Focal adhesion kinase (FAK) transduces adhesion forces into pro-proliferation signals in a variety of cell types. Now, Pirone et al. (page 277) show that FAK also inhibits proliferation when cells lack adequate attachments. The two-sided modulation of proliferation by FAK suggests that adhesion is not a simple on–off switch. Rather, the cell monitors and modulates adhesion in a more graded fashion.
Current dogma suggests that more adhesion leads to more FAK activation and thus proliferation, and that loss of FAK activity would prevent proliferation. But Pirone et al. found that cells lacking FAK or expressing a dominant-negative form of the protein (FRNK) proliferated constitutively, whether they were cultured in high or low adhesive conditions.
Further analysis showed that FAK-null cells or those expressing FRNK had higher levels of RhoA expression than control cells. The increased RhoA led to more cytoskeletal tension and the formation of additional focal adhesions. Wild-type FAK thus seems able not only to sense adhesive forces, but also to limit their generation somehow.
A kinase-dead mutant restored normal proliferation responses to adhesion in FAK-null cells. Thus, unlike its proliferation-inducing function, FAK's ability to inhibit cell division does not require its kinase activity.