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

SOCS-1 tvas originally identified as an inhibitor of interleukin-6 signal t ransduction and is a member of a family of proteins (SOCS-1 to SOCS-7 and C IS) that contain an SH2 domain and a conserved carboxyl-terminal SOCS box m otif. Mutation studies have established that critical contributions from bo th the amino-terminal and SH2 domains are essential for SOCS-1 and SOCS-3 t o inhibit cytokine signaling. inhibition of cytokine-dependent activation o f STAT3 occurred in cells expressing either SOCS-1 or SOCS-3, but unlike SO CS-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 f or SOCS-1 and SOCS-3 action when overexpressed, this domain interacts with elongin proteins and may be important in regulating protein turnover. In ge ne knockout studies, SOCS-1(-/-) mice were born but failed to thrive and di ed within 3 weeks of age with fatty degeneration of the liver and hemopoiet ic infiltration of several organs. The thymus in SOCS-1(-/-) mice was small , the animals were lymphopenic, and deficiencies in B lymphocytes were evid ent within hemopoietic organs, We propose that the absence of SOCS-1 in the se mice prevents lymphocytes and liver cells from appropriately controlling signals from cytokines with cytotoxic side effects.