title: PI4KIIα phosphorylation by GSK3 directs vesicular trafficking to lysosomes.
abstract: Glycogen synthase kinase 3 (GSK3) is essential for normal development and function of the central nervous system. It is especially important for regulating neurotransmission, although the downstream substrates mediating this function are not yet clear. In the present paper, we report the lipid kinase phosphatidylinositol 4-kinase II α (PI4KIIα) is a novel substrate of GSK3 that regulates trafficking and cell-surface expression of neurotransmitter receptors in neurons. GSK3 phosphorylates two distinct sites in the N-terminus of PI4KIIα (Ser5 and Ser47), promoting binding to the adaptor protein 3 (AP-3) complex for trafficking to the lysosome to be degraded. Blocking phosphorylation reduces trafficking to the lysosome, stabilizing PI4KIIα and its cargo proteins for redistribution throughout the cell. Importantly, a reduction in PI4KIIα expression or phosphorylation increases α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression at the surface of hippocampal neurons. These studies implicate signalling between GSK3 and PI4KIIα as a novel regulator of vesicular trafficking and neurotransmission in the brain.
authors.affiliation: *Neurosignalling and Mood Disorders Group, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
authors.forename: James W
authors.initials: JW
authors.lastname: Robinson
authors.affiliation: †School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Iryna
authors.initials: I
authors.lastname: Leshchyns'ka
authors.affiliation: *Neurosignalling and Mood Disorders Group, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
authors.forename: Hovik
authors.initials: H
authors.lastname: Farghaian
authors.affiliation: ‡Diabetes and Obesity Group, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
authors.forename: William E
authors.initials: WE
authors.lastname: Hughes
authors.affiliation: †School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Sytnyk
authors.affiliation: §Functional Genomics Research Group, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Neely
authors.affiliation: *Neurosignalling and Mood Disorders Group, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Cole
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D010766:Phosphorylation / Q000502:physiology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D022161:Transport Vesicles / Q000201:enzymology*
chemical_list: D015778:Minor Histocompatibility Antigens; D017853:Phosphotransferases (Alcohol Group Acceptor); C402182:phosphatidylinositol phosphate 4-kinase; D038362:Glycogen Synthase Kinase 3