Acid sphingomyelinase/ASM is required for cell surface presentation of Met receptor tyrosine kinase in cancer cells
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 01, 2016
- Source ID
- 10.1242/jcs.191684
Entities
People
- Hong Sun
- Hui Zhang
- Linyu Zhu
- Lu Fei
- Naomi Okada
- Xiahui Xiong
- Yongsoon Kim
Organizations
- Foundation for the National Institutes of Health
- National Natural Science Foundation of China
- Peking University
- United States Department of Defense
- University of Nevada, Reno