title: Epidermal growth factor directs sex-specific steroid signaling through Src activation.
abstract: 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.
authors.affiliation: Department of Chemistry, School of Science, The University of Tokyo, and Japan Science and Technology Agency, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Hitosugi
authors.forename: Kazuki
authors.initials: K
authors.lastname: Sasaki
authors.forename: Moritoshi
authors.initials: M
authors.lastname: Sato
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Umezawa
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000201:enzymology; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004705:Endocytosis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D007425:Intracellular Membranes / Q000201:enzymology; D051379:Mice; D046912:Multiprotein Complexes; D011944:Receptors, Androgen / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D004967:Estrogens; D046912:Multiprotein Complexes; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D013196:Dihydrotestosterone; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019061:src-Family Kinases