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The EMBO journal
Mar 15, 2002;21 (6): 1327-38.

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

Xuejun Tian, Gabriel Rusanescu, Weimin Hou, Brian Schaffhausen, Larry A Feig
Author Information
  1. Xuejun Tian: Department of Biochemistry, Tufts University School of Medicine, Boston, MA 02111, USA.
PMID: 11889038 DOI: 10.1093/emboj/21.6.1327

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.

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Grants

  1. R01 CA034722/NCI NIH HHS

MeSH Term

3-Phosphoinositide-Dependent Protein Kinases
Animals
COS Cells
Cell Line, Transformed
Chlorocebus aethiops
Enzyme Activation
Epidermal Growth Factor
GTP Phosphohydrolases
Humans
Peptides
Phosphatidylinositol 3-Kinases
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-akt
Recombinant Fusion Proteins
ral GTP-Binding Proteins
ral Guanine Nucleotide Exchange Factor

Chemicals

Peptides
Proto-Oncogene Proteins
Recombinant Fusion Proteins
ral Guanine Nucleotide Exchange Factor
Epidermal Growth Factor
3-Phosphoinositide-Dependent Protein Kinases
PDPK1 protein, human
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt
GTP Phosphohydrolases
RALA protein, human
ral GTP-Binding Proteins
Journal Article Research Support, U.S. Gov't, P.H.S.

Word Cloud

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