Regulation and function of the calcium/calmodulin-dependent protein kinase IV/protein serine/threonine phosphatase 2A signaling complex.

Anderson KA, Noeldner PK, Reece K, Wadzinski BE, Means AR
J Biol Chem. 2004 279 (30): 31708-16

PMID: 15143065 · DOI:10.1074/jbc.M404523200

Calcium/calmodulin-dependent protein kinase IV (CaMKIV) is a member of the broad substrate specificity class of Ca(2+)/calmodulin (CaM)-dependent protein kinases and functions as a potent stimulator of Ca(2+)-dependent gene expression. Activation of CaMKIV is a transient, tightly regulated event requiring both Ca(2+)/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 Ca(2+)/CaM binding-autoinhibitory domain of CaMKIV is required for association of the kinase with PP2A and that binding of PP2A and Ca(2+)/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 Ca(2+)/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 Ca(2+), CaMKIV binds Ca(2+)/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.

MeSH Terms (22)

Amino Acid Sequence Base Sequence Calcium-Calmodulin-Dependent Protein Kinase Kinase Calcium-Calmodulin-Dependent Protein Kinases Calcium-Calmodulin-Dependent Protein Kinase Type 4 Calcium Signaling Cell Line Cyclic AMP Response Element-Binding Protein DNA Primers Enzyme Activation Humans In Vitro Techniques Molecular Sequence Data Multienzyme Complexes Phosphoprotein Phosphatases Phosphorylation Protein-Serine-Threonine Kinases Protein Phosphatase 2 Recombinant Proteins Sequence Homology, Amino Acid Signal Transduction Transcription, Genetic

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