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The Journal of Neuroscience, October 13, 2004, 24(41):8994-9004; doi:10.1523/JNEUROSCI.3184-04.2004

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Cellular/Molecular
2-Chimaerin, Cyclin-Dependent Kinase 5/p35, and Its Target Collapsin Response Mediator Protein-2 Are Essential Components in Semaphorin 3A-Induced Growth-Cone Collapse

Matthew Brown,^1 * Tom Jacobs,^1 * Britta Eickholt,³ Giovanna Ferrari,^1,2 Mabel Teo,^1,2 Clinton Monfries,^1,2 Robert Z. Qi,⁴ Thomas Leung,² Louis Lim,^1,2 and Christine Hall¹

¹Department of Molecular Neuroscience, Institute of Neurology, University College London, London WC1N 1PJ, United Kingdom, ²GSK-IMCB Group, Institute of Molecular and Cell Biology, Proteos, Singapore 138673, ³Medical Research Council Center for Developmental Neurobiology, Kings College London, New Hunt's House, Guy's Hospital Campus, London SE1 1UL, United Kingdom, and ⁴Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong

Neurite outgrowth is influenced by positive and negative signals that include the semaphorins, an important family of axonal outgrowth inhibitors. Here we report that the Rac GTPase activating protein (GAP)2-chimaerin is involved in Semaphorin 3A (Sema 3A) signaling. In dorsal root ganglion neurons, Sema 3A-induced growth cone collapse was inhibited by 2-chimaerin mutated to eliminate GAP activity or interaction with phosphotyrosine. Activation of 2-chimaerin by phorbol ester caused growth cone collapse. Active 2-chimaerin interacts with collapsin response mediator protein-2 (CRMP-2) and cyclin-dependent kinase (Cdk) 5/p35 kinase through its SH2 and GAP domains, respectively. Cdk5 phosphorylates CRMP-2 at serine 522, possibly facilitating phosphorylation of serine 518 and threonine 514 by glycogen synthase kinase 3 (GSK3), a kinase previously implicated in Sema 3A signaling. Phosphorylation of CRMP-2 serine 522 was essential for Sema 3A-induced growth cone collapse, which is dependent on Cdk5 but not Rho kinase activity. 2-chimaerin, like CRMP-2, can associate with the Sema 3A receptor. These results indicate that active 2-chimaerin Rac GAP, Cdk5/p35, and its substrate CRMP-2, are implicated in the dynamics of growth cone guidance initiated through Sema 3A signaling.

Key words: Sema 3A; RacGTPase; CRMP-2; 2-chimaerin; Cdk5/p35; growth cone collapse

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Received Feb 3, 2004; accepted August 24, 2004.

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