The hominoid-specific oncogene TBC1D3 activates ras and modulates epidermal growth factor receptor signaling and trafficking
The hominoid-specific oncogene TBC1D3 activates ras and modulates epidermal growth factor receptor signaling and trafficking
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DOI：
10.1074/jbc.m800234200
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发表时间：
2008-05-09
影响因子：
4.8
通讯作者：
Stahl, Philip D.
中科院分区：
文献类型：
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作者：
Wainszelbaum, Marisa J.;Charron, Audra J.;Stahl, Philip D.
类人猿和人类特有的基因可能已经进化到可以调节复杂程度更高的信号通路。TBC1D3是一种在17号染色体上由8个类似物编码的类人猿特异性癌基因。初步研究表明，TBC1D3在人体组织中广泛表达（Hodzic， D, Kong， C, Wainszelbaum， M. J, Charron， A. J, Su， X, and Stahl， P. D. (2006) Genomics 88, 731-736）。在这项研究中，我们发现TBC1D3表达对细胞增殖具有强大的影响，并且在人和小鼠细胞系中，表皮生长因子（EGF）进一步增强了这种影响。通过表达TBC1D3， EGF对Erk和蛋白激酶B/Akt通路的激活在幅度和持续时间上都得到增强，而RNA干扰沉默TBC1D3则抑制其激活。光镜和Western blot实验表明，响应EGF的信号传导增加与EGF受体（EGFR）运输和降解的显著延迟相结合，这显著延长了EGFR的寿命。此外，TBC1D3抑制EGFR的多泛素化和c-Cbl的募集。利用Raf1的Ras结合域来监测GTP-Ras，我们发现TBC1D3表达增强了静止细胞中Ras的激活，EGF处理进一步增加了Ras的激活。我们推测TBC1D3可能会改变Ras GTP的负荷。我们得出的结论是，TBC1D3的表达会延迟EGFR降解，降低泛素化，并且无法招募最终失调EGFR信号转导并增强细胞增殖的适配蛋白。生长因子受体转运和GTP-Ras转换的改变可能是最近进化的基因（如TBC1D3）选择性调节类人猿和人类信号传导的位点。
Hominoid- and human-specific genes may have evolved to modulate signaling pathways of a higher order of complexity. TBC1D3 is a hominoid-specific oncogene encoded by a cluster of eight paralogs on chromosome 17. Initial work indicates that TBC1D3 is widely expressed in human tissues (Hodzic, D., Kong, C., Wainszelbaum, M. J., Charron, A. J., Su, X., and Stahl, P. D. ( 2006) Genomics 88, 731-736). In this study, we show that TBC1D3 expression has a powerful effect on cell proliferation that is further enhanced by epidermal growth factor (EGF) in both human and mouse cell lines. EGF activation of the Erk and protein kinase B/Akt pathways is enhanced, both in amplitude and duration, by TBC1D3 expression, whereas RNA interference silencing of TBC1D3 suppresses the activation. Light microscopy and Western blot experiments demonstrate that increased signaling in response to EGF is coupled with a significant delay in EGF receptor (EGFR) trafficking and degradation, which significantly extends the life span of EGFR. Moreover, TBC1D3 suppresses polyubiquitination of the EGFR and the recruitment of c-Cbl. Using the Ras binding domain of Raf1 to monitor GTP-Ras we show that TBC1D3 expression enhances Ras activation in quiescent cells, which is further increased by EGF treatment. We speculate that TBC1D3 may alter Ras GTP loading. We conclude that the expression of TBC1D3 generates a delay in EGFR degradation, a decrease in ubiquitination, and a failure to recruit adapter proteins that ultimately dysregulate EGFR signal transduction and enhance cell proliferation. Altered growth factor receptor trafficking and GTP-Ras turnover may be sites where recently evolved genes such as TBC1D3 selectively modulate signaling in hominoids and humans.