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The Journal of Neuroscience, April 18, 2007, 27(16):4413-4423; doi:10.1523/JNEUROSCI.0725-07.2007

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Cellular/Molecular
A Calcium- and Calmodulin-Dependent Kinase I/Microtubule Affinity Regulating Kinase 2 Signaling Cascade Mediates Calcium-Dependent Neurite Outgrowth

Nataliya V. Uboha,¹ Marc Flajolet,² Angus C. Nairn,^1,2 and Marina R. Picciotto¹

¹Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508, and ²Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021

Correspondence should be addressed to Marina R. Picciotto, Department of Psychiatry, Yale University School of Medicine, 34 Park Street, third floor research, New Haven, CT 06508. Email: marina.picciotto{at}yale.edu.

Calcium is a critical regulator of neuronal differentiation and neurite outgrowth during development, as well as synaptic plasticity in adulthood. Calcium- and calmodulin-dependent kinase I (CaMKI) can regulate neurite outgrowth; however, the signal transduction cascades that lead to its physiological effects have not yet been elucidated. CaMKI was therefore used as bait in a yeast two-hybrid assay and microtubule affinity regulating kinase 2 (MARK2)/Par-1b was identified as an interacting partner of CaMKI in three independent screens. The interaction between CaMKI and MARK2 was confirmed in vitro and in vivo by coimmunoprecipitation. CaMKI binds MARK2 within its kinase domain, but only if it is activated by calcium and calmodulin. Expression of CaMKI and MARK2 in Neuro-2A (N2a) cells and in primary hippocampal neurons promotes neurite outgrowth, an effect dependent on the catalytic activities of these enzymes. In addition, decreasing MARK2 activity blocks the ability of the calcium ionophore ionomycin to promote neurite outgrowth. Finally, CaMKI phosphorylates MARK2 on novel sites within its kinase domain. Mutation of these phosphorylation sites decreases both MARK2 kinase activity and its ability to promote neurite outgrowth. Interaction of MARK2 with CaMKI results in a novel, calcium-dependent pathway that plays an important role in neuronal differentiation.

Key words: calcium; protein-protein interaction; CaMKI; microtubule affinity regulating kinase 2; calcium and calmodulin-dependent protein kinase I; MARK2

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Received July 14, 2006; accepted March 7, 2007.

Correspondence should be addressed to Marina R. Picciotto, Department of Psychiatry, Yale University School of Medicine, 34 Park Street, third floor research, New Haven, CT 06508. Email: marina.picciotto{at}yale.edu.

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