MNAR plays an important role in ERa activation of Src/MAPK and PI3K/Akt signaling pathways
| Autor: | Su Jane Rutledge, James G. Greger, Boris J. Cheskis, Neil Cooch, Sunil Nagpal, Leonard P. Freedman, Christopher McNally, Sean McLarney, Belew Mekonnen, Diane Hauze, Ho-Sun Lam |
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| Rok vydání: | 2008 |
| Předmět: |
MAPK/ERK pathway
Scaffold protein Proto-Oncogene Proteins pp60(c-src) Clinical Biochemistry Biochemistry Phosphatidylinositol 3-Kinases Structure-Activity Relationship Endocrinology Catalytic Domain Cell Line Tumor Humans Phosphorylation Molecular Biology Protein kinase B Cell Proliferation Pharmacology biology Organic Chemistry Estrogen Receptor alpha Estrogens Cell biology Enzyme Activation Gene Expression Regulation Neoplastic Crosstalk (biology) src-Family Kinases Mitogen-activated protein kinase Trans-Activators biology.protein Signal transduction Co-Repressor Proteins Signal Transduction Transcription Factors Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Steroids. 73:901-905 |
| ISSN: | 0039-128X |
| DOI: | 10.1016/j.steroids.2007.12.028 |
| Popis: | 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 p60src (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. |
| Databáze: | OpenAIRE |
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