The paradox of FGFR3 signaling in skeletal dysplasia: why chondrocytes growth arrest while other cells over proliferate.

[achondroplasia]

Somatic mutations in receptor tyrosine kinase FGFR 3 cause excessive cell proliferation , leading to cancer or skin overgrowth . Remarkably , the same mutations inhibit chondrocyte proliferation and differentiation in developing bones , resulting in skeletal dysplasias , such as hypochondroplasia , achondroplasia , SADDAN and thanatophoric dysplasia . A similar phenotype is observed in Noonan syndrome , Leopard syndrome , hereditary gingival fibromatosis , neurofibromatosis type 1 , Costello syndrome , Legius syndrome and cardiofaciocutaneous syndrome . Collectively termed RASopathies , the latter syndromes are caused by germline mutations in components of the RAS /ERK MAP kinase signaling pathway . This article considers the evidence suggesting that FGFR 3 activation in chondrocytes mimics the activation of major oncogenes signaling via the ERK pathway . Subsequent inhibition of chondrocyte proliferation in FGFR 3 -related skeletal dysplasias and RASopathies is proposed to result from activation of defense mechanisms that originally evolved to safeguard mammalian organisms against cancer .

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achondroplasia

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