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

Leia C. Shuhaibar, Jerid W. Robinson, Giulia Vigone, Ninna P. Shuhaibar, Jeremy R. Egbert, Valentina Baena, Tracy F. Uliasz, Deborah Kaback, Siu Pok Yee, Robert Feil, Melanie C. Fisher, Caroline N. Dealy, Lincoln R. Potter, Laurinda A. Jaffe

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8 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere31343
JournaleLife
Volume6
DOIs
StatePublished - Dec 4 2017

Bibliographical note

Funding Information:
We thank Liping Wang and David Rowe for help with x-ray imaging, Hannes Schmidt for his generous gift of the NPR2 antibody, and Viacheslav Nikolaev, Susan Ratzan, and Melina Schuh for helpful discussions. We also thank the reviewers, Gail Mandel, Eric Espiner, and anonymous, for thoughtful and insightful comments. This work was supported by grants from the National Institutes of Health (R37HD014939 to LAJ, R01GM098309 to LRP, T32DK007203 to JWR, and R90DE022526 to NPS), and from the Fund for Science (to LCS, CND, LRP, and LAJ). Eunice Kennedy Shriver National Institute of Child Health and Human Development R37HD014939 Laurinda A Jaffe National Institute of General Medical Sciences R01GM098309 Lincoln R Potter National Institute of Diabetes and Digestive and Kidney Diseases Postdoctoral training grant: T32DK007203 Jerid W Robinson National Institute of Dental and Craniofacial Research Postdoctoral training grant: R90DE022526 Ninna P Shuhaibar Fund for Science Postdoctoral scholarship (mentor) Laurinda A Jaffe Fund for Science Postdoctoral scholarship (postdoc) Leia C Shuhaibar Fund for Science Research grant Caroline N Dealy Lincoln R Potter.

Funding Information:
We thank Liping Wang and David Rowe for help with x-ray imaging, Hannes Schmidt for his generous gift of the NPR2 antibody, and Viacheslav Nikolaev, Susan Ratzan, and Melina Schuh for helpful discussions. We also thank the reviewers, Gail Mandel, Eric Espiner, and anonymous, for thoughtful and insightful comments. This work was supported by grants from the National Institutes of Health (R37HD014939 to LAJ, R01GM098309 to LRP, T32DK007203 to JWR, and R90DE022526 to NPS), and from the Fund for Science (to LCS, CND, LRP, and LAJ).

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