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J. Biol. Chem. 277 (2): 1500-1508

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

A New Role for the p85-Phosphatidylinositol 3-Kinase Regulatory Subunit Linking FRAP to p70 S6 Kinase Activation*

Ana González-GarcíaDagger , Elia GarridoDagger , Carmen HernándezDagger , Beatriz AlvarezDagger , Concepción JiménezDagger , Doreen A. Cantrell§, Nicholas Pullen, and Ana C. CarreraDagger ||

From the Dagger  Department of Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Carretera de Colmenar Km 15, Cantoblanco, Madrid E-28049, Spain, the § Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom, and the  Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058, Basel, Switzerland

The serine/threonine kinase p70 S6 kinase (p70S6K) phosphorylates the 40 S ribosomal protein S6, modulating the translation of an mRNA subset that encodes ribosomal proteins and translation elongation factors. p70S6K is activated in response to mitogenic stimuli and is required for progression through the G1 phase of the cell cycle and for cell growth. Activation of p70S6K is regulated by phosphorylation of seven different residues distributed throughout the protein, a subset of which depends on the activity of p85/p110 phosphatidylinositol 3-kinase (PI3K); in fact, the phosphorylation status of Thr229 and Thr389 is intimately linked to PI3K activity. In the full-length enzyme, however, these sites are also acutely sensitive to the action of FKBP 12-rapamycin-associated protein (FRAP). The mechanism by which PI3K and FRAP cooperate to induce p70S6K activation remains unclear. Here we show that the p85 regulatory subunit of PI3K also controls p70S6K activation by mediating formation of a ternary complex with p70S6K and FRAP. The p85 C-terminal SH2 domain is responsible for p85 coupling to p70S6K and FRAP, because deletion of the C-terminal SH2 domain inhibits complex formation and impairs p70S6K activation by PI3K. Formation of this complex is not required for activation of a FRAP-independent form of p70S6K, however, underscoring the role of p85 in regulating FRAP-dependent p70S6K activation. These studies thus show that, in addition to the contribution of PI3K activity, the p85 regulatory subunit plays a critical role in p70S6K activation.

* This work was supported by grants from the Community of Madrid and from the Spanish Dirección General de Ciencia y Desarrollo Tecnológico. The Department of Immunology and Oncology was founded and is supported by the Spanish Council for Scientific Research and by Amersham Biosciences, Inc.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.

|| To whom correspondence should be addressed: Dept. of Immunology and Oncology, Centro Nacional de Biotecnología, Carretera de Colmenar Km 15, Cantoblanco, Madrid E-28049, Spain.

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

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