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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

Two Domains of the Progesterone Receptor Interact with the Estrogen Receptor and Are Required for... 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 Cecilia Ballaré 1 , 2 , Markus Uhrig 1 , Thomas Bechtold 1 , 2 , Elena Sancho 1 , † , Marina Di Domenico 3 , Antimo Migliaccio 3 , Ferdinando Auricchio 3 and Miguel Beato 1 , 2 , * 1 Institut für Molekularbiologie und Tumorforschung, Philipps-Universität, D-35033 Marburg, Germany 3 Dipartimento di Patología Generale, II Universitá di Napoli, I-80138 Naples, Italy 2 Centre de Regulació Genomica, Universitat Pompeu Fabra, E-08003 Barcelona, Spain 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Molecular and Cellular Biology American Society For Microbiology

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

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

Molecular and Cellular Biology , Volume 23 (6): 1994 – Mar 15, 2003

Abstract

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 Cecilia Ballaré 1 , 2 , Markus Uhrig 1 , Thomas Bechtold 1 , 2 , Elena Sancho 1 , † , Marina Di Domenico 3 , Antimo Migliaccio 3 , Ferdinando Auricchio 3 and Miguel Beato 1 , 2 , * 1 Institut für Molekularbiologie und Tumorforschung, Philipps-Universität, D-35033 Marburg, Germany 3 Dipartimento di Patología Generale, II Universitá di Napoli, I-80138 Naples, Italy 2 Centre de Regulació Genomica, Universitat Pompeu Fabra, E-08003 Barcelona, Spain 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.

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Publisher
American Society For Microbiology
Copyright
Copyright © 2003 by the American society for Microbiology.
ISSN
0270-7306
eISSN
1098-5549
DOI
10.1128/MCB.23.6.1994-2008.2003
Publisher site
See Article on Publisher Site

Abstract

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 Cecilia Ballaré 1 , 2 , Markus Uhrig 1 , Thomas Bechtold 1 , 2 , Elena Sancho 1 , † , Marina Di Domenico 3 , Antimo Migliaccio 3 , Ferdinando Auricchio 3 and Miguel Beato 1 , 2 , * 1 Institut für Molekularbiologie und Tumorforschung, Philipps-Universität, D-35033 Marburg, Germany 3 Dipartimento di Patología Generale, II Universitá di Napoli, I-80138 Naples, Italy 2 Centre de Regulació Genomica, Universitat Pompeu Fabra, E-08003 Barcelona, Spain 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.

Journal

Molecular and Cellular BiologyAmerican Society For Microbiology

Published: Mar 15, 2003

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