Dephosphorylation is the mechanism of fibroblast growth factor inhibition of guanylyl cyclase-B

Jerid W. Robinson, Jeremy R. Egbert, Julia Davydova, Hannes Schmidt, Laurinda A. Jaffe, Lincoln R. Potter

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)222-229
Number of pages8
JournalCellular Signalling
Volume40
DOIs
StatePublished - Dec 2017

Bibliographical note

Funding 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.

Publisher Copyright:
© 2017 Elsevier Inc.

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

Keywords

  • Achondroplasia
  • C-type natriuretic peptide
  • Cyclic GMP
  • Dwarfism
  • Fibroblast growth factor
  • Guanylyl cyclase
  • NPR2

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