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Originally published In Press as doi:10.1074/jbc.M203387200 on July 30, 2002

J. Biol. Chem., Vol. 277, Issue 41, 38021-38028, October 11, 2002
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Direct Identification of Tyrosine 474 as a Regulatory Phosphorylation Site for the Akt Protein Kinase*,

Nelly Marmy Conus, Katherine M. Hannan, Briony E. Cristiano, Brian A. HemmingsDagger , and Richard B. Pearson§

From the Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Locked Bag #1, A'Beckett Street, Melbourne, Vic 8006 Australia and the Dagger  Friedrich Miescher-Institut, P.O. Box 2543, CH-4002 Basel, Switzerland

Understanding the regulation of Akt has been of major interest for elucidating the control of normal cellular physiology as well as malignant transformation. The paradigm for activation of Akt involves phosphatidylinositol 3-kinase-dependent membrane localization followed by activating phosphorylation of Thr-308 and Ser-473. Many of the activating signals for Akt involve the stimulation of receptor and non-receptor tyrosine kinases, and the most potent activator known is the tyrosine phosphatase inhibitor pervanadate, highlighting a possible role for tyrosine phosphorylation in the regulation of the enzyme. In this study we show that activation of Akt by pervanadate or serum is associated with tyrosine phosphorylation of Akt. In addition, in SKOV3 ovarian carcinoma cells that exhibit high basal levels of Akt activity, Akt was tyrosine-phosphorylated in the basal state, and this phosphorylation was further enhanced by both pervanadate and insulin-like growth factor-1. We have used NH2-terminal sequencing and phosphate release analysis to directly identify Tyr-474 as the site of tyrosine phosphorylation. Substitution of Tyr-474 with phenylalanine abolished tyrosine phosphorylation of Akt and resulted in up to 55% inhibition of Akt activation, indicating phosphorylation at Tyr-474 is required for full activation of the kinase. Our data identifies a novel regulatory mechanism for this pleiotropic enzyme that may be applicable to the AGC family of protein kinases given the conserved nature of the COOH-terminal hydrophobic motif containing Tyr-474.

* This work was supported by grants from the Anti Cancer Council of Victoria and Australian Research Council (to R. B. P.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplementary Fig. 4.

§ To whom correspondence should be addressed. Tel.: 61-3-9656-1247; Fax: 61-3-9656-1411; E-mail: r.pearson@pmci.unimelb.edu.au.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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