Palmitoylation regulates the intracellular trafficking and stability of c-Met
PDF | HTML | Supplementary Files | How to cite
Metrics: PDF 1607 views | HTML 2817 views | ?
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
David T. Coleman, e-mail: [email protected]
Keywords: c-Met, palmitoylation, intracellular trafficking, cancer, click chemistry
Received: February 16, 2016 Accepted: March 28, 2016 Published: April 12, 2016
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.