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Proline-rich tyrosine kinase 2 mediates gonadotropin-releasing hormone signaling to a specific extracellularly regulated kinase-sensitive transcriptional locus in the …
Year:
2007
Source of publication :
Molecular Endocrinology
Authors :
Bonfil, David J.
;
.
Volume :
21
Co-Authors:

Stuart Maudsley, Lindsay Davidson, Dimitra Karali, Adam J. Pawson, Rachel Larder, Caroline Pope, Nancy Nelson, Robert P. Millar, Pamela Brown - Medical Research Council Human Reproductive Sciences Unit,The Queen’s Medical Research Institute, Edinburgh EH16 4TJ, Scotland, United Kingdom;

Zvi Naor - Medical Research Council Human Reproductive Sciences Unit ,The Queen’s Medical Research Institute, Edinburgh EH16 4TJ, Scotland, United Kingdom;

Facilitators :
From page:
1216
To page:
1233
(
Total pages:
18
)
Abstract:

G protein-coupled receptor regulation of gene transcription primarily occurs through the phosphorylation of transcription factors by MAPKs. This requires transduction of an activating signal via scaffold proteins that can ultimately determine the outcome by binding signaling kinases and adapter proteins with effects on the target transcription factor and locus of activation. By investigating these mechanisms, we have elucidated how pituitary gonadotrope cells decode an input GnRH signal into coherent transcriptional output from the LH β-subunit gene promoter. We show that GnRH activates c-Src and multiple members of the MAPK family, c-Jun NH2-terminal kinase 1/2, p38MAPK, and ERK1/2. Using dominant-negative point mutations and chemical inhibitors, we identified that calcium-dependent proline-rich tyrosine kinase 2 specifically acts as a scaffold for a focal adhesion/cytoskeleton-dependent complex comprised of c-Src, Grb2, and mSos that translocates an ERK-activating signal to the nucleus. The locus of action of ERK was specifically mapped to early growth response-1 (Egr-1) DNA binding sites within the LH β-subunit gene proximal promoter, which was also activated by p38MAPK, but not c-Jun NH2-terminal kinase 1/2. Egr-1 was confirmed as the transcription factor target of ERK and p38MAPK by blockade of protein expression, transcriptional activity, and DNA binding. We have identified a novel GnRH-activated proline-rich tyrosine kinase 2-dependent ERK-mediated signal transduction pathway that specifically regulates Egr-1 activation of the LH β-subunit proximal gene promoter, and thus provide insight into the molecular mechanisms required for differential regulation of gonadotropin gene expression.

Note:
Related Files :
gonadotropin
Gonadotropin-Releasing Hormone
G protein coupled receptor
G proteins
Kinases
proline
Show More
Related Content
More details
DOI :
https://doi.org/10.1210/me.2006-0053
Article number:
0
Affiliations:
Database:
Google Scholar
Publication Type:
article
;
.
Language:
English
Editors' remarks:
ID:
39217
Last updated date:
02/03/2022 17:27
Creation date:
05/02/2019 09:36
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Scientific Publication
Proline-rich tyrosine kinase 2 mediates gonadotropin-releasing hormone signaling to a specific extracellularly regulated kinase-sensitive transcriptional locus in the …
21

Stuart Maudsley, Lindsay Davidson, Dimitra Karali, Adam J. Pawson, Rachel Larder, Caroline Pope, Nancy Nelson, Robert P. Millar, Pamela Brown - Medical Research Council Human Reproductive Sciences Unit,The Queen’s Medical Research Institute, Edinburgh EH16 4TJ, Scotland, United Kingdom;

Zvi Naor - Medical Research Council Human Reproductive Sciences Unit ,The Queen’s Medical Research Institute, Edinburgh EH16 4TJ, Scotland, United Kingdom;

Proline-rich tyrosine kinase 2 mediates gonadotropin-releasing hormone signaling to a specific extracellularly regulated kinase-sensitive transcriptional locus in the … .

G protein-coupled receptor regulation of gene transcription primarily occurs through the phosphorylation of transcription factors by MAPKs. This requires transduction of an activating signal via scaffold proteins that can ultimately determine the outcome by binding signaling kinases and adapter proteins with effects on the target transcription factor and locus of activation. By investigating these mechanisms, we have elucidated how pituitary gonadotrope cells decode an input GnRH signal into coherent transcriptional output from the LH β-subunit gene promoter. We show that GnRH activates c-Src and multiple members of the MAPK family, c-Jun NH2-terminal kinase 1/2, p38MAPK, and ERK1/2. Using dominant-negative point mutations and chemical inhibitors, we identified that calcium-dependent proline-rich tyrosine kinase 2 specifically acts as a scaffold for a focal adhesion/cytoskeleton-dependent complex comprised of c-Src, Grb2, and mSos that translocates an ERK-activating signal to the nucleus. The locus of action of ERK was specifically mapped to early growth response-1 (Egr-1) DNA binding sites within the LH β-subunit gene proximal promoter, which was also activated by p38MAPK, but not c-Jun NH2-terminal kinase 1/2. Egr-1 was confirmed as the transcription factor target of ERK and p38MAPK by blockade of protein expression, transcriptional activity, and DNA binding. We have identified a novel GnRH-activated proline-rich tyrosine kinase 2-dependent ERK-mediated signal transduction pathway that specifically regulates Egr-1 activation of the LH β-subunit proximal gene promoter, and thus provide insight into the molecular mechanisms required for differential regulation of gonadotropin gene expression.

Scientific Publication
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