MET Suppresses Epithelial VEGFR2 via Intracrine VEGF-induced Endoplasmic Reticulum-associated Degradation

MET Suppresses Epithelial VEGFR2 via Intracrine VEGF-induced Endoplasmic Reticulum-associated Degradation

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...

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Main Authors: Chen, Tom T., Filvaroff, Ellen, Peng, Jing, Marsters, Scot, Jubb, Adrian, Koeppen, Hartmut, Merchant, Mark, Ashkenazi, Avi
Format: Online
Language:English
Published: Elsevier 2015
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486192/
id pubmed-4486192
recordtype oai_dc
spelling pubmed-44861922015-07-01 MET Suppresses Epithelial VEGFR2 via Intracrine VEGF-induced Endoplasmic Reticulum-associated Degradation Chen, Tom T. Filvaroff, Ellen Peng, Jing Marsters, Scot Jubb, Adrian Koeppen, Hartmut Merchant, Mark Ashkenazi, Avi Original Article 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. Elsevier 2015-03-28 /pmc/articles/PMC4486192/ /pubmed/26137585 http://dx.doi.org/10.1016/j.ebiom.2015.03.021 Text en © 2015 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Chen, Tom T.
Filvaroff, Ellen
Peng, Jing
Marsters, Scot
Jubb, Adrian
Koeppen, Hartmut
Merchant, Mark
Ashkenazi, Avi
spellingShingle Chen, Tom T.
Filvaroff, Ellen
Peng, Jing
Marsters, Scot
Jubb, Adrian
Koeppen, Hartmut
Merchant, Mark
Ashkenazi, Avi
MET Suppresses Epithelial VEGFR2 via Intracrine VEGF-induced Endoplasmic Reticulum-associated Degradation
author_facet Chen, Tom T.
Filvaroff, Ellen
Peng, Jing
Marsters, Scot
Jubb, Adrian
Koeppen, Hartmut
Merchant, Mark
Ashkenazi, Avi
author_sort Chen, Tom T.
title MET Suppresses Epithelial VEGFR2 via Intracrine VEGF-induced Endoplasmic Reticulum-associated Degradation
title_short MET Suppresses Epithelial VEGFR2 via Intracrine VEGF-induced Endoplasmic Reticulum-associated Degradation
title_full MET Suppresses Epithelial VEGFR2 via Intracrine VEGF-induced Endoplasmic Reticulum-associated Degradation
title_fullStr MET Suppresses Epithelial VEGFR2 via Intracrine VEGF-induced Endoplasmic Reticulum-associated Degradation
title_full_unstemmed MET Suppresses Epithelial VEGFR2 via Intracrine VEGF-induced Endoplasmic Reticulum-associated Degradation
title_sort met suppresses epithelial vegfr2 via intracrine vegf-induced endoplasmic reticulum-associated degradation
description 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.
publisher Elsevier
publishDate 2015
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486192/
_version_ 1613241945356763136

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