title: Extracellular Signals Induce Glycoprotein M6a Clustering of Lipid Rafts and Associated Signaling Molecules.
abstract: Lipid raft domains, where sphingolipids and cholesterol are enriched, concentrate signaling molecules. To examine how signaling protein complexes are clustered in rafts, we focused on the functions of glycoprotein M6a (GPM6a), which is expressed at a high concentration in developing mouse neurons. Using imaging of lipid rafts, we found that GPM6a congregated in rafts in a GPM6a palmitoylation-dependent manner, thereby contributing to lipid raft clustering. In addition, we found that signaling proteins downstream of GPM6a, such as Rufy3, Rap2, and Tiam2/STEF, accumulated in lipid rafts in a GPM6a-dependent manner and were essential for laminin-dependent polarity during neurite formation in neuronal development.In uteroRNAi targeting of GPM6a resulted in abnormally polarized neurons with multiple neurites. These results demonstrate that GPM6a induces the clustering of lipid rafts, which supports the raft aggregation of its associated downstream molecules for acceleration of neuronal polarity determination. Therefore, GPM6a acts as a signal transducer that responds to extracellular signals.SIGNIFICANCE STATEMENTLipid raft domains, where sphingolipids and cholesterol are enriched, concentrate signaling molecules. We focused on glycoprotein M6a (GPM6a), which is expressed at a high concentration in developing neurons. Using imaging of lipid rafts, we found that GPM6a congregated in rafts in a palmitoylation-dependent manner, thereby contributing to lipid raft clustering. In addition, we found that signaling proteins downstream of GPM6a accumulated in lipid rafts in a GPM6a-dependent manner and were essential for laminin-dependent polarity during neurite formation.In uteroRNAi targeting of GPM6a resulted in abnormally polarized neurons with multiple neurites. These results demonstrate that GPM6a induces the clustering of lipid rafts, which supports the raft aggregation of its associated downstream molecules for acceleration of polarity determination. Therefore, GPM6a acts as a signal transducer that responds to extracellular signals.
authors.affiliation: Department of Neurochemistry and Molecular Cell Biology, Graduate School of Medical and Dental Sciences, and.|Transdiciplinary Research Programs, Niigata University, Niigata 951-8510, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Honda
authors.affiliation: Department of Neurochemistry and Molecular Cell Biology, Graduate School of Medical and Dental Sciences, and.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Neurochemistry and Molecular Cell Biology, Graduate School of Medical and Dental Sciences, and.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Takahashi-Niki
authors.affiliation: Department of Medical Biology, Aichi Medical University, Nagakute, Aichi 480-1195, Japan, and.
authors.forename: Natsuki
authors.initials: N
authors.lastname: Matsushita
authors.affiliation: Department of Neurochemistry and Molecular Cell Biology, Graduate School of Medical and Dental Sciences, and.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Nozumi
authors.affiliation: Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, Aichi 480-0392, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Tabata
authors.affiliation: Department of Neurochemistry and Molecular Cell Biology, Graduate School of Medical and Dental Sciences, and.|Department of Medical Biology, Aichi Medical University, Nagakute, Aichi 480-1195, Japan, and.
authors.forename: Kosei
authors.initials: K
authors.lastname: Takeuchi
authors.affiliation: Department of Neurochemistry and Molecular Cell Biology, Graduate School of Medical and Dental Sciences, and tarokaja@med.niigata-u.ac.jp.|Transdiciplinary Research Programs, Niigata University, Niigata 951-8510, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Igarashi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D016000:Cluster Analysis; D045604:Extracellular Fluid / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D021962:Membrane Microdomains / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D011247:Pregnancy; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C083480:Gpm6a protein, mouse; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins
keywords: GPM6a; cholesterol; growth cone; lipid rafts; palmitoylation; polarity