Open AccessTwo 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
Author(s) -
Cecilia Ballaré,
Markus Uhrig,
Thomas Bechtold,
Elena Sancho,
Marina Di Domenico,
Antimo Migliaccio,
Ferdinando Auricchio,
Miguel Beato
Publication year - 2003
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.23.6.1994-2008.2003
Subject(s) - transactivation , proto oncogene tyrosine protein kinase src , progesterone receptor , biology , mapk/erk pathway , estrogen receptor alpha , estrogen receptor , microbiology and biotechnology , estrogen receptor beta , receptor , cancer research , signal transduction , biochemistry , gene expression , cancer , gene , genetics , breast cancer
In breast cancer cells, estrogens activate the Src/Erk pathway through an interaction of the estrogen receptor alpha (ERalpha) 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 ERalpha, 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 ERalpha. 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 ERalpha 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 ERalpha. Thus, in cells with ERalpha, ERID-I and ERID-II are necessary and sufficient for progestin activation of the endogenous Src/Erk pathway.