Fibroblast growth factor receptors 3 (FGFR3) with K644M/E substi- tutions are associated to the severe skeletal dysplasias: severe achondroplasia with developmental delay and achanthosis nigricans- (SADDAN) and thanatophoric dysplasia(TDII). The high levels of kinase activity of the FGFR3-mutants cause uncompleted biosynthesis that results in the accumulation of the immature/mannose-rich, phosphory- lated receptors in the endoplasmic reticulum (ER) and STATs activation. Here we report that FGFR3 mutants activate Erk1/2 from the ER through an FRS2-independent pathway: instead, a multimeric complex by directly recruiting PLCg, Pyk2 and JAK1 is formed. The Erk1/2 activation from the ER however, is PLCg-independent, since preventing the PLCg/FGFR3 interaction by the Y754F substitution does not inhibit Erks. Furthermore, Erk1/2 activation is abrogated upon treatment with the Src inhibitor PP2, suggesting a role played by a Src family member in the pathway from the ER. Finally we show that the intrinsic kinase activity by mutant receptors is required to allow signaling from the ER. Overall these results highlight how activated FGFR3 exhibits signaling activity in the early phase of its biosynthesis and how segregation in a sub-cellular compartment can affect the FGFR3 multi-faceted capacity to recruit specific substrates.

K644E/M FGFR3 mutants activate Erk1/2 from the endoplasmic reticulum through FRS2a and PLCgamma-independent pathways

LIEVENS, Patricia;LIBOI, Elio Maria
2006

Abstract

Fibroblast growth factor receptors 3 (FGFR3) with K644M/E substi- tutions are associated to the severe skeletal dysplasias: severe achondroplasia with developmental delay and achanthosis nigricans- (SADDAN) and thanatophoric dysplasia(TDII). The high levels of kinase activity of the FGFR3-mutants cause uncompleted biosynthesis that results in the accumulation of the immature/mannose-rich, phosphory- lated receptors in the endoplasmic reticulum (ER) and STATs activation. Here we report that FGFR3 mutants activate Erk1/2 from the ER through an FRS2-independent pathway: instead, a multimeric complex by directly recruiting PLCg, Pyk2 and JAK1 is formed. The Erk1/2 activation from the ER however, is PLCg-independent, since preventing the PLCg/FGFR3 interaction by the Y754F substitution does not inhibit Erks. Furthermore, Erk1/2 activation is abrogated upon treatment with the Src inhibitor PP2, suggesting a role played by a Src family member in the pathway from the ER. Finally we show that the intrinsic kinase activity by mutant receptors is required to allow signaling from the ER. Overall these results highlight how activated FGFR3 exhibits signaling activity in the early phase of its biosynthesis and how segregation in a sub-cellular compartment can affect the FGFR3 multi-faceted capacity to recruit specific substrates.
FGFR3; activating mutations; endoplasmic reticulum; signal transduction; tyrosine kinase receptor
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/32993
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