suppressor of cytokine signaling 3; SOCS-3; cytokine-inducible SH2 protein 3; CIS-3; STAT-induced STAT inhibitor 3; SSI-3 (SOCS3 CIS3 SSI3)

Function

• role in negative regulation of cytokines that signal through the JAK/STAT pathway
• inhibits cytokine signal transduction by binding to tyrosine kinase receptors &/or their subunits including:
  • gp130
  • LIF receptor
  • erythropoietin receptor
  • insulin receptor
  • IL12 receptor
  • GCSF receptor
  • leptin receptor
• binding to JAK2 inhibits its kinase activity
• suppresses fetal liver erythropoiesis
• regulates onset & maintenance of allergic responses mediated by T-helper type 2 cells
• regulates IL-6 signaling in vivo (putative)
• probable substrate recognition component of a SCF-like ECS (elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates ubiquitination & subsequent proteasomal degradation of target proteins
• seems to recognize IL6ST (putative)
• protein modification; protein ubiquitination
• phosphorylated on Tyr after stimulation by the cytokines, IL-2, EPO or IGF1
• interacts with multiple activated proteins of the tyrosine kinase signaling pathway including IGF1 receptor, insulin receptor & JAK2
• binding to JAK2 is mediated through the KIR & SH2 domains to a phosphorylated Tyr within the JAK2 JH1 domain
• binds specific activated Tyr of leptin receptor, EPO receptor, IL12 receptor, GSCF receptor & gp130
• interaction with CSNK1E stabilizes SOCS3 protein
• component of the probable ECS(SOCS3) complex (E3 ubiquitin-protein ligase complex) which contains CUL5, RNF7/RBX2, elongin BC complex & SOCS3
• interacts with CUL5, RNF7, TCEB1 & TCEB2
• interacts with CUL2

Structure

• the ESS & SH2 domains are required for JAK phospho-Tyr binding
• further interaction with the KIR domain is necessary for signal & kinase inhibition
• the SOCS box domain mediates the interaction with the elongin BC complex, an adapter module in different E3 ubiquitin ligase complexes (putative)
• contains 1 SH2 domain
• contains 1 SOCS box domain

Expression

• widely expressed
• high expression in heart, placenta, skeletal muscle, peripheral blood leukocytes, fetal & adult lung, & fetal liver & kidney
• lower expression in thymus

Pathology

• genetic variation in the promoter region of SOCS3 may be associated with susceptibility to atopic dermatitis 4

Pharmacology

• potential therapeutic agent for treating rheumatoid arthritis

More general terms

• suppressor of cytokine signaling family (SOCS family protein)

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=9021
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:9021
• OMIM: https://mirror.omim.org/entry/604176
• OMIM: https://mirror.omim.org/entry/605805
• UniProt: http://www.uniprot.org/uniprot/O14543.html