Palmitoylation regulates the intracellular trafficking and stability of c-Met

• 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
• Format: Article
• Language: English
• 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
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.8706

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.