Abstract
Phosphatidylinositol 4-phosphate 5-kinase (PIP-5kin) regulates actin cytoskeletal reorganization through its product phosphatidylinositol 4,5-bisphosphate. In the present study we demonstrate that PIP-5kin is essential for neurite remodeling, which is regulated by actin cytoskeletal reorganization in neuroblastoma N1E-115 cells. Overexpression of wild-type mouse PIP-5kin-alpha inhibits the neurite formation that is normally stimulated by serum depletion, whereas a lipid kinase-defective mutant of PIP-5kin-alpha, D266A, triggers neurite extension even in the presence of serum and blocks lysophosphatidic acid-induced neurite retraction. These results phenocopy those previously reported for the small GTPase RhoA and its effector p160 Rho-associated coiled coil-forming protein kinase (ROCK). However, the ROCK-specific inhibitor Y-27632 failed to block the inhibition by PIP-5kin-alpha of neurite extension, whereas D266A did block the neurite retraction induced by overexpression of ROCK. These results, taken together, suggest that PIP-5kin-alpha functions as a downstream effector for RhoA/ROCK to couple lysophosphatidic acid signaling to neurite retraction presumably through its product phosphatidylinositol 4,5-bisphosphate.
Highlights
Axon guidance is a critical event in the establishment of neuronal networks during embryogenesis and is regulated by extracellular cues such as chemoattractants and chemorepellents, which are recognized by growth cones at the tips of axons [1, 2]
In the present study we demonstrate that PIP-5kin is essential for neurite remodeling, which is regulated by actin cytoskeletal reorganization in neuroblastoma N1E-115 cells
In mouse neuroblastoma N1E-115 cells, overexpression of a constitutively active mutant of Rho prevents neurite formation [9, 10], and inactivation of endogenous Rho by Clostridium botulinum C3 exoenzyme inhibits the growth cone collapse and neurite retraction induced by lysophosphatidic acid (LPA)1 [9, 10]
Summary
Axon guidance is a critical event in the establishment of neuronal networks during embryogenesis and is regulated by extracellular cues such as chemoattractants and chemorepellents, which are recognized by growth cones at the tips of axons [1, 2]. These results, taken together, suggest that PIP-5kin-␣ functions as a downstream effector for RhoA/ ROCK to couple lysophosphatidic acid signaling to neurite retraction presumably through its product phosphatidylinositol 4,5-bisphosphate.
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