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

Cell Signal. 2017 Dec;40:222-229. doi: 10.1016/j.cellsig.2017.09.021. Epub 2017 Sep 28.

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.

Keywords: Achondroplasia; C-type natriuretic peptide; Cyclic GMP; Dwarfism; Fibroblast growth factor; Guanylyl cyclase; NPR2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chondrocytes / metabolism
  • Cyclic GMP / genetics
  • Disease Models, Animal
  • Dwarfism / genetics*
  • Dwarfism / metabolism
  • Dwarfism / pathology
  • Glutamic Acid / metabolism
  • Humans
  • Natriuretic Peptide, C-Type / genetics*
  • Phosphorylation
  • Rats
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics*
  • Receptor, Fibroblast Growth Factor, Type 3 / metabolism
  • Receptors, Atrial Natriuretic Factor / genetics*
  • Receptors, Atrial Natriuretic Factor / metabolism
  • Signal Transduction

Substances

  • Natriuretic Peptide, C-Type
  • Glutamic Acid
  • Receptor, Fibroblast Growth Factor, Type 3
  • Receptors, Atrial Natriuretic Factor
  • atrial natriuretic factor receptor B
  • Cyclic GMP