Hitosugi Taro, Sasaki Kazuki, Sato Moritoshi, Suzuki Yoshiko, Umezawa Yoshio
Department of Chemistry, School of Science, The University of Tokyo, and Japan Science and Technology Agency, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
J Biol Chem. 2007 Apr 6;282(14):10697-706. doi: 10.1074/jbc.M610444200. Epub 2007 Feb 5.
Estrogens and androgens exert many biological effects that do not require interactions of their receptors with chromosomal DNA. However, it has been a long-standing question how the sex steroid receptors provoke signal transduction outside the nucleus. Here we have shown that epidermal growth factor (EGF) directs sex-specific steroid signaling through Src activation. We have revealed that estrogen (E2)-induced Src activation takes place in, not only plasma, but also endomembranes. This was found ascribed to the existence of EGF and the occurrence of EGF receptor (EGFR)-involved endocytosis of estrogen receptor together with Src. EGFR, estrogen receptor, and Src were found to form a complex upon E2 stimulation. The cell growth of breast cancer-derived MCF-7 cells was found to remarkably increase through the above EGF-involved estrogen-signaling process. In contrast, the androgen 5alpha-dihydrotestosterone-induced Src activation occurs only in the plasma membrane free from the interaction of EGFR with androgen receptor, irrespective of EGF. The cell growth occurred only moderately as a result. The spatial difference in Src activation between E2 and 5alpha-dihydrotestosterone may be responsible for the different extent of observed cell growth.
雌激素和雄激素发挥着许多生物学效应，这些效应并不需要它们的受体与染色体DNA相互作用。然而，性类固醇受体如何在细胞核外引发信号转导一直是个长期存在的问题。在此我们表明，表皮生长因子（EGF）通过Src激活来引导性别特异性类固醇信号传导。我们揭示了雌激素（E2）诱导的Src激活不仅发生在血浆中，也发生在内膜中。这被发现归因于EGF的存在以及雌激素受体与Src一起发生的涉及表皮生长因子受体（EGFR）的内吞作用。发现EGFR、雌激素受体和Src在E2刺激下形成复合物。通过上述涉及EGF的雌激素信号传导过程，发现乳腺癌来源的MCF-7细胞的细胞生长显著增加。相比之下，雄激素5α-二氢睾酮诱导的Src激活仅发生在没有EGFR与雄激素受体相互作用的质膜中，与EGF无关。结果细胞生长仅适度发生。E2和5α-二氢睾酮之间Src激活的空间差异可能是观察到的细胞生长程度不同的原因。
