Transport of PIP(3) by GAKIN, a kinesin-3 family protein, regulates neuronal cell polarity

Phosphatidylinositol-(3,4,5)-trisphosphate (PIP(3)), a product of phosphatidylinositol 3-kinase, is an important second messenger implicated in signal transduction and membrane transport. In hippocampal neurons, the accumulation of PIP(3) 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 PIP(3)-interacting protein, PIP(3)BP, and mediates the transport of PIP(3)-containing vesicles. Recombinant GAKIN and PIP(3)BP form a complex on synthetic liposomes containing PIP(3) 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 PIP(3) at the tip of neurites. In hippocampal neurons, altered accumulation of PIP(3) by overexpression of GAKIN constructs led to the loss of the axonally differentiated neurites. Together, these results suggest that, in neurons, the GAKIN–PIP(3)BP complex transports PIP(3) to the neurite ends and regulates neuronal polarity formation.