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Two Domains of the Progesterone Receptor Interact with the Estrogen Receptor and Are Required for Progesterone Activation of the c-Src/Erk Pathway in Mammalian Cells

2003; Taylor & Francis; Volume: 23; Issue: 6 Linguagem: Inglês

10.1128/mcb.23.6.1994-2008.2003

1098-5549

Cecilia Ballaré, Markus Uhrig, Thomas Bechtold, Elena Sancho, Marina Di Domenico, Antimo Migliaccio, Ferdinando Auricchio, Miguel Beato,

Steroid Chemistry and Biochemistry

AbstractIn breast cancer cells, estrogens activate the Src/Erk pathway through an interaction of the estrogen receptor alpha (ERα) with the SH2 domain of c-Src. Progestins have been reported to activate also this pathway either via an interaction of the progesterone receptor isoform B (PRB) with ERα, which itself activates c-Src, or by direct interaction of PRB with the SH3 domain of c-Src. Here we identify two domains of PRB, ERID-I and -II, mediating a direct interaction with the ligand-binding domain of ERα. ERID-I and ERID-II flank a proline cluster responsible for binding of PRB to c-Src. In mammalian cells, the interaction of PRB with ERα and the progestin activation of the Src/Erk cascade are abolished by deletion of either ERID-I or ERID-II. These regions are not required for transactivation of a progesterone-responsive reporter gene. Mutations in the proline cluster of PRB that prevent a direct interaction with c-Src do not affect the strong activation of c-Src by progestins in the presence of ERα. Thus, in cells with ERα, ERID-I and ERID-II are necessary and sufficient for progestin activation of the endogenous Src/Erk pathway. ACKNOWLEDGMENTSWe thank Vincent Cavaillés (Montpellier), Giulio Superti-Furga (EMBL Heidelberg), and Pierre Chambon (Strasbourg) for various plasmids and Jürg Klug (Marburg) for help in preparing the manuscript.This work was supported by grants from the Deutsche Krebshilfe, the European Union Biomed Program, the Kempkes-Stiftung, and the Associazione Italiana per la Ricerca sul Cancro.