Lim Kinase ans Slingshoot induce neurite growth

Lim Kinase ans Slingshoot induce neurite growth -...

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LIM Kinase and Slingshot Are Critical for Neurite Extension * S Received for publication, November 27, 2006, and in revised form, February 5, 2007 Published, JBC Papers in Press, March 13, 2007, DOI 10.1074/jbc.M610873200 Mitsuharu Endo, Kazumasa Ohashi, and Kensaku Mizuno 1 From the Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan Cofilin and its closely related protein, actin-depolymerizing factor (ADF), are key regulators of actin cytoskeleton dynamics that have been implicated in growth cone motility and neurite extension. Cofilin/ADF are inactivated by LIM kinase (LIMK)- catalyzed phosphorylation and reactivated by Slingshot (SSH)- catalyzed dephosphorylation. Here we examined the roles of cofilin/ADF, LIMKs (LIMK1 and LIMK2), and SSHs (SSH1 and SSH2) in nerve growth factor (NGF)-induced neurite extension. Knockdown of cofilin/ADF by RNA interference almost com- pletely inhibited NGF-induced neurite extension from PC12 cells, and double knockdown of SSH1/SSH2 significantly sup- pressed both NGF-induced cofilin/ADF dephosphorylation and neurite extension from PC12 cells, thus indicating that cofilin/ ADF and their activating phosphatases SSH1/SSH2 are critical for neurite extension. Interestingly, NGF stimulated the activi- ties of both LIMK1 and LIMK2 in PC12 cells, and suppression of LIMK1/LIMK2 expression or activity significantly reduced NGF-induced neurite extension from PC12 cells or chick dorsal root ganglion (DRG) neurons. Inhibition of LIMK1/LIMK2 activityreducedactinfilamentassemblyintheperipheralregion of the growth cone of chick DRG neurons. These results suggest that proper regulation of cofilin/ADF activities through control of phosphorylation by LIMKs and SSHs is critical for neurite extension and that LIMKs regulate actin filament assembly at the tip of the growth cone. The regulation of actin cytoskeleton dynamics plays a funda- mental role in cell shape change, motility, and migration in response to stimuli. In neurons, actin filaments accumulate at the distal tip of the growth cone in the growing neurite, and actin filament dynamics and reorganization are essential for controlling growth cone motility and morphology and deter- mining the direction and speed of neurite extension (1–4). Cofilin and its closely related protein, actin depolymerizing fac- tor (ADF), 2 are key mediators of actin filament dynamics that act by stimulating the depolymerization and severing of actin filaments (5). The activities of cofilin and ADF are inhibited by phosphorylation at Ser-3 by LIM kinases (LIMKs, composed of LIMK1 and LIMK2) (6, 7) and TES kinases (TESKs, composed of TESK1 and TESK2) (8); the inactive Ser-3-phosphorylated cofilin and ADF (P-cofilin/P-ADF) are reactivated by dephos- phorylation by Slingshot (SSH) family protein phosphatases (SSH1, SSH2, and SSH3) (9, 10) and chronophin (a haloacid dehalogenase) (11). Because cofilin/ADF and their upstream
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This note was uploaded on 01/07/2011 for the course BIPN BIPN 144 taught by Professor Bier during the Spring '10 term at UCSD.

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Lim Kinase ans Slingshoot induce neurite growth -...

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