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.
Highlights
The steroid hormone 17β-estradiol (E2) plays an important role in regulating a wide variety of physiological and pathological processes such as development, homeostasis and breast cancer progression (McDonnell and Norris, 2002)
We show that in the human breast carcinoma T47D cells, upon estrogen treatment, p130Cas rapidly and transiently associates with the estrogen receptor α 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 α occurs within 3 minutes of estrogen treatment and is dependent on c-Src kinase activation
Summary
The steroid hormone 17β-estradiol (E2) plays an important role in regulating a wide variety of physiological and pathological processes such as development, homeostasis and breast cancer progression (McDonnell and Norris, 2002). Estrogen has been reported to induce multiple cytosolic signaling processes, such as activation of Src, Ras, Raf, PKC, PKA, potassium channels, intracellular calcium levels and nitric oxide (for reviews, see Cato et al, 2002; Kelly and Levin, 2001; Migliaccio et al, 1996; Segars and Driggers, 2002) Since activation of these signaling molecules depends on cell types studied and the conditions used, the precise nongenomic signaling pathways of estrogen and their functional significance are not yet well understood (Cato et al, 2002; Collins and Webb, 1999; Falkenstein and Wehling, 2000; Foster and Wimalasena, 1996; Revelli et al, 1998)
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