Residue 146 regulates prolactin receptor folding, basal activity and ligand-responsiveness: potential implications in breast tumorigenesis

Chi Zhang; Ibtissem Cherifi; Mads Nygaard; Gitte Wolfsberg Haxholm; Roman L. Bogorad; Marie Bernadet; Patrick England; Isabelle Broutin; Birthe Brandt Kragelund; Jacques-Emmanuel Guidotti; Vincent Goffin

doi:10.1016/j.mce.2014.12.006

Residue 146 regulates prolactin receptor folding, basal activity and ligand-responsiveness: potential implications in breast tumorigenesis

Chi Zhang, Ibtissem Cherifi, Mads Nygaard, Gitte Wolfsberg Haxholm, Roman L. Bogorad, Marie Bernadet, Patrick England, Isabelle Broutin, Birthe Brandt Kragelund, Jacques-Emmanuel Guidotti, Vincent Goffin

Biomolecular Sciences

7 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Molecular and Cellular Endocrinology
Volume	401
Pages (from-to)	173-188
Number of pages	16
ISSN	0303-7207
DOIs	https://doi.org/10.1016/j.mce.2014.12.006
Publication status	Published - 5 Feb 2015

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Zhang, C., Cherifi, I., Nygaard, M., Haxholm, G. W., Bogorad, R. L., Bernadet, M., England, P., Broutin, I., Kragelund, B. B., Guidotti, J.-E., & Goffin, V. (2015). Residue 146 regulates prolactin receptor folding, basal activity and ligand-responsiveness: potential implications in breast tumorigenesis. Molecular and Cellular Endocrinology, 401, 173-188. https://doi.org/10.1016/j.mce.2014.12.006

Zhang, C, Cherifi, I, Nygaard, M, Haxholm, GW, Bogorad, RL, Bernadet, M, England, P, Broutin, I, Kragelund, BB, Guidotti, J-E & Goffin, V 2015, 'Residue 146 regulates prolactin receptor folding, basal activity and ligand-responsiveness: potential implications in breast tumorigenesis', Molecular and Cellular Endocrinology, vol. 401, pp. 173-188. https://doi.org/10.1016/j.mce.2014.12.006

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title = "Residue 146 regulates prolactin receptor folding, basal activity and ligand-responsiveness: potential implications in breast tumorigenesis",

abstract = "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.",

author = "Chi Zhang and Ibtissem Cherifi and Mads Nygaard and Haxholm, {Gitte Wolfsberg} and Bogorad, {Roman L.} and Marie Bernadet and Patrick England and Isabelle Broutin and Kragelund, {Birthe Brandt} and Jacques-Emmanuel Guidotti and Vincent Goffin",

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doi = "10.1016/j.mce.2014.12.006",

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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

PY - 2015/2/5

Y1 - 2015/2/5

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

SN - 0303-7207

VL - 401

SP - 173

EP - 188

JO - Molecular and Cellular Endocrinology

JF - Molecular and Cellular Endocrinology

ER -

Residue 146 regulates prolactin receptor folding, basal activity and ligand-responsiveness: potential implications in breast tumorigenesis

Abstract

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