This Article Full Text Full Text (PDF) All Versions of this Article: 21/5/1216    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Maudsley, S. Articles by Brown, P. Search for Related Content PubMed PubMed Citation Articles by Maudsley, S. Articles by Brown, P.

Proline-Rich Tyrosine Kinase 2 Mediates Gonadotropin-Releasing Hormone Signaling to a Specific Extracellularly Regulated Kinase-Sensitive Transcriptional Locus in the Luteinizing Hormone ß-Subunit Gene

Medical Research Council Human Reproductive Sciences Unit (S.M., Z.N., L.D., D.K., A.J.P., R.L., C.P., N.N., R.P.M., P.B.), The Queen’s Medical Research Institute, Edinburgh EH16 4TJ, Scotland, United Kingdom; and Department of Biochemistry (Z.N., D.B.), The George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel

Address requests for reprints and all correspondence to: Pamela Brown, Medical Research Council Human Reproductive Sciences Unit, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom. E-mail: p.brown{at}hrsu.mrc.ac.uk.

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 ß-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 ß-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 ß-subunit proximal gene promoter, and thus provide insight into the molecular mechanisms required for differential regulation of gonadotropin gene expression.

This article has been cited by other articles:

				J. Xie, K. H. Allen, A. Marguet, K. A. Berghorn, S. P. Bliss, A. M. Navratil, J. L. Guan, and M. S. Roberson Analysis of the Calcium-Dependent Regulation of Proline-Rich Tyrosine Kinase 2 by Gonadotropin-Releasing Hormone Mol. Endocrinol., October 1, 2008; 22(10): 2322 - 2335. [Abstract] [Full Text] [PDF]