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J. Biol. Chem., Vol. 280, Issue 10, 9210-9216, March 11, 2005

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Calcium/Calmodulin-dependent Protein Kinase II (CaMKII) Localization Acts in Concert with Substrate Targeting to Create Spatial Restriction for Phosphorylation^*

Jennifer Tsui¶, Masaki Inagaki||, and Howard Schulman¶**

From the Neurosciences Program and the Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California 94304, the ^||Division of Biochemistry, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Aichi 464-8681, Japan, and the ^¶Department of Neurobiology, Stanford University School of Medicine, Stanford, California 94305

Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) acts in diverse cell types by phosphorylating proteins with key calcium-dependent functions such as synaptic plasticity, electrical excitability, and neurotransmitter synthesis. CaMKII displays calcium-dependent binding to proteins in vitro and translocation to synaptic sites after glutamatergic activity in neurons. We therefore hypothesized that subcellular targeting of CaMKII can direct its substrate specificity in an activity-dependent fashion. Here, we examined whether activity-dependent colocalization of CaMKII and its substrates could result in regulation of substrate phosphorylation in cells. We find that substrates localized at cellular membranes required CaMKII translocation to these compartments to achieve effective phosphorylation. Spatial barriers to phosphorylation could be overcome by translocation and anchoring to the substrate itself or to nearby target proteins within the membrane compartment. In contrast, phosphorylation of a cytoplasmic counterpart of the substrate does not require CaMKII translocation or stable protein-protein binding. Cytosolic phosphorylation is more permissive, exhibiting partial calcium-independence. Localization-dependent substrate specificity can also show more graded levels of regulation within signaling microdomains. We find that colocalization of translocated CaMKII and its substrate to lipid rafts in the plasma membrane can modulate the magnitude of phosphorylation. Thus, dynamic regulation of both substrate and kinase localization provides a powerful and nuanced way to regulate CaMKII signal specificity.

Received for publication, July 8, 2004 , and in revised form, November 22, 2004.

^* This work was supported by National Institutes of Health Grants GM30179 and GM40600. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains two supplemental figures showing Western blots.

^** To whom correspondence should be addressed: SurroMed, Inc. 1430 O'Brien Dr., Menlo Park, CA 94025-1432. Tel.: 650-470-2316; Fax: 650-470-2400; E-mail: hschulman{at}surromed.com.

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