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

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.