p21-activated kinases (PAKs) control actin dynamics and cell migration. On page 465, Leisner et al. report that CIB1, a widely distributed calcium binding protein, activates PAK1 immediately after cells bind fibronectin, whereas more familiar PAK activators such as small GTPases take over after adhesion is established.

CIB1 was identified in platelets where it binds an integrin involved in platelet aggregation. Further study showed that it was expressed in many cells types, leaving open the question of its function.

Leisner et al. found that CIB1 binds to and activates PAK1 in a variety of cell types. The increase in PAK activation when cells contacted fibronectin was CIB1 dependent, whereas only the later activity of PAK required small GTPases including Rac and Cdc42. Overexpression of CIB1 reduced the number of focal adhesions in cells, increased membrane ruffling, and decreased migration on fibronectin. Depletion of CIB1 reduced PAK activity and increased migration on fibronectin.

These data suggest that in addition to regulating platelet aggregation, CIB1 regulates cell migration and actin dynamics in other cell types. Leisner et al. hypothesize that CIB1 works immediately after cells make contact with the extracellular matrix, before the small GTPases bind PAK1. Just how CIB1 slows migration on fibronectin isn't yet clear, however, especially because prior data showed that PAK activity stimulates migration on collagen.