Calcineurin is downstream of the inositol 1,4,5-trisphosphate receptor in the apoptotic and cell growth pathways.
The inositol 1,4,5-trisphosphate receptor (IP(3)R) is a calcium (Ca(2+)) release channel found on the endoplasmic reticulum of virtually all types of cells. Human T lymphocytes (Jurkat) that are made deficient in IP(3)R do not generate Ca(2+) signals in response to T cell receptor stimulation, fail to translocate the nuclear factor for activated T cells to the nucleus, and are remarkably resistant to induction of apoptosis with CD95 (Fas), dexamethasone, gamma irradiation, and T cell receptor stimulation using anti-CD3 antibody. Expression of constitutively active calcineurin A in IP(3)R-deficient T cells restored nuclear factor for activated T cells translocation to the nucleus and dephosphorylation of Bad and rendered the cells sensitive to apoptotic inducers. Induction of apoptosis required both active calcineurin A (DeltaCnA) and activation-dependent colocalization of CnA with its substrate. Thus, the Ca(2+)-dependent phosphatase calcineurin (CnA) is downstream of the IP(3)R in both the cell growth and apoptotic signaling pathways.
Jayaraman
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Departments of Medicine, Molecular Cardiology Program, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
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D017209:Apoptosis; D017252:CD3 Complex / Q000378:metabolism; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000172:deficiency*; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008164:Luminescent Proteins; D008856:Microscopy, Fluorescence; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency*; D015398:Signal Transduction; D013601:T-Lymphocytes; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D051025:bcl-Associated Death Protein
C494819:BAD protein, human; D017252:CD3 Complex; D015220:Calcium Channels; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008164:Luminescent Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D051025:bcl-Associated Death Protein; D049452:Green Fluorescent Proteins; D019703:Calcineurin; D002118:Calcium