FGFR3 signaling in chondrocyte proliferation and terminal differentiation (Homo sapiens)

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Taken from Achondroplasia: Development, Pathenogenesis, and Therapy by Ornitz DM, Legeai-Mallet L [1].

Signaling pathways in the postnatal growth plate. During endochondral bone development, FGF9 and FGF18, derived from the perichondrium and surrounding tissue, signal to FGFR3 in chondrocytes. The balance of chondrocyte proliferation and differentiation is controlled by crosstalk of several signaling pathways. Expression of FGFR3 is enhanced by thyroid hormone (T3/3,3',5'-Triiodothyronine) and suppressed by PTHLH (member of the parathyroid hormone family). FGFR3 signaling results in increased expression of Snail1 (encoded by SNAI1), which is required for activation of STAT1 and MAPK signaling (ERK1/2 and p38 branches). Signaling from PTHLH, IHH and BMPs antagonizes the suppression of chondrocyte proliferation by FGFR3. Both FGFR3 and PTHLH function to suppress chondrocyte differentiation and antagonize the action of Wnt signaling, which promotes differentiation. FGFR3 negatively regulates the autophagy protein, ATG5. Activation of downstream signals: PP2a (encoded by PPP2CA) regulates p107 (encoded by RBL1) activation, and STAT1 regulates p21Waf1/Cip1 (encoded by CKDN1A) activation. Both function to suppress chondrocyte proliferation. Activation of the MAPKs, ERK1, and ERK2, regulate Sox9 expression, which functions to suppress chondrocyte terminal differentiation and endochondral ossification.

Linked with a dotted arrow to the GeneProduct nodes are diseases caused by mutation in the respective gene.

Protein phosphorylation sites were added based on information from PhosphoSitePlus (R), www.phosphosite.org.