Ubiquitination and degradation of the hominoid-specific oncoprotein TBC1D3 is mediated by CUL7 E3 ligase.
Ubiquitination and degradation of the hominoid-specific oncoprotein TBC1D3 is mediated by CUL7 E3 ligase.
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DOI：
10.1371/journal.pone.0046485
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Stahl PD
中科院分区：
文献类型：
--
作者：
Kong C;Samovski D;Srikanth P;Wainszelbaum MJ;Charron AJ;Liu J;Lange JJ;Chen PI;Pan ZQ;Su X;Stahl PD
类人猿特异性TBC 1D 3癌蛋白的表达增强生长因子受体信号传导，随后促进细胞增殖和存活。在这里，我们报告说，TBC 1D 3降解响应生长因子信号，这表明TBC 1D 3的表达是由生长因子驱动的负反馈回路。为了更好地了解TBC 1D 3是如何调节的，我们研究了生长因子受体信号传导对TBC 1D 3翻译后加工和周转的影响。使用酵母双杂交筛选，我们确定了CUL 7，支架亚基的CUL 7 E3连接酶复合物，作为TBC 1D 3相互作用蛋白。我们表明，CUL 7 E3连接酶响应血清刺激而遍在化TBC 1D 3。此外，在下拉实验和体外测定中，TBC 1D 3募集F-box 8（Fbw 8），CUL 7 E3连接酶的底物识别结构域。重要的是，TBC 1D 3的碱性磷酸酶处理抑制了其招募Fbw 8的能力，表明TBC 1D 3磷酸化对其泛素化和降解至关重要。我们的结论是，血清和生长因子刺激TBC 1D 3的泛素化和降解的调节与CUL 7-Fbw 8的相互作用。
Expression of the hominoid-specific TBC1D3 oncoprotein enhances growth factor receptor signaling and subsequently promotes cellular proliferation and survival. Here we report that TBC1D3 is degraded in response to growth factor signaling, suggesting that TBC1D3 expression is regulated by a growth factor-driven negative feedback loop. To gain a better understanding of how TBC1D3 is regulated, we studied the effects of growth factor receptor signaling on TBC1D3 post-translational processing and turnover. Using a yeast two-hybrid screen, we identified CUL7, the scaffolding subunit of the CUL7 E3 ligase complex, as a TBC1D3-interacting protein. We show that CUL7 E3 ligase ubiquitinates TBC1D3 in response to serum stimulation. Moreover, TBC1D3 recruits F-box 8 (Fbw8), the substrate recognition domain of CUL7 E3 ligase, in pull-down experiments and in an in vitro assay. Importantly, alkaline phosphatase treatment of TBC1D3 suppresses its ability to recruit Fbw8, indicating that TBC1D3 phosphorylation is critical for its ubiquitination and degradation. We conclude that serum- and growth factor-stimulated TBC1D3 ubiquitination and degradation are regulated by its interaction with CUL7-Fbw8.
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影响因子：
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