Unique role of SNT-2/FRS2β/FRS3 docking/adaptor protein for negative regulation in EGF receptor tyrosine kinase signaling pathways
Unique role of SNT-2/FRS2β/FRS3 docking/adaptor protein for negative regulation in EGF receptor tyrosine kinase signaling pathways
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DOI：
10.1038/sj.onc.1209656
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发表时间：
2006-10-19
期刊：
影响因子：
8
通讯作者：
Tsuchida, N.
中科院分区：
文献类型：
--
作者：
Huang, L.;Watanabe, M.;Tsuchida, N.
膜连接的对接蛋白SNT-2/FRS 2b/FRS 3响应成纤维细胞生长因子（FGF）和神经营养因子而变得酪氨酸磷酸化，并作为将多种信号传导蛋白（包括Grb 2和Shp 2）募集至FGF受体或神经营养因子受体的平台。我们以前报道，SNT-2不是酪氨酸磷酸化显着响应表皮生长因子（EGF），但它抑制ERK激活通过EGF刺激形成一个复合物与ERK 2。在本报告中，我们发现SNT-2的表达抑制EGF诱导的细胞转化和增殖，并且SNT-2的表达水平在癌症中下调。在表达SNT-2的细胞中，EGF受体（EGFR）信号转导途径中的主要信号分子（包括EGFR的自磷酸化）的活性减弱，但在表达缺乏ERK 2结合结构域的SNT-2突变体的细胞中则未减弱。此外，SNT-2通过磷酸酪氨酸结合（PTB）结构域与EGFR组成性结合，有和没有EGF刺激。用MEK抑制剂U 0126处理细胞部分恢复了表达SNT-2的细胞中MEK和EGFR的磷酸化水平。在这些发现的基础上，我们提出了一种新的机制，负控制EGFR酪氨酸激酶活性与SNT-2招募ERK 2，这是从ERK的负反馈环的网站，最终导致抑制EGF诱导的细胞转化和增殖。
The membrane-linked docking protein SNT-2/FRS2b/FRS3 becomes tyrosine phosphorylated in response to fibroblast growth factors (FGFs) and neurotrophins and serves as a platform for recruitment of multiple signaling proteins, including Grb2 and Shp2, to FGF receptors or neurotrophin receptors. We previously reported that SNT-2 is not tyrosine phosphorylated significantly in response to epidermal growth factor (EGF) but that it inhibits ERK activation via EGF stimulation by forming a complex with ERK2. In the present report, we show that expression of SNT-2 suppressed EGF-induced cell transformation and proliferation, and expression level of SNT-2 is down-regulated in cancer. The activities of the major signaling molecules in EGF receptor ( EGFR) signal transduction pathways, including autophosphorylation of EGFR, were attenuated in cells expressing SNT-2 but not in cells expressing SNT-2 mutants lacking the ERK2-binding domain. Furthermore, SNT-2 constitutively bound to EGFR through the phosphotyrosine binding (PTB) domain both with and without EGF stimulation. Treatment of cells with MEK inhibitor U0126 partially restored the phosphorylation levels of MEK and EGFR in cells expressing SNT-2. On the basis of these findings, we propose a novel mechanism of negative control of EGFR tyrosine kinase activity with SNT-2 by recruiting ERK2, which is the site of negative-feedback loop from ERK, ultimately leading to inhibition of EGF-induced cell transformation and proliferation.