Residue 146 regulates prolactin receptor folding, basal activity and ligand-responsiveness: potential implications in breast tumorigenesis
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Residue 146 regulates prolactin receptor folding, basal activity and ligand-responsiveness : potential implications in breast tumorigenesis. / Zhang, Chi; Cherifi, Ibtissem; Nygaard, Mads; Haxholm, Gitte Wolfsberg; Bogorad, Roman L.; Bernadet, Marie; England, Patrick; Broutin, Isabelle; Kragelund, Birthe Brandt; Guidotti, Jacques-Emmanuel; Goffin, Vincent.
In: Molecular and Cellular Endocrinology, Vol. 401, 2015, p. 173-188.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Residue 146 regulates prolactin receptor folding, basal activity and ligand-responsiveness
T2 - potential implications in breast tumorigenesis
AU - Zhang, Chi
AU - Cherifi, Ibtissem
AU - Nygaard, Mads
AU - Haxholm, Gitte Wolfsberg
AU - Bogorad, Roman L.
AU - Bernadet, Marie
AU - England, Patrick
AU - Broutin, Isabelle
AU - Kragelund, Birthe Brandt
AU - Guidotti, Jacques-Emmanuel
AU - Goffin, Vincent
N1 - Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
PY - 2015
Y1 - 2015
N2 - PRLR(I146L) is the first identified gain-of-function variant of the prolactin receptor (PRLR) that was proposed to be associated with benign breast tumorigenesis. Structural investigations suggested this hydrophobic core position in the extracellular D2 domain to be linked to receptor dimerization. Here, we used a mutational approach to address how the conservative I-to-L substitution induced constitutive activity. Using cell-based assays of different I146-PRLR variants in combination with spectroscopic/nuclear magnetic resonance analyses we found that chemical manipulation of position 146 profoundly altered folding, PRL-responsiveness, and ligand-independent activity of the receptor in a mutation-specific manner. Together, these data further add to the critical role of position 146, showing it to also be crucial to structural integrity thereby imposing on the biological PRLR properties. When stably introduced in MCF-7 (luminal) and MDA-MB231 (mesenchymal) breast cancer cells, the most potent of the PRL-insensitive mutants (PRLR(I146D)) had minimal impact on cell proliferation and cell differentiation status.
AB - PRLR(I146L) is the first identified gain-of-function variant of the prolactin receptor (PRLR) that was proposed to be associated with benign breast tumorigenesis. Structural investigations suggested this hydrophobic core position in the extracellular D2 domain to be linked to receptor dimerization. Here, we used a mutational approach to address how the conservative I-to-L substitution induced constitutive activity. Using cell-based assays of different I146-PRLR variants in combination with spectroscopic/nuclear magnetic resonance analyses we found that chemical manipulation of position 146 profoundly altered folding, PRL-responsiveness, and ligand-independent activity of the receptor in a mutation-specific manner. Together, these data further add to the critical role of position 146, showing it to also be crucial to structural integrity thereby imposing on the biological PRLR properties. When stably introduced in MCF-7 (luminal) and MDA-MB231 (mesenchymal) breast cancer cells, the most potent of the PRL-insensitive mutants (PRLR(I146D)) had minimal impact on cell proliferation and cell differentiation status.
U2 - 10.1016/j.mce.2014.12.006
DO - 10.1016/j.mce.2014.12.006
M3 - Journal article
C2 - 25524456
VL - 401
SP - 173
EP - 188
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
SN - 0303-7207
ER -
ID: 141044199