Moving PIP 3 on Microtubules

Phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ), the product of phosphatidylinositol 3-kinase (PI3K), contributes to the establishment of cell polarity. Horiguchi et al. provide evidence that PIP 3 not only is produced by local activation of PI3K at the plasma membrane but also may be produced at internal membranes and transported by PIP 3 -containing vesicles on microtubules to the growing tips of neuronal projections. First, they determined that GAKIN (guanylate kinase-associated kinesin, also known as KIF13B) interacted with PIP 3 binding protein (PIP 3 BP, also known as centaurin-α) through the GAKIN FHA domain. In vitro GAKIN and PIP 3 BP mediated the movement of PIP 3 liposomes on microtubules. In PC12 (pheochromocytoma 12) cells and culture hippocampal neurons, tagged GAKIN, tagged PIP 3 BP, and a marker for PIP3 were colocalized at the tips of neurites; in hippocampal cells, these three molecules were most abundant in the longest neurite, the axon. Overexpression of a dominant-negative form of GAKIN (with the motor domain deleted) in PC12 cells decreased the abundance of PIP 3 at neurite tips. In hippocampal neurons, overexpression of wild-type GAKIN or dominant-negative GAKIN disrupted the formation of morphologically distinct axon-dendrite structure and produced cells with multiple, highly branched neurites. The authors suggest that PIP 3 produced at internal membranes, for example at internalized receptors, or PIP 3 produced at the cell body may contribute to cell polarity through transport along microtubules to the growth cone. K. Horiguchi, T. Hanada, Y. Fukui, A. H. Chishti, Transport of PIP 3 by GAKIN, a kinesin-3 family protein, regulates neuronal cell polarity. J. Cell Biol. 174 , 425-436 (2006). [Abstract] [Full Text]