Activation of mitogen-activated protein kinase phosphatase 2 by gonadotropin-releasing hormone.
The aim of these studies was to identify the signaling mechanism(s) that contribute to GnRH-induced expression of MAPK phosphatase (MKP)-2, a dual specificity phosphatase that selectively inactivates MAPKs. GnRH receptor activation induced MKP-2 expression in both clonal (alphaT3-1) and primary gonadotropes. Activation of PKC isozymes was sufficient and required for MKP-2 induction. Inhibition of the extracellular signal-regulated kinase (ERK) or c-Jun N-terminal kinase (JNK) but not the p38 MAPK cascade was sufficient to block GnRH-induced MKP-2 expression. Induction of MKP-2 by GnRH was dependent on elevation in intracellular Ca(2+). Inhibition of Ca(2+) influx through L-type voltage-gated calcium channels blocked GnRH-induced MKP-2 expression. Depletion of intracellular Ca(2+) stores with thapsigargin blocked MKP-2 activation by GnRH independent of ERK and JNK activity. These results support the conclusion that MKP-2 induction by GnRH occurs via MAPK-dependent and -independent pathways. One mechanism requires GnRH-induced ERK and JNK activation, while a second MAPK-independent pathway requires a thapsigargin-sensitive calcium signal.
Zhang
T
T
Department of Biomedical Sciences, College of Veterinary Medicine, T6-008a Veterinary Research Tower, Cornell University, Ithaca, NY 14853, USA.
Mulvaney
J M
JM
Roberson
M S
MS
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D054637:Dual-Specificity Phosphatases; D004789:Enzyme Activation / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8; D054639:Mitogen-Activated Protein Kinase Phosphatases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010902:Pituitary Gland / Q000166:cytology; D011493:Protein Kinase C / Q000494:pharmacology; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction
D007987:Gonadotropin-Releasing Hormone; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054648:Protein Phosphatase 2; D054637:Dual-Specificity Phosphatases; C094132:Dusp4 protein, rat; D017027:Protein Tyrosine Phosphatases; D002118:Calcium