title: HMGN2 inducibly binds a novel transactivation domain in nuclear PRLr to coordinate Stat5a-mediated transcription.
abstract: The direct actions of transmembrane receptors within the nucleus remain enigmatic. In this report, we demonstrate that the prolactin receptor (PRLr) localizes to the nucleus where it functions as a coactivator through its interactions with the latent transcription factor signal transducer and activator of transcription 5a (Stat5a) and the high-mobility group N2 protein (HMGN2). We identify a novel transactivation domain within the PRLr that is activated by ligand-induced phosphorylation, an event coupled to HMGN2 binding. The association of the PRLr with HMGN2 enables Stat5a-responsive promoter binding, thus facilitating transcriptional activation and promoting anchorage-independent growth. We propose that HMGN2 serves as a critical regulatory factor in Stat5a-driven gene expression by facilitating the assembly of PRLr/Stat5a onto chromatin and that these events may serve to promote biological events that contribute to a tumorigenic phenotype. Our data imply that phosphorylation may be the molecular switch that activates a cell surface receptor transactivation domain, enabling it to tether chromatin-modifying factors, such as HMGN2, to target promoter regions in a sequence-specific manner.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center and Department of Pathology, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Alyson A
authors.initials: AA
authors.lastname: Fiorillo
authors.forename: Terry R
authors.initials: TR
authors.lastname: Medler
authors.forename: Yvonne B
authors.initials: YB
authors.lastname: Feeney
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Kalie L
authors.initials: KL
authors.lastname: Tommerdahl
authors.forename: Charles V
authors.initials: CV
authors.lastname: Clevenger
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D024242:HMGN2 Protein / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011981:Receptors, Prolactin / Q000737:chemistry* / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D024242:HMGN2 Protein; D011981:Receptors, Prolactin; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D025521:Tumor Suppressor Proteins