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Palmitoylation regulates the intracellular trafficking and stability of c-Met

c-Met is a receptor tyrosine kinase whose activity can promote both mitogenic and motogenic phenotypes involved in tissue development and cancer progression. Herein, we report the first evidence that c-Met is palmitoylated and that palmitoylation facilitates its trafficking and stability. Inhibition...

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Published in:Oncotarget 2016-05, Vol.7 (22), p.32664-32677
Main Authors: Coleman, David T, Gray, Alana L, Kridel, Steven J, Cardelli, James A
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Language:English
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creator Coleman, David T
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Cardelli, James A
description c-Met is a receptor tyrosine kinase whose activity can promote both mitogenic and motogenic phenotypes involved in tissue development and cancer progression. Herein, we report the first evidence that c-Met is palmitoylated and that palmitoylation facilitates its trafficking and stability. Inhibition of palmitoylation reduced the expression of c-Met in multiple cancer cell lines post-transcriptionally. Using surface biotinylation, confocal microscopy, and metabolic labeling we determined that inhibition of palmitoylation reduces the stability of newly synthesized c-Met and causes accumulation at the Golgi. Acyl-biotin exchange and click chemistry-based palmitate labeling indicated the c-Met β-chain is palmitoylated, and site-directed mutagenesis revealed two likely cysteine palmitoylation sites. Moreover, by monitoring palmitoylation kinetics during the biosynthesis and trafficking of c-Met, we revealed that stable palmitoylation occurs in the endoplasmic reticulum prior to cleavage of the 170 kDa c-Met precursor to the mature 140 kDa form. Our data suggest palmitoylation is required for egress from the Golgi for transport to the plasma membrane. These findings introduce palmitoylation as a critical modification of c-Met, providing a novel therapeutic target for c-Met-driven cancers.
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subjects Cell Line, Tumor
Endoplasmic Reticulum - metabolism
Golgi Apparatus - metabolism
Humans
Lipoylation
Protein Transport
Proto-Oncogene Proteins c-met - metabolism
Research Paper
Secretory Pathway
Signal Transduction
title Palmitoylation regulates the intracellular trafficking and stability of c-Met
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