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MET Suppresses Epithelial VEGFR2 via Intracrine VEGF-induced Endoplasmic
Reticulum-associated Degradation
#MMPMID26137585
Chen TT
; Filvaroff E
; Peng J
; Marsters S
; Jubb A
; Koeppen H
; Merchant M
; Ashkenazi A
EBioMedicine
2015[May]; 2
(5
): 406-20
PMID26137585
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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 1?, 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.
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