title: Acid sphingomyelinase 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 have previously found that acid sphingomyelinase (ASM; also known as SMPD1) regulates the conserved DAF-2 (the ortholog IGF-1R in mammals) RTK signaling pathway in Caenorhabditis elegans How ASM and its catalytic products, ceramides, control RTK signaling pathways remain unclear. Here, we report that ASM regulates the homeostasis of Met, an RTK that is frequently overexpressed in various cancers. Inactivation of ASM led to a rapid loss of Met from the plasma membrane, reduced Met phosphorylation and activation, and induced Met accumulation in the trans-Golgi network (TGN). However, trafficking of integrin β3 and vesicular stomatitis virus glycoprotein (VSVG) was largely unaffected. Knockdown of syntaxin 6 (STX6) also blocked the Golgi exit of Met. Depletion of either ASM or STX6 led to aberrant trafficking of Met to lysosomes, promoting its degradation. Our studies reveal that ASM and ceramides, together with STX6 and cholesterol, constitute a new regulatory mechanism for the exit of Met from the Golgi during its biosynthetic route, which is used to rapidly replenish and regulate the plasma membrane levels of Met in various cancer cells.
authors: School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China.|Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, NV 89135, USA.
authors: Linyu
authors: L
authors: Zhu
authors: Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, NV 89135, USA.
authors: Xiahui
authors: X
authors: Xiong
authors: Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, NV 89135, USA.
authors: Yongsoon
authors: Y
authors: Kim
authors: Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, NV 89135, USA.
authors: Naomi
authors: N
authors: Okada
authors: School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China.
authors: Fei
authors: F
authors: Lu
authors: Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, NV 89135, USA.
authors: Hui
authors: H
authors: Zhang
authors: Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, NV 89135, USA Hong.sun@unlv.edu.
authors: Hong
authors: 0000-0003-2100-1451
authors: H
authors: Sun
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D039661:Integrin beta3 / Q000378:metabolism; D008024:Ligands; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D019000:Phosphotyrosine / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D050765:Qa-SNARE Proteins / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000378:metabolism; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: C028391:G protein, vesicular stomatitis virus; D039661:Integrin beta3; D008024:Ligands; D008562:Membrane Glycoproteins; D050765:Qa-SNARE Proteins; C000612950:STX6 protein, human; D014759:Viral Envelope Proteins; D019000:Phosphotyrosine; D002784:Cholesterol; D019859:Proto-Oncogene Proteins c-met; D017526:Receptor, IGF Type 1; D013108:Sphingomyelin Phosphodiesterase
keywords: ASM; Acid Sphingomyelinase; Ceramide; Golgi; Met; RTK; Receptor tyrosine kinase; SMPD1; STX6; Syntaxin 6