Regulation of D-myo-inositol 1,4,5-trisphosphate 3-kinase by cAMP-dependent protein kinase and protein kinase C.
The Ca2(+)-mobilizing second messenger D-myo-inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) is converted to the putative messenger D-myo-inositol 1,3,4,5-tetrakisphosphate by Ins(1,4,5)P3 3-kinase. We found that cAMP-dependent protein kinase and protein kinase C phosphorylate, and thereby modulate, the activity of Ins(1,4,5)P3 3-kinase. cAMP-dependent kinase introduced a stoichiometric amount of phosphate at serine 109 of the 53-kDa polypeptide and caused a 1.8-fold increase in Vmax, whereas the protein kinase C-dependent phosphorylation reduced the Vmax to one-fourth of that of the unphosphorylated enzyme. Upon prolonged incubation, protein kinase C introduced phosphate at multiple sites in Ins(1,4,5)P3 3-kinase, and the resulting inactivation of the enzyme appeared to be well-correlated with the simultaneous phosphorylation of two major sites, serine 109 and serine 175. The Km for Ins(1,4,5)P3 was not affected significantly after phosphorylation by either protein kinase. We propose, therefore, that the phosphorylation of Ins(1,4,5)P3 3-kinase by cAMP-dependent kinase and protein kinase C constitutes mechanisms of cross-talk between cellular signaling pathways that use various second messengers such as inositol phosphates, diacylglycerol, Ca2+, and cAMP.
Sim
S S
SS
Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
Kim
J W
JW
Rhee
S G
SG
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000201:enzymology; D007700:Kinetics; D008969:Molecular Sequence Data; D010449:Peptide Mapping; D010748:Phosphopeptides / Q000302:isolation & purification; D010766:Phosphorylation; D010770:Phosphotransferases / Q000302:isolation & purification / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor); D011493:Protein Kinase C / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D015290:Second Messenger Systems; D014357:Trypsin
D010748:Phosphopeptides; D010770:Phosphotransferases; D011494:Protein Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); C051038:Inositol 1,4,5-trisphosphate 3-kinase; D011493:Protein Kinase C; D014357:Trypsin