Negative regulation of cytokine signaling pathways

Hideo Yasukawa, Atsuo Sasaki, Akihiko Yoshimura

Research output: Contribution to journalReview articlepeer-review

519 Citations (Scopus)


The Janus family of protein tyrosine kinases (JAKs) and STAT transcription factors regulate cellular processes involved in cell growth, differentiation, and transformation through their association with cytokine receptors. The CIS family of proteins (also referred to as the SOCS or SSI family) has been implicated in the regulation of signal transduction by a variety of cytokines. Most of them appear to be induced after stimulation with several different cytokines, and at least three of them (CIS 1, CIS3/SOCS3, and JAB/SOCS 1) negatively regulate cytokine signal transduction by various means: CIS 1 inhibits STAT5 activation by binding to cytokine receptors that recruit STAT5, whereas JAB/SOCS-1 and CIS3/SOCS-3 directly bind to the kinase domain of JAKs, thereby inhibiting tyrosine-kinase activity. Therefore, these CIS family members seem to function in a classical negative feedback loop of cytokine signaling. Biochemical characterization as well as gene disruption studies indicate that JAB/SOCS-1/SSI-1 is an important negative regulator of interferon γ signaling. The mechanisms by which these inhibitors of cytokine signal transduction exert their effects have been extensively studied and will provide useful information for regulating tyrosine-kinase activity.

Original languageEnglish
Pages (from-to)143-164
Number of pages22
JournalAnnual Review of Immunology
Publication statusPublished - 2000
Externally publishedYes


  • CIS
  • Interferon gamma
  • JAB
  • JAK
  • Negative regulation
  • SH2 domain
  • SOCS
  • SSI
  • STAT
  • Tyrosine kinase

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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