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Papers In Press, published online ahead of print June 2, 2004
Department of Cell Growth and Regulation, University of Tokyo, Tokyo 113-0032
Corresponding Author: ttsuruo{at}iam.u-tokyo.ac.jp
The phosphatidylinositide-3-OH kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt and the Raf/mitogen-activated protein kinase (MAPK/Erk) kinase (MEK)/mitogen-activated protein kinase (MAPK) pathways have central roles in the regulation of cell survival and proliferation. Despite their importance, however, the crosstalk between these two pathways has not been fully understood. Here we report that PDK1 promotes MAPK activation in a MEK-dependent manner. In vitro kinase assay revealed that the direct targets of PDK1 in the MAPK pathway were the upstream MAPK kinases MEK1 and MEK2. The identified PDK1 phosphorylation sites in MEK1 and MEK2 are Ser222 and Ser226, respectively, and are known to be essential for full activation. To date, these sites are thought to be phosphorylated by Raf kinases. However, PDK1 gene silencing using small interference RNA (siRNA) demonstrates that PDK1 is associated with maintaining the steady-state phophorylated MEK level and cell growth. The siRNA-mediated downregulation of PDK1 attenuated maximum MEK and MAPK activities but could not prolong MAPK signaling duration. Stable and transient expression of constitutively active MEK1 overcame these effects. Our results suggest a novel crosstalk between the PI3K/PDK1/Akt pathway and the Raf/MEK/MAPK pathway.
J. Biol. Chem, 10.1074/jbc.M402055200
Submitted on February 25, 2004
Revised on June 1, 2004
Accepted on June 2, 2004
Involvement of PDK1 in the MEK/MAPK signal-transduction pathway
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