title: SOCS-6 binds to insulin receptor substrate 4, and mice lacking the SOCS-6 gene exhibit mild growth retardation.
abstract: 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.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research and the Cooperative Research Centre for Cellular Growth Factors, Royal Melbourne Hospital, Victoria 3050, Australia. krebs@wehi.edu.au
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Krebs
authors.forename: Rachel T
authors.initials: RT
authors.lastname: Uren
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.forename: Steven
authors.initials: S
authors.lastname: Rakar
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Zhang
authors.forename: Robyn
authors.initials: R
authors.lastname: Starr
authors.forename: David P
authors.initials: DP
authors.lastname: De Souza
authors.forename: Kathy
authors.initials: K
authors.lastname: Hanzinikolas
authors.forename: Jo
authors.initials: J
authors.lastname: Eyles
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Connolly
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Simpson
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Nicola
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Nicholson
authors.forename: Manuel
authors.initials: M
authors.lastname: Baca
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hilton
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
mesh_terms: D000818:Animals; D001665:Binding Sites; D001786:Blood Glucose / Q000032:analysis; D001824:Body Constitution / Q000235:genetics; D000075065:Elongin; D005260:Female; D006128:Growth / Q000235:genetics*; D006413:Hematopoietic System / Q000378:metabolism; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D001786:Blood Glucose; D000075065:Elongin; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; C491531:Irs4 protein, mouse; D010750:Phosphoproteins; D011506:Proteins; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases