Essential role of type I(alpha) phosphatidylinositol 4-phosphate 5-kinase in neurite remodeling.
Rapid neurite remodeling is fundamental to nervous system development and plasticity and is regulated by Rho family GTPases that signal f-actin reorganization in response to various receptor ligands. Neuronal N1E-115 cells show dramatic neurite retraction and cell rounding in response to serum factors such as lysophosphatidic acid (LPA), sphingosine-1 phosphate (S1P), and thrombin, due to activation of the RhoA-Rho kinase pathway. Type I phosphatidylinositol 4-phosphate 5-kinases (PIPkinase), which regulate cellular levels of PtdIns(4,5)P(2), have been suggested as targets of the RhoA-Rho kinase pathway able to modulate cytoskeletal dynamics. Here, we show that the introduction of Type Ialpha PIPkinase into N1E-115 cells leads to cell rounding and complete inhibition of neurite outgrowth, perhaps through the dissociation of vinculin and the destabilization of focal adhesions. This occurs independently of RhoA, Rho kinase, and the activation of actomyosin contraction. Strikingly, expression of kinase-dead PIPkinase promotes the outgrowth of neurites, which fail to retract in response to LPA, S1P, thrombin, or active RhoA. Moreover, neurite retraction in response to an endogenous neuronal guidance cue, Semaphorin3A, was also dependent on Type Ialpha PIPkinase. Our results suggest an essential role for a Type I PIPkinase during neurite retraction in response to a number of diverse stimuli.
van Horck
Francis P G
FP
Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Lavazais
Emmanuelle
E
Eickholt
Britta J
BJ
Moolenaar
Wouter H
WH
Divecha
Nullin
N
D000818:Animals; D048429:Cell Size / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases; D022001:Focal Adhesions / Q000737:chemistry / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016596:Vinculin / Q000378:metabolism; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008246:Lysophospholipids; D051419:Paxillin; D010750:Phosphoproteins; D016596:Vinculin; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D009219:Myosin-Light-Chain Kinase; D020742:rhoA GTP-Binding Protein