Journal
JOURNAL OF NEUROSCIENCE
Volume 27, Issue 16, Pages 4413-4423Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0725-07.2007
Keywords
calcium; protein-protein interaction; CaMKI; microtubule affinity regulating kinase 2; calcium and calmodulin-dependent protein kinase I; MARK2
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Funding
- NIAAA NIH HHS [AA15632, P50 AA015632] Funding Source: Medline
- NIDA NIH HHS [DA10455, P01 DA010044, DA10044, R29 DA010455, DA00436, K02 DA000436, R01 DA010455] Funding Source: Medline
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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 alpha 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.
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