A signaling complex of Ca2+-calmodulin-dependent protein kinase IV and protein phosphatase 2A.
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).
Westphal
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RS
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Anderson
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KA
Means
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AR
Wadzinski
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BE
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D001921:Brain / Q000201:enzymology; D002118:Calcium / Q000378:metabolism; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D003067:Coenzymes / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D009154:Mutation; D010749:Phosphoprotein Phosphatases / Q000302:isolation & purification / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000201:enzymology*; D014158:Transcription, Genetic
D000952:Antigens, Polyomavirus Transforming; D002147:Calmodulin; D003067:Coenzymes; D017362:Cyclic AMP Response Element-Binding Protein; D011993:Recombinant Fusion Proteins; C517683:CAMK4 protein, human; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517686:Camk4 protein, rat; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D002118:Calcium