Mitogen-activated protein kinase cascade in human normal and tumoral parathyroid cells.
The calcium-sensing receptor (CaR) activation has recently been shown to modulate the ERK1 and ERK2 cascade in different cell lines. The present study investigated this pathway in human normal and tumoral parathyroid cells. In cells from normal parathyroids and almost all hyperplasia increasing extracellular calcium concentrations (Ca(o)(2+)) induced a significant activation of ERK1 and -2, the percent stimulation over basal activity (at 0.5 mM Ca(o)(2+)) being 545 +/- 140 and 800 +/- 205 in normal cells and 290 +/- 71 and 350 +/- 73 in hyperplasia at 1 and 2 mM Ca(o)(2+), respectively. This effect was mediated by CaR because it was mimicked by the receptor agonist gadolinium and neomycin. Basal and Ca(o)(2+)-stimulated ERK1 and -2 activity was nearly abolished by the PKC inhibitor calphostin C, and PKA changes did not affect ERK1 and -2 activity. PI3K blockade by wortmannin, known to prevent G protein betagamma subunit effect on ERK1 and -2, induced a 30% reduction of the Ca(o)(2+)-stimulated ERK1 and -2 activity. Adenomatous cells showed high PKC-dependent ERK1 and -2 activity in resting conditions that was unresponsive to high Ca(o)(2+). A role of MAPK on PTH secretion was suggested by the finding that PD98059, a specific MEK inhibitor, abolished the inhibitory effect of 1.5 mM Ca(o)(2+) on PTH release from normal parathyroid cells. In conclusion, these data first demonstrate that CaR activation, through the PKC pathway and, to a lesser extent, PI3K, increases ERK1 and -2 activity in normal parathyroid cells and this cascade seems to be involved in the modulation of PTH secretion by Ca(o)(2+). Interestingly, this signaling pathway is disrupted in parathyroid tumors.
Corbetta
S
S
Institute of Endocrine Science, Ospedale Maggiore IRCCS, Milan, Italy 20122.
Lania
A
A
Filopanti
M
M
Vicentini
L
L
Ballaré
E
E
Spada
A
A
D000236:Adenoma / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D006801:Humans; D006965:Hyperplasia; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D010280:Parathyroid Glands / Q000378:metabolism / Q000473:pathology; D010281:Parathyroid Hormone / Q000378:metabolism; D010282:Parathyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000378:metabolism; D012016:Reference Values
D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; D020928:Mitogen-Activated Protein Kinases