Activation of the Estrogen Receptor Through Phosphorylation by Mitogen-Activated Protein Kinase

• Published in: Science (American Association for the Advancement of Science) 1995-12, Vol.270 (5241), p.1491-1494
• Main Authors: Kato, Shigeaki, Endoh, Hideki, Masuhiro, Yoshikazu, Kitamoto, Takuya, Uchiyama, Shimami, Sasaki, Haruna, Masushige, Shoichi, Gotoh, Yukiko, Nishida, Eisuke, Kawashima, Hiroyuki, Metzger, Daniel, Chambon, Pierre
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Biochemistry, Molecular Biology; Biological and medical sciences; Breast cancer; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell growth; Cell Line; Cell physiology; Cell receptors; Cell structures and functions; Cellular biology; COS cells; Enzyme Activation; Epidermal Growth Factor - pharmacology; Estradiol - analogs & derivatives; Estradiol - pharmacology; Estrogen; Estrogen Antagonists - pharmacology; Estrogen receptors; Estrogens; Fundamental and applied biological sciences. Psychology; Genetic mutation; Growth factors; Hormone receptors. Growth factor receptors. Cytokine receptors. Prostaglandin receptors; Humans; Life Sciences; Mitogen-Activated Protein Kinase Kinases; Molecular and cellular biology; Molecular Sequence Data; Mutation; Phosphorylation; Physiological aspects; Polyunsaturated Alkamides; Promoter regions; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases - metabolism; Proteins; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-raf; Proto-Oncogene Proteins p21(ras) - metabolism; Receptors; Receptors, Estrogen - chemistry; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Recombinant Fusion Proteins - metabolism; Reporter genes; Serine - metabolism; Signal transduction; Somatomedins - pharmacology; Tamoxifen - analogs & derivatives; Tamoxifen - pharmacology; Transactivation; Transcriptional Activation - drug effects; Transfection
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.270.5241.1491

The phosphorylation of the human estrogen receptor (ER) serine residue at position 118 is required for full activity of the ER activation function 1 (AF-1). This Ser$^{118}$ is phosphorylated by mitogen-activated protein kinase (MAPK) in vitro and in cells treated with epidermal growth factor (EGF) and insulin-like growth factor (IGF) in vivo. Overexpression of MAPK kinase (MAPKK) or of the guanine nucleotide binding protein Ras, both of which activate MAPK, enhanced estrogen-induced and antiestrogen (tamoxifen)-induced transcriptional activity of wild-type ER, but not that of a mutant ER with an alanine in place of Ser$^{118}$. Thus, the activity of the amino-terminal AF-1 of the ER is modulated by the phosphorylation of Ser$^{118}$ through the Ras-MAPK cascade of the growth factor signaling pathways.