Abstract
Stimulation of T lymphocytes results in a rapid increase in intracellular calcium concentration ([Ca2+]i) that parallels the activation of Ca2+-calmodulin-dependent protein kinase IV (CaMKIV), a nuclear enzyme that can phosphorylate and activate the cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB). However, inactivation of CaMKIV occurs despite the sustained increase in [Ca2+]i that is required for T cell activation. A stable and stoichiometric complex of CaMKIV with protein serine-threonine phosphatase 2A (PP2A) was identified in which PP2A dephosphorylates CaMKIV and functions as a negative regulator of CaMKIV signaling. In Jurkat T cells, inhibition of PP2A activity by small t antigen enhanced activation of CREB-mediated transcription by CaMKIV. These findings reveal an intracellular signaling mechanism whereby a protein serine-threonine kinase (CaMKIV) is regulated by a tightly associated protein serine-threonine phosphatase (PP2A).
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigens, Polyomavirus Transforming / metabolism
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Brain / enzymology
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Calcium / metabolism
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Calcium-Calmodulin-Dependent Protein Kinase Type 4
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Calcium-Calmodulin-Dependent Protein Kinases / isolation & purification
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Calmodulin / metabolism
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Coenzymes / metabolism
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Cyclic AMP Response Element-Binding Protein / metabolism
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Enzyme Activation
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Humans
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Jurkat Cells
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Lymphocyte Activation
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Mutation
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Phosphoprotein Phosphatases / isolation & purification
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Phosphoprotein Phosphatases / metabolism*
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Phosphorylation
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Protein Phosphatase 2
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Rats
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Recombinant Fusion Proteins / metabolism
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Signal Transduction*
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T-Lymphocytes / enzymology*
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Transcription, Genetic
Substances
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Antigens, Polyomavirus Transforming
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Calmodulin
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Coenzymes
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Cyclic AMP Response Element-Binding Protein
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Recombinant Fusion Proteins
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CAMK4 protein, human
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Calcium-Calmodulin-Dependent Protein Kinase Type 4
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Calcium-Calmodulin-Dependent Protein Kinases
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Camk4 protein, rat
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Phosphoprotein Phosphatases
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Protein Phosphatase 2
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Calcium