Follicle-stimulating hormone activates extracellular signal-regulated kinase but not extracellular signal-regulated kinase kinase through a 100-kDa phosphotyrosine phosphatase

Joshua Cottom, Lisa M. Salvador, Evelyn T. Maizels, Scott Reierstad, Youngkyu Park, Daniel W. Carr, Monika A. Davare, Johannes W Hell, Stephen S. Palmer, Paul Dent, Hisaaki Kawakatsu, Masato Ogata, Mary Hunzicker-Dunn

Research output: Contribution to journalArticle

103 Scopus citations

Abstract

In this report we sought to elucidate the mechanism by which the follicle-stimulating hormone (FSH) receptor signals to promote activation of the p42/p44 extracellular signal-regulated protein kinases (ERKs) in granulosa cells. Results show that the ERK kinase MEK and upstream intermediates Raf-1, Ras, Src, and L-type Ca2+ channels are already partially activated in vehicle-treated cells and that FSH does not further activate them. This tonic stimulatory pathway appears to be restrained at the level of ERK by a 100-kDa phosphotyrosine phosphatase that associates with ERK in vehicle-treated cells and promotes dephosphorylation of its regulatory Tyr residue, resulting in ERK inactivation. FSH promotes the phosphorylation of this phosphotyrosine phosphatase and its dissociation from ERK, relieving ERK from inhibition and resulting in its activation by the tonic stimulatory pathway and consequent translocation to the nucleus. Consistent with this premise, FSH-stimulated ERK activation is inhibited by the cell-permeable protein kinase A-specific inhibitor peptide Myr-PKI as well as by inhibitors of MEK, Src, a Ca2+ channel blocker, and chelation of extracellular Ca2+. These results suggest that FSH stimulates ERK activity in immature granulosa cells by relieving an inhibition imposed by a 100-kDa phosphotyrosine phosphatase.

Original languageEnglish (US)
Pages (from-to)7167-7179
Number of pages13
JournalJournal of Biological Chemistry
Volume278
Issue number9
DOIs
StatePublished - Feb 28 2003
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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    Cottom, J., Salvador, L. M., Maizels, E. T., Reierstad, S., Park, Y., Carr, D. W., Davare, M. A., Hell, J. W., Palmer, S. S., Dent, P., Kawakatsu, H., Ogata, M., & Hunzicker-Dunn, M. (2003). Follicle-stimulating hormone activates extracellular signal-regulated kinase but not extracellular signal-regulated kinase kinase through a 100-kDa phosphotyrosine phosphatase. Journal of Biological Chemistry, 278(9), 7167-7179. https://doi.org/10.1074/jbc.M203901200