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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

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

Abstract

In 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

Topics: Transcriptional Regulation
Publisher: American Society for Microbiology
Year: 2003
DOI identifier: 10.1128/MCB.23.6.1994-2008.2003
OAI identifier: oai:pubmedcentral.nih.gov:149459
Provided by: PubMed Central
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