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MBC in Press, published online ahead of print November 1, 2006
Mol. Biol. Cell 10.1091/mbc.E06-05-0467

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Submitted on May 31, 2006
Revised on October 16, 2006
Accepted on October 19, 2006

Akt-PDK1 Complex Mediates EGF-induced Membrane Protrusion through Ral Activation

Hisayoshi Yoshizaki,*{dagger} Naoki Mochizuki,* Yukiko Gotoh,{ddagger} and Michiyuki Matsuda{dagger}

*Department of Structural Analysis, National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan; {dagger}Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; {ddagger}Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan

Monitoring Editor: Martin A. Schwartz

We studied the spatio-temporal regulation of Akt, PtdIns(3,4)P2, and PtdIns(3,4,5)P3 by using probes based on the principle of fluorescence resonance energy transfer (FRET). On EGF stimulation, the amount of PtdIns(3,4,5)P3 was increased diffusely in the plasma membrane, whereas that of PtdIns(3,4)P2 was increased more in the nascent lamellipodia than in the plasma membrane of the central region. The distribution and time course of Akt activation was similar to that of increased PtdIns(3,4)P2 levels, which were most prominent in the nascent lamellipodia. Meanwhile, we found that upon EGF stimulation PDK1 was also recruited to nascent lamellipodia in an Akt-dependent manner. Because PDK1 is known to activate Ral GTPase and because Ral is required for EGF-induced lamellipodial protrusion, we speculated that the PDK1-Akt complex may be indispensable for the induction of lamellipodia. In agreement with this idea, EGF-induced lamellipodia formation was promoted by the overexpression of Akt and inhibited by an Akt inhibitor or a Ral-binding domain of Sec5. These results identified the Akt-PDK1 complex as an upstream positive regulator of Ral GTPase in the induction of lamellipodial protrusion.

Address correspondence to: Michiyuki Matsuda (matsudam{at}path1.med.kyoto-u.ac.jp)




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