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Interaction of the Growth Hormone Receptor with Cytokine-Induced Src Homology Domain 2 Protein in Rat Adipocytes

Department of Physiology, University of Massachusetts Medical School (L.D., G.P.F., L.-R.T., H.M.G.), Worcester, Massachusetts 01655; and Medical Institute of Bioregulation, Kyushu University (A.Y.), Fukuoka 812-8582, Japan

Address all correspondence and requests for reprints to: Dr. G. Peter Frick, Department of Physiology, University of Massachusetts Medical School, Worcester, Massachusetts 01655. E-mail: peter.frick{at}umassmed.edu.

GH stimulates the phosphorylation of tyrosine residues in the GH receptor (GHR), Janus kinase 2 (JAK2), and other signaling proteins in a transient manner that subsides within 1 h. To assess the possible roles of cytokine-induced Src homology domain 2 (SH2) (CIS/SOCS) proteins in these transient responses, we studied the expression and disposition of CIS/SOCS proteins in rat adipocytes, a physiological target of GH action. A tyrosine-phosphorylated protein that appears to be the GHR was coprecipitated from extracts of GH-treated adipocytes with -CIS. In contrast, no tyrosine-phosphorylated adipocyte proteins were recovered after immunoprecipitation with -SOCS3, although coprecipitation of GHR with SOCS3 was readily detected in extracts of 3T3-F442A fibroblasts. Interaction of GHR with CIS peaked between 2 and 10 min after adipocytes were treated with GH, when tyrosine phosphorylation of the GHR was maximal. By 60 min after GH, tyrosine phosphorylation of the GHR declined to very low levels, and its interaction with CIS was reduced correspondingly. Proteasome inhibitors prevented the decline in tyrosine-phosphorylated GHR and prolonged interaction of GHR and CIS for at least 1 h. These findings demonstrate the interaction of CIS with the GHR in vivo and suggest that CIS may enhance degradation of the receptor by a proteasomal pathway.

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