Journal
CELLULAR SIGNALLING
Volume 40, Issue -, Pages 222-229Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2017.09.021
Keywords
Achondroplasia; C-type natriuretic peptide; Cyclic GMP; Dwarfism; Fibroblast growth factor; Guanylyl cyclase; NPR2
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Funding
- National Institutes of Health [R01GM098309, R37HD014939, T32DK007203]
- German Research Foundation (DFG) [FOR 2060, HSCHM 2371/1]
- Fund for Science and the Hormone Receptor Fund
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Activating mutations in fibroblast growth factor receptor 3 (FGFR3) and inactivating mutations of guanylyl cyclase-B (GC-B, also called NPRB or NPR2) cause dwarfism. FGF exposure inhibits GC-B activity in a chondrocyte cell line, but the mechanism of the inactivation is not known. Here, we report that FGF exposure causes dephosphorylation of GC-B in rat chondrosarcoma cells, which correlates with a rapid, potent and reversible inhibition of C-type natriuretic peptide-dependent activation of GC-B. Cells expressing a phosphomimetic mutant of GC-B that cannot be inactivated by dephosphorylation because it contains glutamate substitutions for all known phosphorylation sites showed no decrease in GC-B activity in response to FGF. We conclude that FGF rapidly inactivates GC-B by a reversible dephosphorylation mechanism, which may contribute to the signaling network by which activated FGFR3 causes dwarfism.
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