Oncotarget

Research Papers:

Palmitoylation regulates the intracellular trafficking and stability of c-Met

David T. Coleman _, Alana L. Gray, Steven J. Kridel and James A. Cardelli

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Oncotarget. 2016; 7:32664-32677. https://doi.org/10.18632/oncotarget.8706

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Abstract

David T. Coleman1, Alana L. Gray1, Steven J. Kridel2, James A. Cardelli1

1Department of Microbiology and Immunology and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center-Shreveport, LA 71130, USA

2Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 25157, USA

Correspondence to:

David T. Coleman, e-mail: dcole1@lsuhsc.edu

Keywords: c-Met, palmitoylation, intracellular trafficking, cancer, click chemistry

Received: February 16, 2016    Accepted: March 28, 2016    Published: April 12, 2016

ABSTRACT

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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