Suppressor of Cytokine Signaling 6 (SOCS6) Negatively Regulates Flt3 Signal Transduction through Direct Binding to Phosphorylated Tyrosines 591 and 919 of Flt3
Suppressor of Cytokine Signaling 6 (SOCS6) Negatively Regulates Flt3 Signal Transduction through Direct Binding to Phosphorylated Tyrosines 591 and 919 of Flt3
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DOI：
10.1074/jbc.m112.376111
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发表时间：
2012-10-19
影响因子：
4.8
通讯作者：
Ronnstrand, Lars
中科院分区：
文献类型：
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作者：
Kazi, Julhash U.;Sun, Jianmin;Ronnstrand, Lars
酪氨酸激酶Flt3受体是造血过程中重要的生长因子受体，该受体的功能获得性突变有助于急性髓系白血病的转化。SOCS6 （suppressor of cytokine signaling 6）是E3泛素连接酶SOCS家族的一员，可以调节受体酪氨酸激酶信号转导。在本研究中，我们分析了SOCS6在Flt3信号转导中的作用。结果表明，配体刺激Flt3可诱导SOCS6与Flt3结合，SOCS6酪氨酸磷酸化。磷酸肽分析表明，SOCS6直接与Flt3的磷酸酪氨酸591和919结合。通过稳定转染Flt3和/或SOCS6的Ba/F3细胞，我们发现SOCS6的存在可以增强Flt3的泛素化，以及受体的内化和降解。在转染的Ba/F3和UT-7细胞以及OCI-AML-5细胞中，SOCS6的存在也诱导Erk1/2的活化较弱，但Akt的活化不明显。SOCS6的缺失促进了Flt3致癌内部串联复制诱导的Ba/F3和UT-7细胞增殖。综上所述，这些结果表明SOCS6负调控Flt3激活、下游Erk信号通路和细胞增殖。
The receptor tyrosine kinase Flt3 is an important growth factor receptor in hematopoiesis, and gain-of-function mutations of the receptor contribute to the transformation of acute myeloid leukemia. SOCS6 ( suppressor of cytokine signaling 6) is a member of the SOCS family of E3 ubiquitin ligases that can regulate receptor tyrosine kinase signal transduction. In this study, we analyzed the role of SOCS6 in Flt3 signal transduction. The results show that ligand stimulation of Flt3 can induce association of SOCS6 and Flt3 and tyrosine phosphorylation of SOCS6. Phosphopeptide fishing indicated that SOCS6 binds directly to phosphotyrosines 591 and 919 of Flt3. By using stably transfected Ba/F3 cells with Flt3 and/or SOCS6, we show that the presence of SOCS6 can enhance ubiquitination of Flt3, as well as internalization and degradation of the receptor. The presence of SOCS6 also induces weaker activation of Erk1/2, but not Akt, in transfected Ba/F3 and UT-7 cells and in OCI-AML-5 cells. The absence of SOCS6 promotes Ba/F3 and UT-7 cell proliferation induced by oncogenic internal tandem duplications of Flt3. Taken together, these results suggest that SOCS6 negatively regulates Flt3 activation, the downstream Erk signaling pathway, and cell proliferation.