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J. Cell Biol. 174 (3): 425-436

Copyright © 2006 by the Rockefeller University Press.

Article

Transport of PIP3 by GAKIN, a kinesin-3 family protein, regulates neuronal cell polarity

Kaori Horiguchi1,2, Toshihiko Hanada1, Yasuhisa Fukui2, , and Athar H. Chishti1

1 Department of Pharmacology and Cancer Center, University of Illinois College of Medicine, Chicago, IL 60612
2 Department of Applied Biological Chemistry, Graduate School of Agriculture and Life Science, University of Tokyo, Tokyo 113-0032, Japan

Correspondence to Athar H. Chishti: chishti{at}uic.edu

Abstract: Phosphatidylinositol-(3,4,5)-trisphosphate (PIP3), a product of phosphatidylinositol 3-kinase, is an important second messenger implicated in signal transduction and membrane transport. In hippocampal neurons, the accumulation of PIP3 at the tip of neurite initiates the axon specification and neuronal polarity formation. We show that guanylate kinase–associated kinesin (GAKIN), a kinesin-like motor protein, directly interacts with a PIP3-interacting protein, PIP3BP, and mediates the transport of PIP3-containing vesicles. Recombinant GAKIN and PIP3BP form a complex on synthetic liposomes containing PIP3 and support the motility of the liposomes along microtubules in vitro. In PC12 cells and cultured hippocampal neurons, transport activity of GAKIN contributes to the accumulation of PIP3 at the tip of neurites. In hippocampal neurons, altered accumulation of PIP3 by overexpression of GAKIN constructs led to the loss of the axonally differentiated neurites. Together, these results suggest that, in neurons, the GAKIN–PIP3BP complex transports PIP3 to the neurite ends and regulates neuronal polarity formation.

Abbreviations used in this paper: DN, dominant-negative; FHA, forkhead-associated; GAKIN, guanylate kinase–associated kinesin; MAGUK, membrane-associated guanylate kinase; PC, phosphatidylcholine; PH, pleckstrin homology; PI, phosphatidylinositol; PI3P, PI-(3)-phosphate; PIP2, PI-(4,5)-bisphosphate; PIP3, PI-(3,4,5)-trisphosphate; Rh-PE, rhodamine-phosphatidylethanolamine; Trx, thioredoxin.

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