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21 (6): 1327-1338

Copyright © 2002 by the European Molecular Biology Organization.

PDK1 mediates growth factor-induced Ral-GEF activation by a kinase-independent mechanism

Xuejun Tian, Gabriel Rusanescu, Weimin Hou, Brian Schaffhausen, and Larry A. Feig1

Department of Biochemistry, Tufts University School of Medicine, Boston, MA 02111, USA
1 Corresponding author e-mail: larry.feig{at}tufts.edu

Abstract: Ras proteins transduce extracellular signals to intracellular signaling pathways by binding to and promoting the activation of at least three classes of downstream signaling molecules: Raf kinases, phosphoinositide-3-kinase (PI3-K) and Ral guanine nucleotide exchange factors (Ral-GEFs). Previous work has demonstrated that epidermal growth factor (EGF) activates Ral-GEFs, at least in part, by a Ras-mediated redistribution of the GEFs to their target, Ral-GTPases, in the plasma membrane. Here we show that Ral-GEF stimulation by EGF involves an additional mechanism, PI3-K-dependent kinase 1 (PDK1)-induced enhancement of Ral-GEF catalytic activity. Remarkably, this PDK1 function is not dependent upon its kinase activity. Instead, the non-catalytic N-terminus of PDK1 mediates the formation of an EGF-induced complex with the N-terminus of the Ral-GEF, Ral-GDS, thereby relieving its auto-inhibitory effect on the catalytic domain of Ral-GDS. These results elucidate a novel function for PDK1 and demonstrate that two Ras effector pathways cooperate to promote Ral-GTPase activation.

Key Words: Keywords: PDK1/Ral/Ral-GDS/Ras/signal transduction

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