Positive effect of protein kinase A on the transcriptional activity of the nuclear factor of activated T-cell family proteins occurs via several different signal transduction mechanisms
2007
Inaskina, I. | Serfling, E. | Jankevics, E.
The transcriptional activation of members of the nuclear factor of activated T-cell (NFAT) family is generally regulated by dynamic interplay between calcineurin and Ras/Raf/Erk protein kinase cascade, on the one hand, and active Ser/Thr protein kinases counteracting activity of calcineurin, on the other. Activation of calcineurin mediates the nuclear translocation of NFAT factors, but activation of classical Ras/Raf/Erk and further protein kinase cascades controls the transcriptional activation of NFATs and the induction of APE-1. Several Ser/Thr protein kinases have been described to phophorylate NFAT proteins, thereby counteracting the activity of calcineurin, among them glycogen syntase kinase-3 (GSK-3), casein kinases Ialpha (CKIalpha) and II (CKII), Erk, PKC and protein kinase A (PKA) as well as MAP/SAP kinases Erk1, JNK3 and p38alpha. We investigated the effect of GSK-3 and PKA on the transcriptional activity of NFAT family proteins-NFATc1/A, NFATc1/C, NFATc2, and NFATc3 using full-length expression vectors, NFATc1/Gal4 chimeras and different reporters. Our results demonstrate that overexpression of GSK-3 dramatically inhibited transcriptional activity of all coexpressed proteins, while overexpression of PKA significantly increased the level of NFATc-mediated reporter gene production. We suggest that positive effect of PKA is a sum of several distinct effects caused by different mechanisms. The functional assay using NFATc1/Gal4 chimera with serine 269 mutated to alanine reveals that direct effect of PKA on the transcription activity of NFATc1 is accomplishing through phosphorylation of Ser**269 and it is negative.
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