Epidermal growth factor modulates tyrosine phosphorylation of p130Cas. Involvement of phosphatidylinositol 3'-kinase and actin cytoskeleton.
Epidermal growth factor (EGF) treatment of Rat-1 cells expressing human EGF receptor results in the modification of the tyrosine phosphorylation of the p130 Crk-associated substrate (Cas), a novel signaling molecule residing in focal adhesions. At low, mitogenic concentrations (<10 ng/ml), EGF treatment induced a rapid and transient tyrosine phosphorylation of Cas and promoted the formation of a Cas-adapter protein Crk complex in intact cells. The increase in tyrosine phosphorylation of Cas paralleled an increase in the cellular content of actin stress fibers and occurred via a pathway that depended on the integrity of the cytoskeleton. Further, phosphatidylinositol 3'-kinase activity was found to be required for the EGF-stimulated Cas phosphorylation and actin polymerization. At high concentrations (>30 ng/ml), EGF treatment resulted in the tyrosine dephosphorylation of Cas in a time-dependent manner with a concomitant decrease in the length and number of actin stress fibers. Thus, Cas exhibits an unusual bell-shaped dose-response curve in response to EGF stimulation. These results demonstrate a novel signaling role for EGF in inducing changes in tyrosine phosphorylation of Cas and Cas-Crk complex formation and suggest that Cas could be a signaling component in EGF-mediated signal transduction.
Ojaniemi
M
M
La Jolla Cancer Research Center, The Burnham Institute, La Jolla, California 92037, USA.
Vuori
K
K
D000199:Actins / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D050719:Crk-Associated Substrate Protein; D015638:Cytochalasin D / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D004261:DNA Replication; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000494:pharmacology*; D020690:GTPase-Activating Proteins; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism; D051381:Rats; D050717:Retinoblastoma-Like Protein p130; D014443:Tyrosine / Q000378:metabolism*
D000199:Actins; D050719:Crk-Associated Substrate Protein; D015638:Cytochalasin D; D004815:Epidermal Growth Factor; D020690:GTPase-Activating Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D011506:Proteins; D050717:Retinoblastoma-Like Protein p130; D014443:Tyrosine; C493841:BCAR1 protein, human; C493843:Bcar1 protein, rat