Follicle-stimulating hormone activates extracellular signal-regulated kinase but not extracellular signal-regulated kinase kinase through a 100-kDa phosphotyrosine phosphatase.
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 Ca(2+) 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 Ca(2+) channel blocker, and chelation of extracellular Ca(2+). These results suggest that FSH stimulates ERK activity in immature granulosa cells by relieving an inhibition imposed by a 100-kDa phosphotyrosine phosphatase.
Cottom
Joshua
J
Department of Cell, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Salvador
Lisa M
LM
Maizels
Evelyn T
ET
Reierstad
Scott
S
Park
Youngkyu
Y
Carr
Daniel W
DW
Davare
Monika A
MA
Hell
Johannes W
JW
Palmer
Stephen S
SS
Dent
Paul
P
Kawakatsu
Hisaaki
H
Ogata
Masato
M
Hunzicker-Dunn
Mary
M
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology*; D006107:Granulosa Cells / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D010053:Ovary / Q000201:enzymology; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D021381:Protein Transport; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012756:Sheep; D015398:Signal Transduction; D013449:Sulfonamides; D013997:Time Factors; D014443:Tyrosine / Q000737:chemistry
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D013449:Sulfonamides; D014443:Tyrosine; D005640:Follicle Stimulating Hormone; C482123:Braf protein, rat; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D002118:Calcium