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J. Biol. Chem., Vol. 279, Issue 30, 31708-31716, July 23, 2004

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Regulation and Function of the Calcium/Calmodulin-dependent Protein Kinase IV/Protein Serine/Threonine Phosphatase 2A Signaling Complex^*

Kristin A. Anderson, Pamela K. Noeldner, Kelie Reece, Brian E. Wadzinski, and Anthony R. Means¶

From the Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710 and the Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6600

Calcium/calmodulin-dependent protein kinase IV (CaMKIV) is a member of the broad substrate specificity class of Ca²⁺/calmodulin (CaM)-dependent protein kinases and functions as a potent stimulator of Ca²⁺-dependent gene expression. Activation of CaMKIV is a transient, tightly regulated event requiring both Ca²⁺/CaM binding and phosphorylation of the kinase on T200 by an upstream CaMK kinase (CaMKK). Previously, CaMKIV was shown to stably associate with protein serine/threonine phosphatase 2A (PP2A), which was proposed to play a role in negatively regulating the kinase. Here we report that the Ca²⁺/CaM binding-autoinhibitory domain of CaMKIV is required for association of the kinase with PP2A and that binding of PP2A and Ca²⁺/CaM appears to be mutually exclusive. We demonstrate that inhibition of the CaMKIV/PP2A association in cells results in enhanced CaMKIV-mediated gene transcription that is independent of Ca²⁺/CaM. The enhanced transcriptional activity correlates with the elevated level of phospho-T200 that accumulates when CaMKIV is prevented from interacting with PP2A. Collectively, these data suggest a molecular basis for the sequential activation and inactivation of CaMKIV. First, in response to an increase in intracellular Ca²⁺, CaMKIV binds Ca²⁺/CaM and becomes phosphorylated on T200 by CaMKK. These events result in the generation of autonomous activity required for CaMKIV-mediated transcriptional regulation. The CaMKIV-associated PP2A then dephosphorylates CaMKIV T200, thereby terminating autonomous activity and CaMKIV-mediated gene transcription.

Received for publication, April 23, 2004

^* This work was supported by National Institutes of Health Grants GM-33976, HD07503 (to A. R. M.), and GM-51366 (to B. E. W.). 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.

^¶ To whom correspondence should be addressed. Tel.: 919-681-6209; Fax: 919-681-7767; E-mail: means001{at}mc.duke.edu.

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