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Molecular and Cellular Biology, July 2002, p. 4567-4578, Vol. 22, No. 13
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.13.4567-4578.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

SOCS-6 Binds to Insulin Receptor Substrate 4, and Mice Lacking the SOCS-6 Gene Exhibit Mild Growth Retardation

Danielle L. Krebs,1* Rachel T. Uren,1 Donald Metcalf,1 Steven Rakar,1 Jian-Guo Zhang,1 Robyn Starr,1 David P. De Souza,1 Kathy Hanzinikolas,1 Jo Eyles,1 Lisa M. Connolly,2 Richard J. Simpson,2 Nicos A. Nicola,1 Sandra E. Nicholson,1 Manuel Baca,1 Douglas J. Hilton,1 and Warren S. Alexander1

The Walter and Eliza Hall Institute of Medical Research and the Cooperative Research Centre for Cellular Growth Factors,1 Joint Protein Structure Laboratory of the Walter and Eliza Hall Institute and Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria 3050, Australia2

Received 25 October 2001/ Returned for modification 11 December 2001/ Accepted 2 April 2002

SOCS-6 is a member of the suppressor of cytokine signaling (SOCS) family of proteins (SOCS-1 to SOCS-7 and CIS) which each contain a central SH2 domain and a carboxyl-terminal SOCS box. SOCS-1, SOCS-2, SOCS-3, and CIS act to negatively regulate cytokine-induced signaling pathways; however, the actions of SOCS-4, SOCS-5, SOCS-6, and SOCS-7 remain less clear. Here we have used both biochemical and genetic approaches to examine the action of SOCS-6. We found that SOCS-6 and SOCS-7 are expressed ubiquitously in murine tissues. Like other SOCS family members, SOCS-6 binds to elongins B and C through its SOCS box, suggesting that it might act as an E3 ubiquitin ligase that targets proteins bound to its SH2 domain for ubiquitination and proteasomal degradation. We investigated the binding specificity of the SOCS-6 and SOCS-7 SH2 domains and found that they preferentially bound to phosphopeptides containing a valine in the phosphotyrosine (pY) +1 position and a hydrophobic residue in the pY +2 and pY +3 positions. In addition, these SH2 domains interacted with a protein complex consisting of insulin receptor substrate 4 (IRS-4), IRS-2, and the p85 regulatory subunit of phosphatidylinositol 3-kinase. To investigate the physiological role of SOCS-6, we generated mice lacking the SOCS-6 gene. SOCS-6-/- mice were born in a normal Mendelian ratio, were fertile, developed normally, and did not exhibit defects in hematopoiesis or glucose homeostasis. However, both male and female SOCS-6-/- mice weighed approximately 10% less than wild-type littermates.

* Corresponding author. Mailing address: The Walter and Eliza Hall Institute of Medical Research, Post Office, Royal Melbourne Hospital, Victoria 3050, Australia. Phone: 61-3-9345-2525. Fax: 61-3-9345-2616. E-mail: krebs{at}wehi.edu.au.

Molecular and Cellular Biology, July 2002, p. 4567-4578, Vol. 22, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.13.4567-4578.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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