title: p130Cas interacts with estrogen receptor alpha and modulates non-genomic estrogen signaling in breast cancer cells.
abstract: Steroid hormones bind to their receptors and trans-activate target genes. Rapid non-genomic action of steroid hormones has been proposed in addition to the one at the genomic level. Estrogen has been described to activate c-Src kinase and this activation has been shown to be responsible for estrogen-dependent mitogenicity. A major substrate of c-Src kinase activity is the cytoskeletal protein p130Cas, originally identified in v-Src-transformed cells. We show that in the human breast carcinoma T47D cells, upon estrogen treatment, p130Cas rapidly and transiently associates with the estrogen receptor alpha in a multi-molecular complex containing the c-Src kinase and the p85 subunit of PI 3-kinase. Association of p130Cas with the estrogen receptor alpha occurs within 3 minutes of estrogen treatment and is dependent on c-Src kinase activation. Transient overexpression of p130Cas in T47D cells increases estrogen-dependent Src kinase and Erk1/2 MAPKs activities and accelerates their kinetics of stimulation. A similar effect was detected on estrogen-dependent cyclin D1 expression, suggesting a role for p130Cas in regulating estrogen-dependent cell cycle progression. Double-stranded small RNA interference (siRNA) by silencing endogenous p130Cas protein, was sufficient to inhibit estrogen-dependent Erk1/2 MAPKs activity and cyclin D1 induction, demonstrating the requirement of p130Cas in such events. Therefore, our data show that the adaptor protein p130Cas associates with the estrogen receptor transducing complex, regulating estrogen-dependent activation of c-Src kinase and downstream signaling pathways.
authors.affiliation: Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, Via Santena 5 bis, 10126 Turin, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Cabodi
authors.forename: Laura
authors.initials: L
authors.lastname: Moro
authors.forename: Germano
authors.initials: G
authors.lastname: Baj
authors.forename: Monica
authors.initials: M
authors.lastname: Smeriglio
authors.forename: Paola
authors.initials: P
authors.lastname: Di Stefano
authors.forename: Silvana
authors.initials: S
authors.lastname: Gippone
authors.forename: Nicola
authors.initials: N
authors.lastname: Surico
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Silengo
authors.forename: Emilia
authors.initials: E
authors.lastname: Turco
authors.forename: Guido
authors.initials: G
authors.lastname: Tarone
authors.forename: Paola
authors.initials: P
authors.lastname: Defilippi
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D050719:Crk-Associated Substrate Protein; D019938:Cyclin D1 / Q000378:metabolism; D004789:Enzyme Activation; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D007700:Kinetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D016160:Retinoblastoma Protein; D050717:Retinoblastoma-Like Protein p130; D015398:Signal Transduction; D019061:src-Family Kinases / Q000737:chemistry / Q000378:metabolism
chemical_list: C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; D047628:Estrogen Receptor alpha; D004967:Estrogens; D011506:Proteins; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D050717:Retinoblastoma-Like Protein p130; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3