An EGF receptor/Ral-GTPase signaling cascade regulates c-Src activity and substrate specificity

doi:10.1093/emboj/19.4.623

Account Information

Guest Alerts | Access Rights | My Account | Sign In

An EGF receptor/Ral-GTPase signaling cascade regulates c-Src activity and substrate specificity

Takanori Goi, Michail Shipitsin, Zhimin Lu, David A. Foster, Stephan G. Klinz and Larry A. Feig

Department of Biochemistry, Tufts University School of Medicine, Boston, MA 02111 and ¹ Department of Biological Sciences, Hunter College of The City of New York, New York, NY 10021, USA
² Corresponding author
e-mail: lfeig{at}opal.tufts.edu

c-Src is a membrane-associated tyrosine kinase that can be activated by many types of extracellular signals, and can regulatethe function of a variety of cellular protein substrates. We demonstratethat epidermal growth factor (EGF) and $beta$ -adrenergic receptorsactivate c-Src by different mechanisms leading to the phosphorylationof distinct sets of c-Src substrates. In particular, we foundthat EGF receptors, but not $beta$ ₂-adrenergic receptors, activatedc-Src by a Ral-GTPase-dependent mechanism. Also, c-Src activatedby EGF treatment or expression of constitutively activated Ral-GTPaseled to tyrosine phosphorylation of Stat3 and cortactin, but notShc or subsequent Erk activation. In contrast, c-Src activatedby isoproterenol led to tyrosine phosphorylation of Shc and subsequentErk activation, but not tyrosine phosphorylation of cortactinor Stat3. These results identify a role for Ral-GTPases in theactivation of c-Src by EGF receptors and the coupling of EGF totranscription through Stat3 and the actin cytoskeleton throughcortactin. They also show that c-Src kinase activity can be useddifferently by individual extracellular stimuli, possibly contributingto their ability to generate unique cellular responses.