Tyrosine phosphorylation disrupts elongin interaction and accelerates SOCS3 degradation
Tyrosine phosphorylation disrupts elongin interaction and accelerates SOCS3 degradation
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DOI：
10.1074/jbc.m303170200
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发表时间：
2003-08-22
影响因子：
4.8
通讯作者：
Cacalano, NA
中科院分区：
文献类型：
--
作者：
Haan, S;Ferguson, P;Cacalano, NA
细胞因子信号转导抑制因子（SOCS）是细胞因子和生长因子诱导的信号转导的负反馈抑制因子。C末端SOCS盒区域被认为最有可能通过延伸蛋白C相互作用来调节SOCS蛋白稳定性。在本研究中，我们发现SOCS 3在保守的SOCS盒中的两个酪氨酸残基Tyr（204）和Tyr（221）处的磷酸化可以抑制SOCS 3-elongin C的相互作用并激活蛋白酶体介导的SOCS 3降解。JAK介导的SOCS 3磷酸化降低了SOCS 3蛋白的半衰期，并且需要Tyr（204）和Tyr（221）的磷酸化来完全使SOCS 3不稳定。相反，SOCS 3的磷酸化缺陷突变体Y204 F、Y221 F在活化的Jak 2和受体酪氨酸激酶存在下保持稳定。SOCS 3稳定性与结合延伸蛋白C的相对量相关，因为SOCS 3-谷胱甘肽S-转移酶融合蛋白的体外磷酸化消除了其与延伸蛋白C相互作用的能力。此外，与显著增加的延伸蛋白C共沉淀的SOCS 3/SOCS 1嵌合体比野生型SOCS 3显著更稳定。这些数据表明，与延伸蛋白C的相互作用稳定了SOCS 3蛋白的表达，SOCS盒酪氨酸残基的磷酸化破坏了复合物并增强了蛋白酶体介导的SOCS 3降解。
The suppressors of cytokine signaling (SOCS) are negative feedback inhibitors of cytokine and growth factor-induced signal transduction. The C-terminal SOCS box region is thought to regulate SOCS protein stability most likely via an elongin C interaction. In the present study, we have found that phosphorylation of SOCS3 at two tyrosine residues in the conserved SOCS box, Tyr(204) and Tyr(221), can inhibit the SOCS3-elongin C interaction and activate proteasome-mediated SOCS3 degradation. Jak-mediated phosphorylation of SOCS3 decreased SOCS3 protein half-life, and phosphorylation of both Tyr(204) and Tyr(221) was required to fully destabilize SOCS3. In contrast, a phosphorylation-deficient mutant of SOCS3, Y204F, Y221F, remained stable in the presence of activated Jak2 and receptor tyrosine kinases. SOCS3 stability correlated with the relative amount that bound elongin C, because in vitro phosphorylation of a SOCS3-glutathione S-transferase fusion protein abolished its ability to interact with elongin C. In addition, a SOCS3/SOCS1 chimera that co-precipitates with markedly increased elongin C, was significantly more stable than wild-type SOCS3. The data suggest that interaction with elongin C stabilizes SOCS3 protein expression and that phosphorylation of SOCS box tyrosine residues disrupts the complex and enhances proteasome-mediated degradation of SOCS3.