Epidermal Growth Factor Directs Sex-specific Steroid Signaling through Src Activation

• Published in: The Journal of biological chemistry Vol. 282; no. 14; pp. 10697 - 10706
• Main Authors: Hitosugi, Taro, Sasaki, Kazuki, Sato, Moritoshi, Suzuki, Yoshiko, Umezawa, Yoshio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.04.2007; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Breast Neoplasms - enzymology; Cell Line, Tumor; Cytoplasm - enzymology; Dihydrotestosterone - pharmacology; Endocytosis - drug effects; Enzyme Activation - drug effects; Epidermal Growth Factor - pharmacology; ErbB Receptors - metabolism; Estrogens - pharmacology; Female; Intracellular Membranes - enzymology; Mice; Multiprotein Complexes; Receptors, Androgen - metabolism; Receptors, Estrogen - metabolism; Sex Characteristics; Signal Transduction - drug effects; src-Family Kinases - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M610444200

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 5α-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 5α-dihydrotestosterone may be responsible for the different extent of observed cell growth.