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Mol. Cell. Biol. 20 (19): 7109-7120

Copyright © 2000 by the American Society for Microbiology. All rights reserved.

Molecular and Cellular Biology, October 2000, p. 7109-7120, Vol. 20, No. 19
Copyright © 2000, American Society for Microbiology. All rights reserved.

New Role for Shc in Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway

Haihua Gu,1,* Hiroyuki Maeda,1 James J. Moon,2 James D. Lord,2 Monique Yoakim,1 Brad H. Nelson,2 and Benjamin G. Neel1

Cancer Biology Program, Division of Hematology-Oncology, Department of Medicine, Beth Israel-Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts 02115,1 and Virginia Mason Research Center and Department of Immunology, University of Washington, Seattle, Washington 981952

Received 20 April 2000/Accepted 12 June 2000

Most, if not all, cytokines activate phosphatidylinositol 3-kinase (PI-3K). Although many cytokine receptors have direct binding sites for the p85 subunit of PI-3K, others, such as the interleukin-3 (IL-3) receptor beta common chain (beta c) and the IL-2 receptor beta chain (IL-2Rbeta ), lack such sites, leaving the mechanism by which they activate PI-3K unclear. Here, we show that the protooncoprotein Shc, which promotes Ras activation by recruiting the Grb2-Sos complex in response to stimulation of cytokine stimulation, also signals to the PI-3K/Akt pathway. Analysis of Yright-arrowF and "add-back" mutants of beta c shows that Y577, the Shc binding site, is the major site required for Gab2 phosphorylation in response to cytokine stimulation. When fused directly to a mutant form of IL-2Rbeta that lacks other cytoplasmic tyrosines, Shc can promote Gab2 tyrosyl phosphorylation. Mutation of the three tyrosyl phosphorylation sites of Shc, which bind Grb2, blocks the ability of the Shc chimera to evoke Gab2 tyrosyl phosphorylation. Overexpression of mutants of Grb2 with inactive SH2 or SH3 domains also blocks cytokine-stimulated Gab2 phosphorylation. The majority of cytokine-stimulated PI-3K activity associates with Gab2, and inducible expression of a Gab2 mutant unable to bind PI-3K markedly impairs IL-3-induced Akt activation and cell growth. Experiments with the chimeric receptors indicate that Shc also signals to the PI-3K/Akt pathway in response to IL-2. Our results suggest that cytokine receptors lacking direct PI-3K binding sites activate Akt via a Shc/Grb2/Gab2/PI-3K pathway, thereby regulating cell survival and/or proliferation.

* Corresponding author. Mailing address: Cancer Biology Program, Beth Israel-Deaconess Medical Center, H.I.M. 1043, 77 Avenue Louis Pasteur, Boston, MA 02115. Phone: (617) 667-5601. Fax: (617) 975-5617. E-mail: hgu{at}

Molecular and Cellular Biology, October 2000, p. 7109-7120, Vol. 20, No. 19
Copyright © 2000, American Society for Microbiology. All rights reserved.

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Transient Activation of Jun N-terminal Kinases and Protection from Apoptosis by the Insulin-like Growth Factor I Receptor Can Be Suppressed by Dicumarol.
D. Krause, A. Lyons, C. Fennelly, and R. O'Connor (2001)
J. Biol. Chem. 276, 19244-19252
   Abstract »    Full Text »    PDF »
Phosphoinositide 3-Kinase-dependent Regulation of Interleukin-3-induced Proliferation. INVOLVEMENT OF MITOGEN-ACTIVATED PROTEIN KINASES, SHP2 AND Gab2.
B. L. Craddock, J. Hobbs, C. E. Edmead, and M. J. Welham (2001)
J. Biol. Chem. 276, 24274-24283
   Abstract »    Full Text »    PDF »
Endothelin-1 Induces Serine Phosphorylation of the Adaptor Protein p66Shc and Its Association with 14-3-3 Protein in Glomerular Mesangial Cells.
M. Foschi, F. Franchi, J. Han, G. L. Villa, and A. Sorokin (2001)
J. Biol. Chem. 276, 26640-26647
   Abstract »    Full Text »    PDF »
TEL-JAK2 Mediates Constitutive Activation of the Phosphatidylinositol 3'-Kinase/Protein Kinase B Signaling Pathway.
M. H.-H. Nguyen, J. M.-Y. Ho, B. K. Beattie, and D. L. Barber (2001)
J. Biol. Chem. 276, 32704-32713
   Abstract »    Full Text »    PDF »
The Cytoprotective Effects of the Glycoprotein 130 Receptor-coupled Cytokine, Cardiotrophin-1, Require Activation of NF-kappa B.
R. Craig, M. Wagner, T. McCardle, A. G. Craig, and C. C. Glembotski (2001)
J. Biol. Chem. 276, 37621-37629
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The Roles of Phosphatidylinositol 3-Kinase and Protein Kinase Czeta for Thrombopoietin-induced Mitogen-activated Protein Kinase Activation in Primary Murine Megakaryocytes.
P. Rojnuckarin, Y. Miyakawa, N. E. Fox, J. Deou, G. Daum, and K. Kaushansky (2001)
J. Biol. Chem. 276, 41014-41022
   Abstract »    Full Text »    PDF »
Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins.
S. H. Ong, Y. R. Hadari, N. Gotoh, G. R. Guy, J. Schlessinger, and I. Lax (2001)
PNAS 98, 6074-6079
   Abstract »    Full Text »    PDF »

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