HER2 stabilizes EGFR and itself by altering autophosphorylation patterns in a manner that overcomes regulatory mechanisms and promotes proliferative and transformation signaling.
HER2 stabilizes EGFR and itself by altering autophosphorylation patterns in a manner that overcomes regulatory mechanisms and promotes proliferative and transformation signaling.
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DOI：
10.1038/onc.2012.418
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发表时间：
2013-08-29
期刊：
影响因子：
8
通讯作者：
Agazie, Y. M.
中科院分区：
文献类型：
--
作者：
Hartman, Z.;Zhao, H.;Agazie, Y. M.
乳腺癌的原因之一是人表皮生长因子受体2（HER 2）的过度表达。增强的受体自磷酸化和对激活诱导的下调的抗性已被认为是HER 2诱导的持续信号传导和细胞转化的机制。然而，这些可能性背后的分子机制仍不完全清楚。在本报告中，我们提供的证据表明，HER 2过表达不会导致受体过度自磷酸化，但会以有利于受体稳定性和持续信号传导的方式改变模式。具体而言，HER 2过表达阻断EGFR酪氨酸在Y1045和Y1068上的磷酸化，Y1045和Y1068分别是c-Cbl和Grb 2的已知对接位点，同时促进Y1173上的磷酸化，Y1173是Gab衔接蛋白和磷脂酶C γ（PLCγ）的已知对接位点。在这些条件下，HER 2本身在Y1221/1222上磷酸化，没有已知的作用，并且在对应于EGFR的Y1173的Y1248上磷酸化。有趣的是，Grb 2和c-Cbl结合位点上抑制的EGFR自磷酸化与受体稳定性和持续信号传导相关，表明HER 2通过改变自磷酸化模式来完成这些任务。与这些发现一致，EGFR（Y1068 F-EGFR）上Grb 2结合位点的突变赋予对配体诱导的降解的抗性，这反过来诱导持续的信号传导，并增加细胞增殖和转化。这些发现表明EGFR上的Grb 2结合位点对于信号传导是多余的，但对于受体调节是关键的。另一方面，HER 2中推定的Grb 2结合位点（Y1139）的突变不影响稳定性、信号传导或转化，表明HER 2中的Y1139可能不作为Grb 2结合位点。与EGFR在HER 2信号传导中的作用一致，EGFR表达的抑制减少了HER 2诱导的锚定非依赖性生长和肿瘤发生。这些结果表明，补充HER 2靶向治疗与抗EGFR药物可能是有益的HER 2阳性乳腺癌。
One of the causes of breast cancer is overexpression of the human epidermal growth factor receptor 2 (HER2). Enhanced receptor autophosphorylation and resistance to activation-induced down regulation have been suggested as mechanisms for HER2-induced sustained signaling and cell transformation. However, the molecular mechanisms underlying these possibilities remain incompletely understood. In the current report, we present evidence that show that HER2 overexpression does not lead to receptor hyper-autophosphorylation, but alters patterns in a manner that favors receptor stability and sustained signaling. Specifically, HER2 overexpression blocks EGFR tyrosine phosphorylation on Y1045 and Y1068, the known docking sites of c-Cbl and Grb2, respectively, while promoting phosphorylation on Y1173, the known docking site of the Gab adaptor proteins and phospholipase C gamma (PLCγ). Under these conditions, HER2 itself is phosphorylated on Y1221/1222, with no known role, and on Y1248 that corresponds to Y1173 of EGFR. Interestingly, suppressed EGFR autophosphorylation on the Grb2 and c-Cbl binding sites correlated with receptor stability and sustained signaling, suggesting that HER2 accomplishes these tasks by altering autophosphorylation patterns. In conformity with these findings, mutation of the Grb2 binding site on EGFR (Y1068F-EGFR) conferred resistance to ligand-induced degradation which in turn induced sustained signaling, and increased cell proliferation and transformation. These findings suggest that the Grb2 binding site on EGFR is redundant for signaling, but critical for receptor regulation. On the other hand, mutation of the putative Grb2 binding site in HER2 (Y1139) did not affect stability, signaling or transformation, suggesting that Y1139 in HER2 may not serve as a Grb2 binding site. In agreement with the role of EGFR in HER2 signaling, inhibition of EGFR expression reduced HER2-induced anchorage-independent growth and tumorigenesis. These results imply that complementing HER2-targeted therapies with anti-EGFR drugs may be beneficial in HER2-positive breast cancer.
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