The guanine nucleotide exchange factor Tiam1 promotes cell migration by regulating the turnover of cell–matrix adhesions, Wang et al. reveal.
Migrating cells polarize to form a protrusive front and a retracting tail. The Rac GTPase helps establish and maintain this polarity by stimulating membrane protrusion and promoting the rapid turnover of integrin-based adhesions at the cell’s leading edge. Integrins activate Rac in response to cell adhesion, but how they do this is unclear. Wang et al. found that Tiam1, a Rac activator required for polarized cell migration, binds to talin, an adaptor protein that connects integrins to signaling molecules and the actin cytoskeleton.
Tiam1 colocalized with talin at adhesions, particularly at the cell front, but was displaced when talin was depleted by RNAi. Cells lacking either talin or Tiam1 showed decreased Rac activation in response to integrin adhesion, delaying cell spreading and polarization. And adhesion turnover was slower at the leading edge, thus inhibiting cell migration. Talin-deficient cells could be rescued by the re-expression of wild-type talin but not of talin mutants unable to bind or recruit Tiam1 to adhesions.
Tiam1’s localization to adhesions was also regulated by the PAR polarity complex, which binds to Tiam1 through PAR3 and phosphorylates it via atypical protein kinase C (aPKC). Depleting PAR3 or inhibiting aPKC prevented adhesion-induced Rac activation and cell spreading. The researchers speculate that the phosphorylation of Tiam1 by aPKC promotes the exchange factor’s association with talin, allowing integrin-based adhesions to stimulate Rac and promote polarized cell migration.