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SOCS2 Can Enhance Interleukin-2 (IL-2) and IL-3 Signaling by Accelerating SOCS3 Degradation

Gillian M. Tannahill,^1, Joanne Elliott,^1, Anna C. Barry,¹ Linda Hibbert,² Nicolas A. Cacalano,³ and James A. Johnston^1*

Infection and Immunity Group, Centre for Cancer Research and Cell Biology, Queens University, 97 Lisburn Rd., Belfast BT9 7BL, United Kingdom,¹ DNAX Research Institute, 901 California Avenue, Palo Alto, California 94304,² Department of Radiation Oncology, UCLA Center for Health Sciences, Los Angeles, California 90095³

Received 1 March 2005/ Returned for modification 13 April 2005/ Accepted 18 July 2005

Cytokine responses can be regulated by a family of proteins termed suppressors of cytokine signaling (SOCS) which can inhibit the JAK/STAT pathway in a classical negative-feedback manner. While the SOCS are thought to target signaling intermediates for degradation, relatively little is known about how their turnover is regulated. Unlike other SOCS family members, we find that SOCS2 can enhance interleukin-2 (IL-2)- and IL-3-induced STAT phosphorylation following and potentiate proliferation in response to cytokine stimulation. As a clear mechanism for these effects, we demonstrate that expression of SOCS2 results in marked proteasome-dependent reduction of SOCS3 and SOCS1 protein expression. Furthermore, we provide evidence that this degradation is dependent on the presence of an intact SOCS box and that the loss of SOCS3 is enhanced by coexpression of elongin B/C. This suggests that SOCS2 can bind to SOCS3 and elongin B/C to form an E3 ligase complex resulting in the degradation of SOCS3. Therefore, SOCS2 can enhance cytokine responses by accelerating proteasome-dependent turnover of SOCS3, suggesting a mechanism for the gigantism observed in SOCS2 transgenic mice.

G.M.T. and J.E. contributed equally to this work.

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