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Overexpression-mediated activation of MET in the Golgi promotes HER3/ERBB3 phosphorylation

Oncogene volume 38, pages 1936–1950 (2019)Cite this article

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Abstract

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.

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Acknowledgements

We thank M. Moasser for insightful discussions and members of the Jura lab for valuable discussions and input on experimental design and execution. This work was supported partially by the grant from the National Institute of General Medical Sciences to N.J. (R01 GM109176), Susan G. Komen Foundation Career Catalyst Research Grant to N.J. (CCR14299947), Lung Cancer Research Foundation Grant to N.J. and the grant from National Institute of Dental and Craniofacial Research to J.G. (R01 DE023685).

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  1. Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, 94158, USA

    Nicole Michael Frazier & Natalia Jura

  2. Department of Otolaryngology – Head and Neck Surgery, University of California, San Francisco, CA, 94113, USA

    Toni Brand & Jennifer Grandis

  3. Division of Hematology and Oncology – University of California, San Francisco, San Francisco, CA, 94158, USA

    John D. Gordan

  4. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, 94158, USA

    Natalia Jura

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Frazier, N.M., Brand, T., Gordan, J.D. et al. Overexpression-mediated activation of MET in the Golgi promotes HER3/ERBB3 phosphorylation. Oncogene 38, 1936–1950 (2019). https://doi.org/10.1038/s41388-018-0537-0

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