| First Author | Zhou X | Year | 2013 |
| Journal | Am J Physiol Renal Physiol | Volume | 304 |
| Issue | 7 | Pages | F908-17 |
| PubMed ID | 23324178 | Mgi Jnum | J:194347 |
| Mgi Id | MGI:5473463 | Doi | 10.1152/ajprenal.00591.2012 |
| Citation | Zhou X, et al. (2013) Inhibitory phosphorylation of GSK-3beta by AKT, PKA, and PI3K contributes to high NaCl-induced activation of the transcription factor NFAT5 (TonEBP/OREBP). Am J Physiol Renal Physiol 304(7):F908-17 |
| abstractText | High NaCl activates the transcription factor nuclear factor of activated T cells 5 (NFAT5), leading to increased transcription of osmoprotective target genes. Kinases PKA, PI3K, AKT1, and p38alpha were known to contribute to the high NaCl-induced increase of NFAT5 activity. We now identify another kinase, GSK-3beta. siRNA-mediated knock-down of GSK-3beta increases NFAT5 transcriptional and transactivating activities without affecting high NaCl-induced nuclear localization of NFAT5 or NFAT5 protein expression. High NaCl increases phosphorylation of GSK-3beta-S9, which inhibits GSK-3beta. In GSK-3beta-null mouse embryonic fibroblasts transfection of GSK-3beta, in which serine 9 is mutated to alanine, so that it cannot be inhibited by phosphorylation at that site, inhibits high NaCl-induced NFAT5 transcriptional activity more than transfection of wild-type GSK-3beta. High NaCl-induced phosphorylation of GSK-3beta-S9 depends on PKA, PI3K, and AKT, but not p38alpha. Overexpression of PKA catalytic subunit alpha or of catalytically active AKT1 reduces inhibition of NFAT5 by GSK-3beta, but overexpression of p38alpha together with its catalytically active upstream kinase, MKK6, does not. Thus, GSK-3beta normally inhibits NFAT5 by suppressing its transactivating activity. When activated by high NaCl, PKA, PI3K, and AKT1, but not p38alpha, increase phosphorylation of GSK-3beta-S9, which reduces the inhibitory effect of GSK-3beta on NFAT5, and thus contributes to activation of NFAT5. |
