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Abstract
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 as the SOCS or SSI family) has been implicated in the regulation of signal transduction by a variety of cytokines. Among them, we have shown that JAB/SOCS-1 is strongly induced by inter-feron-γ and forced expression of JAB/SOCS-1 conferred cells interferon resitance. This resistance was caused by inhibition of JAK1 and JAK2 activation in response to IFNγ. Moreover, recent detailed analysis of JABISOCS-1 knockout mice revealed that JABISOCS-1 is indeed a “negative feedback regulator” that determine the sensitivity of cells to IFNγ. Using in vitro mutagensis, we defined a functional structure of JAB/SOCS-1 and proposed a mechanism for how JAB inhibits JAK kinase activity.