Mechanism of nuclear calcium signaling by inositol 1,4,5-trisphosphate produced in the nucleus, nuclear located protein kinase C and cyclic AMP-dependent protein kinase.
Nuclear phospholipase C-gamma 1 can be phosphorylated by nuclear membrane located epidermal growth factor receptor sequel to epidermal growth factor-mediated signaling to the nucleus. The function of mouse liver phospholipase C-gamma 1 is attributed to a 120 kDa protein fragment which has been found to be a proteolytic product of the 150 kDa native nuclear enzyme. The tyrosine-phosphorylated 120 kDa protein band interacts with activated EGFR, binds phosphatidyl-3-OH kinase enhancer, and activates nuclear phosphatidylinositol-3-OH-kinase, and is capable of generating diacylglycerol in response to the epidermal growth factor signal to the nucleus in vivo. Thus a mechanism for nuclear production of inositol-1,4,5-trisphophate is unraveled. Nuclear generated inositol-1,4,5-trisphophate interacts with the inner membrane located inositol-1,4,5-trisphophate receptor and sequesters calcium into the nucleoplasm. Nuclear inositol-1,4,5-trisphophate receptor is phosphorylated by native nuclear protein kinase C which enhances the receptor-ligand interaction. Nuclear calcium-ATPase and inositol-1,3,4,5-tetrakisphophate receptor are located on the outer nuclear membrane, thus facilitating calcium transport into the nuclear envelope lumen either by ATP or inositol-1,3,4,5-tetrakisphophate depending upon the external free calcium concentrations. Nuclear calcium ATPase is phosphorylated by cyclic AMP-dependent protein kinase with enhanced calcium pumping activity. A holistic picture emerges here where tyrosine phosphorylation compliments serine phosphorylation of key moieties regulating nuclear calcium signaling. Evidence are forwarded in favor of proteolysis having a profound implications in nuclear calcium homeostasis in particular and signal transduction in general.
Klein
Christian
C
INSERM U575, University Louis Pasteur, 11 rue Humann, 67000 Strasbourg, France.
Malviya
Anant N
AN
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction
D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; C061107:inositol-1,3,4,5-tetrakisphosphate receptor; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D000252:Calcium-Transporting ATPases; D002118:Calcium