title: Interaction of STAT6 with its co-activator SRC-1/NCoA-1 is regulated by dephosphorylation of the latter via PP2A.
abstract: Regulation of gene expression represents a central issue in signal-regulated cellular responses. STAT6 is a critical mediator of IL-4 stimulated gene activation. To mediate this function, STAT6 recruits co-activator complexes. We have previously shown that STAT6 binds the PAS-B domain of the co-activator NCoA-1 via an LXXLL motif in its transactivation domain. Our recent finding that the PAS-B domain of NCoA-1 is also essential for co-activator complex formation points to an additional level of regulation of the co-activator assembly. In this study, we discovered that dephosphorylation of NCoA-1 is essential for the interaction with STAT6 and for IL-4-dependent transcriptional activation. PP2A dephosphorylates NCoA-1 and facilitates the activation of STAT6 target genes. Interestingly, simultaneous inhibition of phosphatase and cyclin-dependent kinases rescues the NCoA-1/STAT6 interaction. Moreover, arrest of cells at G1/S results in enhanced NCoA-1 phosphorylation. In summary, our results indicate that the interaction of NCoA-1 and STAT6 is dynamically regulated by the phosphatase PP2A and by cyclin-dependent kinases. This provides a mechanism for integrating transcriptional regulation by STAT6 with cell cycle progression.
authors.affiliation: Friedrich-Schiller-University, Jena Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine, Hans-Knöll-Str 2, 07743 Jena, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Münz
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Litterst
authors.forename: Edith
authors.initials: E
authors.lastname: Pfitzner
mesh_terms: D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology; D056920:Nuclear Receptor Coactivator 1 / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D050800:STAT6 Transcription Factor; D015847:Interleukin-4; D056920:Nuclear Receptor Coactivator 1; D018844:Cyclin-Dependent Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2