Laminin-10/11 and fibronectin differentially regulate integrin-dependent Rho and Rac activation via p130(Cas)-CrkII-DOCK180 pathway.
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.
Gu
J
J
Division of Protein Chemistry, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Sumida
Y
Y
Sanzen
N
N
Sekiguchi
K
K
D002465:Cell Movement / Q000502:physiology; D050719:Crk-Associated Substrate Protein; D005353:Fibronectins / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D039201:Integrin alpha3beta1; D016023:Integrins / Q000502:physiology*; D007797:Laminin / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D050717:Retinoblastoma-Like Protein p130; D014407:Tumor Cells, Cultured; D020744:rac GTP-Binding Proteins; D018909:src Homology Domains
C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; C099818:DOCK1 protein, human; D005353:Fibronectins; D039201:Integrin alpha3beta1; D016023:Integrins; D007797:Laminin; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D050717:Retinoblastoma-Like Protein p130; D011494:Protein Kinases; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins