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PDK1 mediates growth factor‐induced Ral‐GEF activation by a kinase‐independent mechanism
Author(s) -
Tian Xuejun,
Rusanescu Gabriel,
Hou Weimin,
Schaffhausen Brian,
Feig Larry A.
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/21.6.1327
Subject(s) - medical school , library science , medicine , medical education , computer science
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.