Abstract
In vivo metabolic labeling showed that orphan nuclear receptor TR2 could be phosphorylated. Systematic studies were conducted using specific kinases/phosphatase inhibitors to determine the enzymes responsible for TR2 phosphorylation and the effects of TR2 phosphorylation on its protein stability and activation of its target gene. The data showed that protein kinase C (PKC)-mediated phosphorylation enhanced the activating ability of TR2 on target gene RARbeta as well as its stability through protection from proteosome-mediated degradation. Several PKC-mediated potential serine/threonine phosphorylation sites on TR2 protein were predicted from the computer analysis using NetPhos software (http://us.expasy.org) and were commensurate by in vitro phosphorylation of purified TR2 protein using PKC enzyme. Two phosphorylation sites at Ser-461 and Ser-568 were identified by LC-ESI-MS/MS. Point mutations at Ser-568 or Ser-461 were prepared and evaluated for their biological activity. Ser-568, but not Ser-461, mutation significantly reduced PKC-mediated TR2 protein stability and its transcriptional activity.
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