RT Journal Article
SR Electronic
T1 A Calcium- and Calmodulin-Dependent Kinase Iα/Microtubule Affinity Regulating Kinase 2 Signaling Cascade Mediates Calcium-Dependent Neurite Outgrowth
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 4413
OP 4423
DO 10.1523/JNEUROSCI.0725-07.2007
VO 27
IS 16
A1 Nataliya V. Uboha
A1 Marc Flajolet
A1 Angus C. Nairn
A1 Marina R. Picciotto
YR 2007
UL http://www.jneurosci.org/content/27/16/4413.abstract
AB 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. CaMKIα 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.