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Elife. 2017 Dec 4;6. pii: e31343. doi: 10.7554/eLife.31343.

Dephosphorylation of the NPR2 guanylyl cyclase contributes to inhibition of bone growth by fibroblast growth factor.

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Department of Cell Biology, University of Connecticut Health Center, Farmington, United States.
Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, United States.
Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany.
Center for Regenerative Medicine and Skeletal Development, University of Connecticut Health Center, Farmington, United States.
Contributed equally


Activating mutations in fibroblast growth factor (FGF) receptor 3 and inactivating mutations in the NPR2 guanylyl cyclase both cause severe short stature, but how these two signaling systems interact to regulate bone growth is poorly understood. Here, we show that bone elongation is increased when NPR2 cannot be dephosphorylated and thus produces more cyclic GMP. By developing an in vivo imaging system to measure cyclic GMP production in intact tibia, we show that FGF-induced dephosphorylation of NPR2 decreases its guanylyl cyclase activity in growth plate chondrocytes in living bone. The dephosphorylation requires a PPP-family phosphatase. Thus FGF signaling lowers cyclic GMP production in the growth plate, which counteracts bone elongation. These results define a new component of the signaling network by which activating mutations in the FGF receptor inhibit bone growth.


NPR2 guanylyl cyclase; chondrocyte; cyclic GMP; dephosphorylation; developmental biology; fibroblast growth factor; growth plate; mouse; stem cells

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