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

Weizhou Zhang; Cong S Zong; Ulrich Hermanto; Pablo Lopez-Bergami; Ze'ev Ronai; Lu-Hai Wang

doi:10.1128/MCB.26.2.413-424.2006

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

Journal article

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

Weizhou Zhang, Cong S Zong, Ulrich Hermanto, Pablo Lopez-Bergami, Ze'ev Ronai and Lu-Hai Wang

Molecular and cellular biology, Vol.26(2), pp.413-424

01/15/2006

DOI: 10.1128/MCB.26.2.413-424.2006

PMCID: PMC1346890

PMID: 16382134

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https://www.ncbi.nlm.nih.gov/pmc/articles/1346890View

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Abstract

ABSTRACT 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.

Details

Title: Subtitle: RACK1 Recruits STAT3 Specifically to Insulin and Insulin-Like Growth Factor 1 Receptors for Activation, Which Is Important for Regulating Anchorage-Independent Growth
Creators: Weizhou Zhang - Department of Microbiology
Cong S Zong - Department of Molecular and Cellular Oncology
Ulrich Hermanto - Department of Radiation Oncology, M. D. Anderson Cancer Center, University of Texas, Houston, Texas 77030
Pablo Lopez-Bergami - Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029
Ze'ev Ronai - Signal Transduction Program, The Burnham Institute, La Jolla, California 92037
Lu-Hai Wang - Department of Microbiology
Resource Type: Journal article
Publication Details: Molecular and cellular biology, Vol.26(2), pp.413-424
DOI: 10.1128/MCB.26.2.413-424.2006
PMID: 16382134
PMCID: PMC1346890
NLM abbreviation: Mol Cell Biol
ISSN: 0270-7306
eISSN: 1098-5549
Language: English
Date published: 01/15/2006
Academic Unit: Radiation Oncology
Record Identifier: 9984083876902771

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