Calcium, Calcineurin, and the Control of Transcription

Abstract

interleukin capacitance-regulated activation channels protein kinase C c-Jun NH2-terminal kinase mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase Calcineurin (PP2B), a serine/threonine phosphatase controlled by cellular calcium, was originally identified in extracts of mammalian brain. Within the past few years this phosphatase has been implicated in a wide variety of biological responses including lymphocyte activation, neuronal and muscle development, neurite outgrowth, and morphogenesis of vertebrate heart valves. Progress in this area has been greatly accelerated by the drugs cyclosporin A and FK506, which use a unique mechanism of action to achieve near genome-specific nanomolar inhibition of calcineurin. This minireview will focus on the role of calcineurin in regulating transcription during development, primarily through its dephosphorylation of downstream targets such as the calcineurin-dependent, cytoplasmic subunits of the NF-AT transcription complex.Calcineurin and Regulation of Nuclear Import of NF-ATc Family MembersThe Ca2+, calcineurin/NF-AT signaling pathway was defined about 10 years ago (1Shaw J.-P. Utz P.J. Durand D.B. Toole J.J. Emmel E.A. Crabtree G.R. Science. 1988; 241: 202-205Crossref PubMed Scopus (10) Google Scholar, 2Flanagan W.M. Corthesy B. Bram R.J. Crabtree G.R. Nature. 1991; 352: 803-807Crossref PubMed Scopus (946) Google Scholar, 3Liu J. Farmer Jr., J.D. Lane W.S. Friedman J. Weissman I. Schreiber S.L. Cell. 1991; 66: 807-815Abstract Full Text PDF PubMed Scopus (3567) Google Scholar, 4Clipstone N.A. Crabtree G.R. Nature. 1992; 357: 695-697Crossref PubMed Scopus (1463) Google Scholar) and was one of the first signaling pathways to bridge the cell membrane with the nucleus. Although the pathway is simple (Fig. 1), multiple levels of regulation impinge upon it, making it adaptable for many functions in a wide variety of cell types. The pathway was defined by a strategy of working backward from the nucleus to the cell membrane Ca2+ channels in T lymphocytes. The regulatory regions of the IL-21 gene were identified and found to bind a cyclosporin-sensitive transcription complex called NF-AT1 (1Shaw J.-P. Utz P.J. Durand D.B. Toole J.J. Emmel E.A. Crabtree G.R. Science. 1988; 241: 202-205Crossref PubMed Scopus (10) Google Scholar, 5Siebenlist U. Durand D.B. Bressler P. Holbrook N.J. Norris C.A. Kamoun M. Kant J.A. Crabtree G.R. Mol. Cell. Biol. 1986; 6: 3042-3049Crossref PubMed Scopus (121) Google Scholar, 6Durand D.B. Bush M.R. Morgan J.G. Weiss A. Crabtree G.R. J. Exp. Med. 1987; 165: 395-407Crossref PubMed Scopus (117) Google Scholar, 7Emmel E.A. Verweij C.L. Durand D.B. Higgins K.M. Lacy E. Crabtree G.R. Science. 1989; 246: 1617-1620Crossref PubMed Scopus (571) Google Scholar). This transcription complex was shown to be made up of cytoplasmic (NFATc) and nuclear (NFATn) components (2Flanagan W.M. Corthesy B. Bram R.J. Crabtree G.R. Nature. 1991; 352: 803-807Crossref PubMed Scopus (946) Google Scholar). The cytoplasmic component translocated into the nucleus with a calcium signal, and the import was blocked by the drugs FK506 and cyclosporin A (2Flanagan W.M. Corthesy B. Bram R.J. Crabtree G.R. Nature. 1991; 352: 803-807Crossref PubMed Scopus (946) Google Scholar). Identification of calcineurin as the in vitro and in vivo target of FK506 and cyclosporin A (3Liu J. Farmer Jr., J.D. Lane W.S. Friedman J. Weissman I. Schreiber S.L. Cell. 1991; 66: 807-815Abstract Full Text PDF PubMed Scopus (3567) Google Scholar,4Clipstone N.A. Crabtree G.R. Nature. 1992; 357: 695-697Crossref PubMed Scopus (1463) Google Scholar) established calcineurin was for the nuclear import of NF-ATc S.L. Crabtree G.R. 1992; Full Text PDF PubMed Scopus Google Scholar). a for cell NF-AT activation many the of the capacitance-regulated activation channels and identified it as the of Ca2+ NF-AT import N.A. Bram R.J. Crabtree G.R. Full Text PDF PubMed Scopus Google Scholar, M. Crabtree G.R. J. Biol. PubMed Scopus Google Scholar, N.A. Crabtree G.R. Nature. PubMed Scopus Google functions in this pathway by the cytoplasmic subunits of the NF-AT1 transcription complex J. A. Nature. PubMed Scopus Google Scholar, N.A. Crabtree G.R. PubMed Scopus Google Scholar, J. A. J. Biol. Full Text Full Text PDF PubMed Scopus Google which by G.R. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar) and which cytoplasmic to nuclear as originally (2Flanagan W.M. Corthesy B. Bram R.J. Crabtree G.R. Nature. 1991; 352: 803-807Crossref PubMed Scopus (946) Google Scholar). Calcineurin to NF-ATc through a in the of the which functions as J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, A. Crabtree G.R. Nature. PubMed Scopus Google Scholar, J. A. Science. PubMed Scopus Google Scholar). This the phosphatase and its of the in a the phosphatase and its Calcineurin the to and the of NF-ATc N.A. Crabtree G.R. PubMed Scopus Google Scholar, P. Crabtree G.R. Science. PubMed Scopus Google Schol