Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (PPAR)-binding protein (PBP). Stimulation of transcriptional regulation by mitogen-activated protein kinase

Parimal Misra, Edward D. Owuor, Wenge Li, Songtao Yu, Chao Qi, Kirstin Meyer, Yi Jun Zhu, M. Sambasiva Rao, A. N.Tony Kong, Janardan K. Reddy

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Peroxisome proliferator-activated receptor (PPAR)-binding protein (PBP) is an important coactivator for PPARγ and other transcription factors. PBP is an integral component of a maltiprotein thyroid hormone receptor-associated protein (TRAP)/vitamin D3 receptor-interacting protein (DRIP)/activator-recruited cofactor (ARC) complex required for transcriptional activity. To study the regulation of PBP by cellular signaling pathways, we identified the phosphorylation sites of PBP. Using a combination of in vitro and in vivo approaches and mutagenesis of PBP phosphorylation sites, we identified six phosphorylation sites on PBP: one exclusive protein kinase A (PKA) phosphorylation site at serine 656, two protein kinase C (PKC) sites at serine 796 and serine 1345, a common PKA/PKC site at serine 756, and two extracellular signal-regulated kinase 2 sites of the mitogen-activated protein kinase (MAPK) family at threonine 1017 and threonine 1444. Binding of PBP to PPARγ1 or retinoid-X-receptor for 9-cis-retinoic acid (RXR) is independent of their phosphorylation states, implying no changes in protein-protein interaction after modification by phosphorylation. Overexpression of RafBXB, an activated upstream kinase of the MAPK signal transduction pathway, exerts a significant additive inductive effect on PBP coactivator function. This effect is significantly diminished by overexpression of Raf-BXB301, a dominant negative mutant of RafBXB. These results identify phosphorylation as a regulatory modification event of PBP and demonstrate that PBP phosphorylation by Raf/MEK/MAPK cascade exerts a positive effect on PBP coactivator function. The functional role of PKA and PKC phosphorylation sites in PBP remains to be elucidated.

Original languageEnglish (US)
Pages (from-to)48745-48754
Number of pages10
JournalJournal of Biological Chemistry
Issue number50
StatePublished - Dec 13 2002


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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