Abstract
Many extracellular signals stimulate phosphatidylinositol-3-kinase, which in turn activates the Rac1 GTPase, the protein kinase Akt and the Akt Thr 308 upstream kinase PDK1. Active Rac1 stimulates a number of events, including substrate phosphorylation by a subgroup of the PAK family of kinases. The combined effects of Rac1, PDK1 and Akt are crucial for cell migration, growth, survival, metabolism and tumorigenesis. Here we show that Rac1 stimulates a second, kinase-independent function of PAK1. The PAK1 kinase domain serves as a scaffold to facilitate Akt stimulation by PDK1 and to aid recruitment of Akt to the membrane. PAK differentially activates subpopulations of Akt. These findings reveal scaffolding functions of PAK that regulate the efficiency, localization and specificity of the PDK1–Akt pathway.
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Acknowledgements
We thank Jonathan A. Cooper, Michael E. Greenberg and members of the Gotoh Laboratory for critical reading of the manuscript, encouragement and helpful discussion. We also thank Michael E. Greenberg and Steve M. Shamah for phosphorylated Bad antibody and phosphorylated PAK1 antibody, and Masaki Inagaki for PAK construct. This work was supported in part by Grants-Aid from the Ministry of Education, Science, Sports and Culture of Japan, SORST of the Japan Science and Technology Corporation, Global COE Program (Integrative Life Science Based on the Study of Biosignaling Mechanisms), MEXT, the Mitsubishi Foundation, the Uehara Foundation and the Princess Takamatsu Foundation.
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M.H. and K.O. performed all the experiments and analysed the data; C.Y. assisted with the experiments shown in Supplementary Information, Fig. S5b; Y.G. supervised the study.
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Higuchi, M., Onishi, K., Kikuchi, C. et al. Scaffolding function of PAK in the PDK1–Akt pathway. Nat Cell Biol 10, 1356–1364 (2008). https://doi.org/10.1038/ncb1795
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DOI: https://doi.org/10.1038/ncb1795
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