Abstract
Growth hormone (GH)-inducible suppressors of cytokine signaling (SOCS/CIS proteins) inhibit GH receptor (GHR) signaling to STAT5b via phosphotyrosine-dependent binding interactions with the tyrosine kinase JAK2 (SOCS-1) and/or the cytoplasmic tail of GHR (CIS and SOCS-3). Presently, we investigate the mechanism of CIS inhibition and CIS's role in down-regulating GHR-JAK2 signaling to STAT5b in cells exposed to GH continuously. CIS is shown to inhibit GHR-JAK2 signaling by two distinct mechanisms: by a partial inhibition that is decreased at elevated STAT5b levels and may involve competition between CIS and STAT5b for common GHR cytoplasmic tail phosphotyrosine-binding sites; and by a time-dependent inhibition, not seen with SOCS-1 or SOCS-3, that involves proteasome action. Investigation of the latter mechanism revealed that GH stimulates degradation of CIS, but not SOCS-3. The proteasome inhibitor MG132 blocked this protein degradation and also blocked the inhibitory action of CIS, but not that of SOCS-1 or SOCS-3, on STAT5b signaling. Proteasome-dependent degradation of CIS, most likely in the form of a (GHR-JAK2)-CIS complex, is therefore proposed to be an important step in the time-dependent CIS inhibition mechanism. Finally, the down-regulation of GHR-JAK2 signaling to STAT5b seen in continuous GH-treated cells could be prevented by treatment of cells with the proteasome inhibitor MG132 or by expression of CIS-R107K, a selective, dominant-negative inhibitor of CIS activity. These findings lead us to propose that the cytokine signaling inhibitor CIS is a key mediator of the STAT5b desensitization response seen in cells and tissues exposed to GH chronically, such as adult female rat liver.
Highlights
Growth hormone (GH)-inducible tyrosine phosphorylation reaction catalyzed by the GH receptor (GHR)-associated tyrosine kinase JAK2
Multiple cytokine and growth factor-inducible SOCS/CIS proteins have the potential to inhibit GHR-JAK2 signaling via distinct mechanisms, with SOCS-1 serving as a direct inhibitor of the tyrosine kinase JAK2 [52], and SOCS-3 and CIS exerting their inhibitory action by binding to distinguishable subsets of phosphotyrosine residues in the GHR cytoplasmic domain [32, 38]
We further elucidate the inhibitory actions of the GH-inducible inhibitor CIS, and we identify several key features that distinguish the inhibitory mechanism of CIS from that of SOCS-1 and SOCS-3
Summary
GH-inducible tyrosine phosphorylation reaction catalyzed by the GHR-associated tyrosine kinase JAK2. Liver STAT5b is strongly, and repeatedly, activated in adult male rats in response to each incoming plasma GH pulse [16], while in adult female rats the near continuous presence of GH in plasma leads to substantial down-regulation of GHRJAK2-dependent signaling to STAT5b [17]. This down-regulation of signaling from GHR-JAK2 to STAT5b is readily evident in liver cells exposed to GH continuously, where the downregulation requires protein synthesis [18, 19]. CIS and the Desensitization of STAT5b Signaling in a manner that is dependent on membrane proximal GHR phosphotyrosine residues, in the case of SOCS-3; and inhibition of GHR-JAK2 signaling via membrane-distal GHR phosphotyrosine residues, in the case of CIS and SOCS-2 [32, 38]
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