Receptor tyrosine kinases (RTKs) are embedded in the lipid bilayer of the plasma membrane but the specific roles of various lipids in cell signaling remain largely uncharacterized. We previously found that ASM (acid sphingomyelinase) regulates the conserved DAF2/IGF-1R RTK signaling pathway in Caenorhabditis elegans. How ASM and its catalytic product ceramides control RTK signaling pathways remain unclear. Here, we report that ASM regulates the homeostasis of Met, a RTK that is frequently over-expressed in various cancers. Inactivation of ASM led to a rapid disappearance of Met from the plasma membrane, reduced Met phosphorylation/activation, and induced Met accumulation in the trans-Golgi-network (TGN). However, integrin β3 and VSVG are largely unaffected. Ablation of syntaxin STX6 also blocked the Golgi exit of Met. Depletion of either ASM or STX6 led to aberrantly traffic of Met to lysosomes, promoting its degradation. Our studies reveal that ASM and ceramides, together with STX6 and cholesterol, constitute a novel regulatory mechanism for the Golgi exit of Met during its biosynthetic route to rapidly replenish and regulate the plasma membrane levels of Met in various cancer cells.
- Received May 3, 2016.
- Accepted September 30, 2016.
- © 2016. Published by The Company of Biologists Ltd