FGFR3 signaling in chondrocyte proliferation and terminal differentiation (WP4767)

Homo sapiens

Taken from Achondroplasia: Development, Pathenogenesis, and Therapy by Ornitz DM, Legeai-Mallet L [https://www.ncbi.nlm.nih.gov/pubmed/27987249]. 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.


Ritchie Lee , Denise Slenter , Kristina Hanspers , Egon Willighagen , and Eric Weitz


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Homo sapiens


Skeletal Dysplasia


Pathway Ontology

thyroid hormone signaling pathway fibroblast growth factor signaling pathway parathyroid hormone signaling pathway

Cell Type Ontology


Disease Ontology

Muenke Syndrome


Label Type Compact URI Comment
3,3',5'-Triiodothyronine Metabolite chebi:11684
THRA GeneProduct ensembl:ENSG00000126351
PTH1R GeneProduct ensembl:ENSG00000160801
MAPK12 GeneProduct ensembl:ENSG00000188130
SNAI1 GeneProduct ensembl:ENSG00000124216
MAPK14 GeneProduct ensembl:ENSG00000112062
PTHLH GeneProduct ensembl:ENSG00000087494
FGF18 GeneProduct ensembl:ENSG00000156427
FGF9 GeneProduct ensembl:ENSG00000102678
MAPK11 GeneProduct ensembl:ENSG00000185386
STAT1 GeneProduct ensembl:ENSG00000115415
ATG5 GeneProduct ensembl:ENSG00000057663
IHH GeneProduct ensembl:ENSG00000163501
BMP2 GeneProduct ensembl:ENSG00000125845
RAF1 GeneProduct ensembl:ENSG00000132155
MAPK13 GeneProduct ensembl:ENSG00000156711
FGFR3 GeneProduct ensembl:ENSG00000068078
NPR2 GeneProduct ensembl:ENSG00000159899
CNP GeneProduct ensembl:ENSG00000173786
PTH1R GeneProduct ensembl:ENSG00000160801
BMP4 GeneProduct ensembl:ENSG00000125378
SOX9 GeneProduct ensembl:ENSG00000125398
RBL1 GeneProduct ensembl:ENSG00000080839
CDKN1A GeneProduct ensembl:ENSG00000124762
RBL1 GeneProduct ensembl:ENSG00000080839
PPP2CA GeneProduct ensembl:ENSG00000113575
MAP2K1 GeneProduct ensembl:ENSG00000169032
MAP2K2 GeneProduct ensembl:ENSG00000126934
MAPK1 GeneProduct ensembl:ENSG00000100030
MAPK3 GeneProduct ensembl:ENSG00000102882


  1. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E. Nucleic Acids Res. 2015 Jan;43(Database issue):D512-20. PubMed Europe PMC Scholia
  2. Achondroplasia: Development, pathogenesis, and therapy. Ornitz DM, Legeai-Mallet L. Dev Dyn. 2017 Apr;246(4):291–309. PubMed Europe PMC Scholia