Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, 94158, USA.
Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco, CA, 94113, USA.
Oncogene. 2019 Mar;38(11):1936-1950. doi: 10.1038/s41388-018-0537-0. Epub 2018 Nov 2.
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 subfamily, 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 ligand-independent MET activation. Phosphorylation of HER3 by its canonical co-receptors, 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 other 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.
受体酪氨酸激酶 (RTKs) 的配体依赖性寡聚化导致其通过细胞外和细胞内受体结构域的高度特异性构象变化而被激活。这些构象变化对于每个 RTK 亚家族都是独特的，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，并在许多癌细胞系中磷酸化不相关的 RTK。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（HER3 或 ERBB3）的机制，HER3 是一种催化失活的 RTK，其磷酸化被描述为对针对 EGFR 和 HER2 的抑制剂的耐药性的重要组成部分。我们发现，在未转化的细胞中，HER3 不会在配体刺激下被 MET 磷酸化，而是在 MET 表达水平增加的情况下被磷酸化，这导致配体非依赖性 MET 激活。其典型共受体 EGFR 和 HER2 对 HER3 的磷酸化是通过结合 HER3 激酶结构域的变构位点来实现的，但当 HER3 被 MET 磷酸化时，该位点不需要。我们还观察到，在 MET 通过其细胞外结构域的切割进行翻译后加工之前，HER3 在沿着分泌途径成熟的过程中优先与 MET 相互作用。这导致磷酸化的 HER3 在高尔基器中积累。我们进一步表明，除了 HER3 之外，MET 还磷酸化高尔基体中的其他 RTK，这表明这种机制不限于 HER3 磷酸化。这些数据表明，MET 过表达与其在高尔基内质网膜中的异常激活之间存在联系，并表明 MET 和其他 RTK 之间的非典型相互作用发生在受体成熟过程中。我们的研究强调了 MET 信号在癌症中的一个新方面，这是治疗性抗体无法抑制的。
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