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.
Keywords:
AKT; ERAD; HGF; IRE1; MEK; PI3 kinase; VEGF; XBP1.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Proliferation / drug effects
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DNA-Binding Proteins / metabolism
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Endoplasmic Reticulum-Associated Degradation* / drug effects
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Endoribonucleases / metabolism
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism*
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Epithelial Cells / pathology
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Humans
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Intracellular Space / drug effects
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Intracellular Space / metabolism*
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Lysine / metabolism
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Mice
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Models, Biological
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Neoplasms / metabolism
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Neoplasms / pathology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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Protein Binding / drug effects
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Protein Processing, Post-Translational / drug effects
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Protein Serine-Threonine Kinases / metabolism
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Proteolysis / drug effects
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Proto-Oncogene Proteins c-met / metabolism*
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Regulatory Factor X Transcription Factors
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Signal Transduction* / drug effects
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Transcription Factors / metabolism
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Ubiquitination / drug effects
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Up-Regulation / drug effects
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Vascular Endothelial Growth Factor A / pharmacology*
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Vascular Endothelial Growth Factor Receptor-2 / metabolism*
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X-Box Binding Protein 1
Substances
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DNA-Binding Proteins
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Regulatory Factor X Transcription Factors
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Transcription Factors
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Vascular Endothelial Growth Factor A
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X-Box Binding Protein 1
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XBP1 protein, human
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Xbp1 protein, mouse
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Proto-Oncogene Proteins c-met
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Vascular Endothelial Growth Factor Receptor-2
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ERN1 protein, human
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Protein Serine-Threonine Kinases
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Endoribonucleases
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Lysine