tested for proteins phosphorylated on tyrosine, an indicator of activation. The team found that two phosphorylated proteins abounded in cells reared on fibronectin—an ECM component and integrin ligand—but not in cells raised on plastic. One of these proteins, the researchers demonstrated, was FAK (Burridge et al., 1992). The other was paxillin, which later research linked to cell movement. Lipfert et al. (1992) observed a similar pattern of phosphorylation in platelets that snuggle up to the clot protein thrombin.

When Burridge and colleagues dosed cells with herbimycin A, which blocks phosphorylation of tyrosines, they noted fewer focal adhesions and fewer of the polymerized actin filaments that normally attach to these adhesion sites. Those results suggest that FAK responds to integrin stimulation by helping to mold focal adhesions and modify the actin cytoskeleton, says Romer (now at the Johns Hopkins School of Medicine in Baltimore, Maryland). Burridge went on to show that the molecular switch called Rho spurs formation of focal adhesions by increasing the contractility of actin fibers (Chrzanowska-Wodnicka and Burridge, 1996).

Meanwhile, other experiments have revealed that FAK's influence extends to cell spreading and movement (Romer et al., 1994; Gilmore and Romer, 1996; Yano et al., 2004), proliferation (Zhao et al., 1998), and survival (Frisch et al., 1996). All of these functions involve integrins. Furthermore, research by Turner (now at the SUNY Medical Center in Syracuse, New York) and colleagues indicated that paxillin, the other focal adhesion protein phosphorylated in the original work, forms a signaling complex that helps instigate cell spreading and motility (West et al., 2001; Brown and Turner, 2004).