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Molecular and Cellular Biology, January 2006, p. 413-424, Vol. 26, No. 2
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.2.413-424.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

RACK1 Recruits STAT3 Specifically to Insulin and Insulin-Like Growth Factor 1 Receptors for Activation, Which Is Important for Regulating Anchorage-Independent Growth{dagger}

Weizhou Zhang,1 Cong S. Zong,2 Ulrich Hermanto,3 Pablo Lopez-Bergami,4 Ze'ev Ronai,5 and Lu-Hai Wang1*

Department of Microbiology,1 Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029,4 Department of Molecular and Cellular Oncology,2 Department of Radiation Oncology, M. D. Anderson Cancer Center, University of Texas, Houston, Texas 77030,3 Signal Transduction Program, The Burnham Institute, La Jolla, California 920375

Received 21 April 2005/ Returned for modification 3 June 2005/ Accepted 20 October 2005

Current understanding of the activation of STATs is through binding between the SH2 domain of STATs and phosphotyrosine of tyrosine kinases. Here we demonstrate a novel role of RACK1 as an adaptor for insulin and insulin-like growth factor 1 receptor (IGF-1R)-mediated STAT3 activation specifically. Intracellular association of RACK1 via its N-terminal WD domains 1 to 4 (WD1-4) with insulin receptor (IR)/IGF-1R is augmented upon respective ligand stimulation, whereas association with STAT3 is constitutive. Purified RACK1 or RACK1 WD1-4 associates directly with purified IR, IGF-1R, and STAT3 in vitro. Insulin induces multiprotein complex formation of RACK1, IR, and STAT3. Overexpression or downregulation of RACK1 greatly enhances or decreases, respectively, IR/IGF-1R-mediated activation of STAT3 and its target gene expression. Site-specific mutants of IR and IGF-1R impaired in RACK1 binding are ineffective in mediating recruitment and activation of STAT3 as well as in insulin- or IGF-1-induced protection of cells from anoikis. RACK1-mediated STAT3 activation is important for insulin and IGF-1-induced anchorage-independent growth in certain ovarian cancer cells. We conclude that RACK1 mediates recruitment of STAT3 to IR and IGF-1R specifically for activation, suggesting a general paradigm for the need of an adaptor in mediating activation of STATs by receptor protein tyrosine kinases.

* Corresponding author. Mailing address: Department of Microbiology, One Gustave L. Levy Place, Box 1124, New York, NY 10029-6574. Phone: (212) 241-3759. Fax: (212) 534-1684. E-mail: lu-hai.wang{at}mssm.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, January 2006, p. 413-424, Vol. 26, No. 2
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.2.413-424.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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