High NaCl-induced inhibition of PTG (protein targeting to glycogen) contributes to activation of NFAT5 through attenuation of the negative effect of SHP-1.

High NaCl-induced inhibition of PTG (protein targeting to glycogen) contributes to activation of NFAT5 through attenuation of the negative effect of SHP-1. Am J Physiol Renal Physiol. 2013 May 29; Authors: Zhou X, Wang H, Burg MB, Ferraris JD Abstract Activation of the transcription factor NFAT5 by high NaCl involves changes in phosphorylation. By siRNA screening we previously found that PTG, a regulatory subunit of protein phosphatase1 (PP1), contributes to regulation of high NaCl-induced NFAT5 transcriptional activity. The present study addresses the mechanism involved. We find that high NaCl-induced inhibition of PTG elevates NFAT5 activity by increasing NFAT5 transactivating activity, protein abundance, and nuclear localization. PTG acts via a catalytic subunit, PP1γ. PTG associates physically with PP1γ and NaCl reduces both this association and remaining PTG-associated PP1γ activity. High NaCl-induced phosphorylation of p38, ERK and SHP-1 contributes to activation of NFAT5. Knockdown of PTG does not affect phosphorylation of p38 or ERK. However, PTG and PP1γ bind to SHP-1, and knock down of either PTG or PP1γ increases high NaCl-induced phosphorylation of SHP-1-S591, which inhibits SHP-1. Mutation of SHP-1-S591 to alanine, which cannot be phosphorylated, increases inhibition of NFAT5 by SHP-1. Thus, high NaCl reduces the stimulatory effect of PTG and PP1γ on SHP-1, which in turn reduces the inhibitory effect of SHP-1 on NFAT5. Our f...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research