Abstract
The alpha(5) chain-containing laminin isoforms, laminins-10 and -11 (laminin-10/11), are the major components of the basement membrane, having potent cell-adhesive activity. We examined the cell-adhesive and integrin-mediated signaling activities of laminin-10/11 in comparison to fibronectin, the best characterized extracellular adhesive ligand. We found that laminin-10/11 are more active than fibronectin in promoting cell migration and preferentially activate Rac, not Rho, via the p130(Cas)-CrkII-DOCK180 pathway. Cells adhering to fibronectin develop stress fibers and focal contacts, whereas cells adhering to laminin-10/11 do not, consistent with the high cell migration-promoting activity of laminin-10/11. Pull-down assays of GTP-loaded Rac and Rho demonstrated the preferential activation of Rac on laminin-10/11, in contrast to the activation of Rho on fibronectin. Activation of Rac by laminin-10/11 was associated with the phosphorylation of p130(Cas) and an increased formation of a p130(Cas)-CrkII-DOCK180 complex. Cell migration on laminin-10/11 was suppressed by the expression of either a dominant-negative Rac or CrkII mutants defective in p130(Cas) or DOCK180 binding. This is the first report demonstrating a distinct activation of Rho family GTPases resulting from adhesion to different extracellular ligands.
Highlights
The ligation of integrins triggers a multitude of signaling events, including activation of tyrosine kinases and subsequent phosphorylation of multiple cellular proteins such as focal adhesion kinase (FAK), p130Cas, and paxillin
We explored the mechanisms of cell spreading and migration over LN-10/11 with an emphasis on integrinmediated signaling pathways
LN-10/11 induce the formation of protrusive structures such as membrane ruffles and lamellipodia; FN enhances the formation of actin stress fibers and focal contacts
Summary
The ligation of integrins triggers a multitude of signaling events, including activation of tyrosine kinases and subsequent phosphorylation of multiple cellular proteins such as focal adhesion kinase (FAK), p130Cas, and paxillin. LN-10/11 preferentially activate Rac, but not Rho, through an ␣31 integrin-dependent pathway involving a p130Cas-CrkII-DOCK180 complex, thereby strongly
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