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PI4KIIalpha phosphorylation by GSK3 directs vesicular trafficking to lysosomes


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 alpha (PI4KIIalpha) 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 PI4KIIalpha (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 PI4KIIalpha and its cargo proteins for redistribution throughout the cell. Importantly, a reduction in PI4KIIalpha expression or phosphorylation increases alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression at the surface of hippocampal neurons. These studies implicate signalling between GSK3 and PI4KIIalpha as a novel regulator of vesicular trafficking and neurotransmission in the brain.

Type Journal
ISBN 1470-8728 (Electronic) 0264-6021 (Linking)
Authors Robinson, J. W. ; Leshchyns'ka, I. ; Farghaian, H. ; Hughes, W. E. ; Sytnyk, V. ; Neely, G. G. ; Cole, A. R.;
Responsible Garvan Author (missing name)
Published Date 2014-01-01
Published Volume 464
Published Issue 1
Published Pages 145-56
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version