Signal transduction of the constitutively activated Fibroblast Growth Factor Receptor 3 (FGFR3)

Fibroblast growth factor receptor 3 (FGFR3) belong to the tyrosine kinase receptor (RTK) family and plays a pivotal role in skeletal development being a negative regulator of bone growth as target disruption of the mouse FGFR3 gene causes a skeletal overgrowth. Many other mutations located in different domain of FGFR3 have been associated with skeletal diseases with graded severity, in particular gain-of-function mutation affecting the codon 650 within the critical kinase domain of FGFR3. The aim of our study was to investigate, in vitro, on the role by a mutant FGFR3 associated to the severe achondroplasia with developmental delay and achanthosis nigricans (SADDAN) on cytoskeletal organization. The SADDAN mutant revealed the unpaired trafficking of the immature mannose-rich 120kDa SADDAN receptor that remain localized in the ER, and transducers signal in its immature from leading to ERKs activation trough FRS2α and PLCγ-independent pathways. We have questioned whether the intracellular position of FGFR3 signalling has a critical role on the receptor-induced phenotype. Our findings indicate that PLCPyk2, paxillin interact with the immature FGFR3-SADDAN glycomers from the ER. These events are associated to an increased phosphorylation of paxillin/Pyk2 and the perturbed actin cytoskeltal organization. Preventing the PLC/FGFR3 interaction by the Y754F amino acid substitution in FGFR3 results in the failure of both Pyk2 recruitment and paxillin enhanced phosphorylation and restores the receptor full maturation on cell surface. We propose that PLC through its early engagement with the immature FGFR3-SADDAN confers a functional signalling activity to the receptor thus forcing its permanence in the ER. Altogether the data presented herein indicate that the interaction between PLC and the activated receptor in the ER are key events to determine the FGFR3-SADDAN-perturbed cytoskeletal organization and suggest that actin cytoskeleton is a target for the FGFR3-induced skeletal dysplasias.