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Molecular and Cellular Biology, March 2003, p. 1994-2008, Vol. 23, No. 6
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.6.1994-2008.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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,{dagger} Marina Di Domenico,3 Antimo Migliaccio,3 Ferdinando Auricchio,3 and Miguel Beato1,2*

Institut für Molekularbiologie und Tumorforschung, Philipps-Universität, D-35033 Marburg, Germany,1 Dipartimento di Patología Generale, II Universitá di Napoli, I-80138 Naples, Italy,3 Centre de Regulació Genomica, Universitat Pompeu Fabra, E-08003 Barcelona, Spain2

Received 7 June 2002/ Returned for modification 29 August 2002/ Accepted 18 December 2002

In breast cancer cells, estrogens activate the Src/Erk pathway through an interaction of the estrogen receptor alpha (ER{alpha}) 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 ER{alpha}, 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 ER{alpha}. 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 ER{alpha} 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 ER{alpha}. Thus, in cells with ER{alpha}, ERID-I and ERID-II are necessary and sufficient for progestin activation of the endogenous Src/Erk pathway.

* Corresponding author. Mailing address: Centre de Regulació Genomica, Universitat Pompeu Fabra, Pg.Maritim 37-49, E-08003 Barcelona, Spain. Phone: 34-93 224 0901. Fax: 34-93 224 0899. E-mail: miguel.beato{at}crg.es.

{dagger} Present address: Department of Immunology, University Medical Center, 3584 CX Utrecht, The Netherlands.

Molecular and Cellular Biology, March 2003, p. 1994-2008, Vol. 23, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.6.1994-2008.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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