title: MET Suppresses Epithelial VEGFR2 via Intracrine VEGF-induced Endoplasmic Reticulum-associated Degradation.
abstract: Hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) drive cancer through their respective receptors, MET and VEGF receptor 2 (VEGFR2). VEGFR2 inhibits MET by promoting MET dephosphorylation. However, whether MET conversely regulates VEGFR2 remains unknown. Here we show that MET suppresses VEGFR2 protein by inducing its endoplasmic-reticulum-associated degradation (ERAD), via intracrine VEGF action. HGF-MET signaling in epithelial cancer cells promoted VEGF biosynthesis through PI3-kinase. In turn, VEGF and VEGFR2 associated within the ER, activating inositol-requiring enzyme 1α, and thereby facilitating ERAD-mediated depletion of VEGFR2. MET disruption upregulated VEGFR2, inducing compensatory tumor growth via VEGFR2 and MEK. However, concurrent disruption of MET and either VEGF or MEK circumvented this, enabling more profound tumor inhibition. Our findings uncover unique cross-regulation between MET and VEGFR2-two RTKs that play significant roles in tumor malignancy. Furthermore, these results suggest rational combinatorial strategies for targeting RTK signaling pathways more effectively, which has potentially important implications for cancer therapy.
authors.affiliation: Cancer Immunology, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Tom T
authors.initials: TT
authors.lastname: Chen
authors.affiliation: Cancer Immunology, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Filvaroff
authors.affiliation: In Vivo Pharmacology, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Peng
authors.affiliation: Cancer Immunology, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Scot
authors.initials: S
authors.lastname: Marsters
authors.affiliation: Research Pathology, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Jubb
authors.affiliation: Research Pathology, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.affiliation: In Vivo Pharmacology, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.affiliation: Cancer Immunology, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D060746:Endoplasmic Reticulum-Associated Degradation / Q000187:drug effects; D004722:Endoribonucleases / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D004722:Endoribonucleases; D008239:Lysine; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D019859:Proto-Oncogene Proteins c-met; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C528229:ERN1 protein, human
keywords: AKT; ERAD; HGF; IRE1; MEK; PI3 kinase; VEGF; XBP1