Suppressors of cytokine signaling (SOCS): Negative regulators of signal transduction

Warren S. Alexander, Robyn Starr, Donald Metcalf, Sandra E. Nicholson, Alison Farley, Andrew G. Elefanty, Marta Brysha, Benjamin T. Kile, Rachel Richardson, Manuel Baca, Jian Guo Zhang, Tracy A. Willson, Elizabeth M. Viney, Naomi S. Sprigg, Steven Rakar, Jason Corbin, Sandra Mifsud, Ladina Dirago, Dale Cary, Nicos A. NicolaDouglas J. Hilton

Research output: Contribution to journalReview ArticleResearchpeer-review

94 Citations (Scopus)

Abstract

SOCS-1 was originally identified as an inhibitor of interleukin-6 signal transduction and is a member of a family of proteins (SOCS-1 to SOCS-7 and CIS) that contain an SH2 domain and a conserved carboxyl-terminal SOCS box motif. Mutation studies have established that critical contributions from both the amino-terminal and SH2 domains are essential for SOCS-1 and SOCS-3 to inhibit cytokine signaling. Inhibition of cytokine-dependent activation of STAT3 occurred in cells expressing either SOCS-1 or SOCS-3, but unlike SOCS- 1, SOCS-3 did not directly interact with or inhibit the activity of JAK kinases. Although the conserved SOCS box motif appeared to be dispensable for SOCS-1 and SOCS-3 action when overexpressed, this domain interacts with elongin proteins and may be important in regulating protein turnover. In gene knockout studies, SOCS-1(-/-) mice were born but faded to thrive and died within 3 weeks of age with fatty degeneration of the liver and hemopoietic infiltration of several organs. The thymus in SOCS-1(-/-) mice was small, the animals were lymphopenic, and deficiencies in B lymphocytes were evident within hemopoietic organs. We propose that the absence of SOCS-1 in these mice prevents lymphocytes and liver cells from appropriately controlling signals from cytokines with cytotoxic side effects.

Original languageEnglish
Pages (from-to)588-592
Number of pages5
JournalJournal of leukocyte biology
Volume66
Issue number4
Publication statusPublished - 1999
Externally publishedYes

Keywords

  • JAK
  • STAT

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