An EGF receptor/Ral-GTPase signaling cascade regulates c-Src activity and substrate specificity.
c-Src is a membrane-associated tyrosine kinase that can be activated by many types of extracellular signals, and can regulate the function of a variety of cellular protein substrates. We demonstrate that epidermal growth factor (EGF) and beta-adrenergic receptors activate c-Src by different mechanisms leading to the phosphorylation of distinct sets of c-Src substrates. In particular, we found that EGF receptors, but not beta(2)-adrenergic receptors, activated c-Src by a Ral-GTPase-dependent mechanism. Also, c-Src activated by EGF treatment or expression of constitutively activated Ral-GTPase led to tyrosine phosphorylation of Stat3 and cortactin, but not Shc or subsequent Erk activation. In contrast, c-Src activated by isoproterenol led to tyrosine phosphorylation of Shc and subsequent Erk activation, but not tyrosine phosphorylation of cortactin or Stat3. These results identify a role for Ral-GTPases in the activation of c-Src by EGF receptors and the coupling of EGF to transcription through Stat3 and the actin cytoskeleton through cortactin. They also show that c-Src kinase activity can be used differently by individual extracellular stimuli, possibly contributing to their ability to generate unique cellular responses.
Goi
T
T
Department of Biochemistry, Tufts University School of Medicine, Boston, MA 02111, USA.
Shipitsin
M
M
Lu
Z
Z
Foster
D A
DA
Klinz
S G
SG
Feig
L A
LA
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006801:Humans; D016716:PC12 Cells; D010766:Phosphorylation; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013379:Substrate Specificity; D015534:Trans-Activators / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D020725:ral GTP-Binding Proteins / Q000378:metabolism*
D004268:DNA-Binding Proteins; D018343:Receptors, Adrenergic, beta-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494088:Stat3 protein, rat; D015534:Trans-Activators; D014443:Tyrosine; D066246:ErbB Receptors; D016392:Proto-Oncogene Proteins pp60(c-src); D020558:GTP Phosphohydrolases; D020725:ral GTP-Binding Proteins