HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: M600180-MCP200v1 5/11/2072    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Glossary Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Huq, M. D. M. Articles by Wei, L.-N. Search for Related Content PubMed PubMed Citation Articles by Huq, M. D. M. Articles by Wei, L.-N. Social Bookmarking                      What's this?

---

Research

Modulation of Testicular Receptor 4 Activity by Mitogen-activated Protein Kinase-mediated Phosphorylation^*

M. D. Mostaqul Huq, Pawan Gupta, Nien-Pei Tsai and Li-Na Wei

From the Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455

Testicular receptor 4 (TR4) is an orphan member of the nuclear receptor superfamily. Despite the lack of identified ligands, its functional role has been demonstrated both in animals and cell cultures. However, it remains unclear how the biological activity of TR4 is regulated without specific ligands. In this study, we showed that in the absence of specific ligands the activity of TR4 could be modulated by mitogen-activated protein kinase (MAPK)-mediated phosphorylation of its activation function 1 (AF-1) domain. A mass spectrometry-based proteome analysis of TR4 expressed in insect cells revealed three phosphorylation sites in its AF-1 domain, specifically on Ser¹⁹, Ser⁵⁵, and Ser⁶⁸. Site-directed mutagenesis studies demonstrated the functionality of phosphorylation on Ser¹⁹ and Ser⁶⁸ but not Ser⁵⁵. We also demonstrated that MAPK-mediated phosphorylation of the AF-1 domain rendered TR4 a repressor, mediated through the preferential recruitment of corepressor RIP140. Dephosphorylation of its AF-1 made TR4 an activator due to its selective recruitment of coactivator, P300/cyclic AMP-responsive element binding protein-binding protein-associated factor (PCAF). The biological effects were validated by using the wild type TR4 and its constitutive negative (dephosphorylated) and constitutive positive (phosphorylated) mutants in the studies of regulation of its natural target gene, apoE. This study uncovered, for the first time, a ligand-independent mechanism underlying the biological activity of TR4 that was mediated by MAPK-mediated receptor phosphorylation of AF-1 domain.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				G. Li, Y.-F. Lee, S. Liu, Y. Cai, S. Xie, N.-C. Liu, B.-Y. Bao, Z. Chen, and C. Chang Oxidative Stress Stimulates Testicular Orphan Receptor 4 through Forkhead Transcription Factor Forkhead Box O3a Endocrinology, July 1, 2008; 149(7): 3490 - 3499. [Abstract] [Full Text] [PDF]

				K. D. Baker, R. B. Beckstead, D. J. Mangelsdorf, and C. S. Thummel Functional interactions between the Moses corepressor and DHR78 nuclear receptor regulate growth in Drosophila Genes & Dev., February 15, 2007; 21(4): 450 - 464. [Abstract] [Full Text] [PDF]