Figure 7. A working model of the crosstalk between NPR2 and FGFR3 signaling pathways in regulating bone elongation, emphasizing the dephosphorylation and inactivation of NPR2 in response to FGFR3 signaling (orange box).

This diagram shows only some aspects of FGFR3 signaling in the growth plate; see Karuppaiah et al. (2016) and Ornitz and Legeai-Mallet (2017) for current models showing other components as well. Our findings indicate that FGF activation of its receptor FGFR3 acts by way of a PPP family phosphatase to decrease the phosphorylation and activity of the NPR2 guanylyl cyclase, thus reducing production of cGMP. Cyclic GMP increases bone growth by activating the cGMP-dependent protein kinase PRKG2. FGFR3 also acts by way of the mitogen-activated protein kinase (MAPK) to oppose bone elongation. One consequence of PRKG2 kinase activation is to inhibit MAPK (solid blue line), with the net effect of increasing bone elongation. PRKG2 may act by other pathways as well, as depicted by the dotted blue line. See main text for references.