Overexpression-mediated activation of MET in the Golgi promotes HER3/ERBB3 phosphorylation.
Overexpression-mediated activation of MET in the Golgi promotes HER3/ERBB3 phosphorylation.
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DOI：
10.1038/s41388-018-0537-0
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发表时间：
2019-03
期刊：
影响因子：
8
通讯作者：
Jura N
中科院分区：
文献类型：
--
作者：
Frazier NM;Brand T;Gordan JD;Grandis J;Jura N
受体酪氨酸激酶（RTK）的配体依赖性寡聚化通过细胞外和细胞内受体结构域的高度特异性构象变化导致其活化。这些构象变化对于每个RTK亚家族是独特的，限制了不相关RTK之间的交叉激活。原癌基因MET受体酪氨酸激酶克服了这些结构限制，并使许多癌细胞系中不相关的RTK磷酸化。这些相互作用的分子基础尚不清楚。我们研究了MET磷酸化人表皮生长因子受体-3（HER 3或ERBB 3）的机制，这是一种催化受损的RTK，MET的磷酸化作用被描述为对靶向EGFR和HER 2的抑制剂耐药性的重要组成部分。我们发现，在未转化的细胞中，HER 3不会被MET磷酸化以响应配体刺激，而是增加MET表达水平，这导致MET以配体非依赖性方式活化。通过其典型的二聚化配偶体EGFR和HER 2对HER 3的磷酸化是通过接合HER 3激酶结构域上的变构位点来实现的，但是当HER 3被MET磷酸化时，该位点不是必需的。我们还观察到HER 3在MET成熟期间沿着分泌途径优先与MET相互作用，然后MET通过其细胞外结构域内的切割进行翻译后加工。这导致磷酸化的HER 3在高尔基体中积累。我们进一步表明，除了HER 3，MET磷酸化高尔基体中的其他RTK，这表明这种机制不仅限于HER 3磷酸化。这些数据表明MET过表达和其在高尔基体内膜中的异常激活之间的联系，并表明MET和不相关的RTK之间的非典型相互作用发生在受体成熟期间。我们的研究突出了癌症中MET信号传导的一个新方面，这是治疗性抗体无法抑制的。
Ligand-dependent oligomerization of receptor tyrosine kinases (RTKs) results in their activation through highly specific conformational changes in the extracellular and intracellular receptor domains. These conformational changes are unique for each RTK sub-family, limiting cross-activation between unrelated RTKs. The proto-oncogene MET receptor tyrosine kinase overcomes these structural constraints and phosphorylates unrelated RTKs in numerous cancer cell lines. The molecular basis for these interactions is unknown. We investigated the mechanism by which MET phosphorylates the human epidermal growth factor receptor-3 (HER3 or ERBB3), a catalytically impaired RTK whose phosphorylation by MET has been described as an essential component of drug resistance to inhibitors targeting EGFR and HER2. We find that in untransformed cells, HER3 is not phosphorylated by MET in response to ligand stimulation, but rather to increasing levels of MET expression, which results in MET activation in a ligand-independent manner. Phosphorylation of HER3 by its canonical dimerization partners, EGFR and HER2, is achieved by engaging an allosteric site on the HER3 kinase domain, but this site is not required when HER3 is phosphorylated by MET. We also observe that HER3 preferentially interacts with MET during its maturation along the secretory pathway, before MET is post-translationally processed by cleavage within its extracellular domain. This results in accumulation of phosphorylated HER3 in the Golgi apparatus. We further show that in addition to HER3, MET phosphorylates other RTKs in the Golgi, suggesting that this mechanism is not limited to HER3 phosphorylation. These data demonstrate a link between MET overexpression and its aberrant activation in the Golgi endomembranes and suggest that non-canonical interactions between MET and unrelated RTKs occur during maturation of receptors. Our study highlights a novel aspect of MET signaling in cancer that would not be accessible to inhibition by therapeutic antibodies.
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影响因子：
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作者：
Casadevall, David;Gimeno, Javier;Arriola, Edurne
通讯作者：
Arriola, Edurne
影响因子：
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作者：
Coleman DT;Gray AL;Kridel SJ;Cardelli JA
通讯作者：
Cardelli JA
影响因子：
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作者：
Garrett, TPJ;McKern, NM;Ward, CW
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Ward, CW
影响因子：
56.9
作者：
BOTTARO, DP;RUBIN, JS;AARONSON, SA
通讯作者：
AARONSON, SA
影响因子：
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作者：
Dimou A;Non L;Chae YK;Tester WJ;Syrigos KN
通讯作者：
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