title: Transforming growth factor-beta1 inhibits type I inositol 1,4,5-trisphosphate receptor expression and enhances its phosphorylation in mesangial cells.
abstract: A potentially important cross-talk characteristic of transforming growth factor-beta (TGF-beta) is to inhibit platelet-derived growth factor-induced intracellular calcium rise (Baffy, G., Sharma, K., Shi, W., Ziyadeh, F. N., and Williamson, J. R. (1995) Biochem. Biophys. Res. Commun. 210, 378-383) in murine mesangial cells. The present study examined the possible basis for this effect by evaluating the regulation of the type I inositol 1,4,5-trisphosphate receptor (IP3R) by TGF-beta. TGF-beta1 down-regulates IP3R protein expression by >90% with maximal and half-maximal effects after 8 and 2 h, respectively. TGF-beta1 also decreased IP3R mRNA expression by 59% after 1 h. Phosphorylation of the IP3R was also demonstrated as early as 15 min after TGF-beta1 exposure. Back phosphorylation assays of IP3R from TGF-beta1-treated mesangial cells with protein kinase A (PKA), indicated that TGF-beta1-induced phosphorylation of the IP3R occurs at similar sites as for PKA. In vitro kinase assays using the known IP3R peptide substrates for PKA, RPSGRRESLTSFGNP and ARRDSVLAAS, demonstrated that TGF-beta1 induces phosphorylation of both peptides (158 and 123% of control values, respectively). TGF-beta1-induced phosphorylation was prevented by the addition of the PKA inhibitor peptide in the in vitro kinase assay. It is proposed that TGF-beta-mediated effects on the IP3R may be an important characteristic of its ability to modulate the response of cells to factors that employ IP3R-mediated calcium release.
authors.affiliation: Department of Medicine, Nephrology Division, Thomas Jefferson University School of Medicine, Philadelphia, Pennsylvania 19107, USA. sharma1@jeflin.tju.edu
authors.forename: K
authors.initials: K
authors.lastname: Sharma
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.forename: S
authors.initials: S
authors.lastname: Bokkala
authors.forename: S K
authors.initials: SK
authors.lastname: Joseph
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D015220:Calcium Channels / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry*; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D002531:Cerebellum / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018076:DNA, Complementary; D005920:Glomerular Mesangium / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D013539:Simian virus 40; D013379:Substrate Specificity; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015220:Calcium Channels; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008024:Ligands; D010446:Peptide Fragments; D010750:Phosphoproteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D005576:Colforsin; D017868:Cyclic AMP-Dependent Protein Kinases