title: MNAR plays an important role in ERa activation of Src/MAPK and PI3K/Akt signaling pathways.
abstract: Estrogens play a critical role in the regulation of cellular proliferation, differentiation, and apoptosis. Evidence indicates that this regulation is mediated by a complex interface of direct control of gene expression (so-called "genomic action") and by regulation of cell-signaling/phosphorylation cascades (referred to as the "non-genomic", or "extranuclear" action). However, the mechanisms of the non-genomic action of estrogens are not well defined. We have recently described the identification of a novel scaffold protein termed MNAR (modulator of non-genomic action of estrogen receptor), that couples conventional steroid receptors with extranuclear signal transduction pathways, thus potentially providing additional and tissue- or cell-specific level of steroid hormone regulation of cell functions. We have demonstrated that the MNAR is required for ER alpha (ERa) interaction with p60(src) (Src), which leads to activation of Src/MAPK pathway. Our new data also suggest that activation of cSrc in response to E2 leads to MNAR phosphorylation, interaction with p85, and activation of the PI3 and Akt kinases. These data therefore suggest that MNAR acts as an important scaffold that integrates ERa action in regulation of important signaling pathways. ERa non-genomic action has been suggested to play a key role in estrogen-induced cardio-, neuro-, and osteo-protection. Therefore, evaluation of the molecular crosstalk between MNAR and ERa may lead to development of functionally selective ER modulators that can separate between beneficial, prodifferentiative effects in bone, the cardiovascular system and the CNS and the "detrimental", proliferative effects in reproductive tissues and organs.
authors.affiliation: Department of Women's Health and Musculoskeletal Biology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, United States. cheskib@wyeth.com
authors.forename: Boris J
authors.initials: BJ
authors.lastname: Cheskis
authors.forename: James
authors.initials: J
authors.lastname: Greger
authors.forename: Neil
authors.initials: N
authors.lastname: Cooch
authors.forename: Christopher
authors.initials: C
authors.lastname: McNally
authors.forename: Sean
authors.initials: S
authors.lastname: Mclarney
authors.forename: Ho-Sun
authors.initials: HS
authors.lastname: Lam
authors.forename: Su
authors.initials: S
authors.lastname: Rutledge
authors.forename: Belew
authors.initials: B
authors.lastname: Mekonnen
authors.forename: Diane
authors.initials: D
authors.lastname: Hauze
authors.forename: Sunil
authors.initials: S
authors.lastname: Nagpal
authors.forename: Leonard P
authors.initials: LP
authors.lastname: Freedman
mesh_terms: D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056970:Co-Repressor Proteins; D004789:Enzyme Activation; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D056970:Co-Repressor Proteins; D047628:Estrogen Receptor alpha; D004967:Estrogens; D019869:Phosphatidylinositol 3-Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); D015534:Trans-Activators; D014157:Transcription Factors; D019061:src-Family Kinases; C506487:ESR1 protein, human; C438485:PELP1 protein, human