EGF receptor activity is essential for adhesion-induced stress fiber formation and cofilin phosphorylation.
Integrin-mediated cell adhesion induces activation of the EGF receptor tyrosine kinase independently of the soluble growth factor ligand. EGFR activation is instrumental for subsequent activation of additional signaling pathways in adherent cells, including the Ras-MAP kinase pathway and the phosphatidylinositol 3-kinase/Akt pathway. We demonstrate here that integrin-dependent EGFR activation is also essential for adhesion-induced formation of actin stress fibers, focal adhesion localization and tyrosine phosphorylation of the adapter protein paxillin, as well as transcriptional activation of the serum response factor. All these events are known to be mediated by the small GTPase RhoA. EGFR activity was not found to regulate the activity status of RhoA, however. Instead, we found that EGFR activity is required for integrin-induced phosphorylation of cofilin. Cofilin is an actin-binding protein, which, when unphosphorylated, stimulates depolymerization and severing of actin filaments. Thus, in the absence of the kinase activity of the EGFR, cofilin remains dephosphorylated and depolymerizes actin filaments, rendering cells unable to respond to RhoA signaling. These studies demonstrate adhesion-dependent regulation of cofilin phosphorylation, and identify a novel role for EGFR in integrin signaling.
Marcoux
Nathaly
N
Cancer Center, The Burnham Institute, La Jolla, CA 92037, USA.
Vuori
Kristiina
K
D008841:Actin Cytoskeleton / Q000502:physiology; D000818:Animals; D002448:Cell Adhesion; D051340:Cofilin 2 / Q000378:metabolism*; D016895:Culture Media, Serum-Free; D066246:ErbB Receptors / Q000378:metabolism*; D016023:Integrins / Q000502:physiology; D051379:Mice; D041681:NIH 3T3 Cells; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D026362:Serum Response Factor / Q000378:metabolism; D015398:Signal Transduction; D022502:Stress Fibers / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D051340:Cofilin 2; D016895:Culture Media, Serum-Free; D016023:Integrins; D051419:Paxillin; D026362:Serum Response Factor; D019000:Phosphotyrosine; D066246:ErbB Receptors; D020742:rhoA GTP-Binding Protein