A signaling complex of ca2+-calmodulin-dependent protein kinase IV and protein phosphatase 2A

• Published in: Science (American Association for the Advancement of Science) 1998-05, Vol.280 (5367), p.1258-1261
• Main Authors: WESTPHAL, R. S, ANDERSON, K. A, MEANS, A. R, WADZINSKI, B. E
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Polyomavirus Transforming - metabolism; Biological and medical sciences; Brain - enzymology; Calcium - metabolism; Calcium-Calmodulin-Dependent Protein Kinase Type 4; Calcium-Calmodulin-Dependent Protein Kinases - genetics; Calcium-Calmodulin-Dependent Protein Kinases - isolation & purification; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Calmodulin; Calmodulin - metabolism; Cell physiology; Cell research; Coenzymes - metabolism; Cyclic AMP Response Element-Binding Protein - metabolism; Cytological research; Enzyme Activation; Fundamental and applied biological sciences. Psychology; Humans; Jurkat Cells; Lymphocyte Activation; Molecular and cellular biology; Mutation; Phosphoprotein Phosphatases - isolation & purification; Phosphoprotein Phosphatases - metabolism; Phosphorylation; Protein Phosphatase 2; Rats; Recombinant Fusion Proteins - metabolism; Signal Transduction; T-Lymphocytes - enzymology; Transcription, Genetic
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.280.5367.1258

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).