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.
Bibliographical noteFunding Information:
We thank Kari Jacobsen for expert preparation of the GC-B-WT and GC-B-7E adenoviruses. This work was supported by National Institutes of Health Grants, R01GM098309 to LRP, R37HD014939 to LAJ, T32DK007203 to JWR, by a German Research Foundation (DFG) grant (FOR 2060, HSCHM 2371/1 ) to HS and by the Fund for Science and the Hormone Receptor Fund.
© 2017 Elsevier Inc.
- C-type natriuretic peptide
- Cyclic GMP
- Fibroblast growth factor
- Guanylyl cyclase