K644E/M FGFR3 mutants activate Erk1/2 from the endoplasmic reticulum through FRS2 alpha and PLC gamma-independent pathways.
Fibroblast growth factor receptors 3 (FGFR3) with K644M/E substitutions 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, phosphorylated 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 PLCgamma, Pyk2 and JAK1 is formed. The Erk1/2 activation from the ER however, is PLCgamma-independent, since preventing the PLCgamma/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.
Division of Biochemistry, Department of Morphological and Biomedical Sciences, University of Verona Medical School, 37134 Verona, Italy.
Patricia M-J
PM
Lievens
Alessandro
A
Roncador
Elio
E
Liboi
D000130:Achondroplasia / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D051966:Phospholipase C gamma / Q000502:physiology*; D051381:Rats; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D013796:Thanatophoric Dysplasia / Q000235:genetics
C488187:FRS2alpha protein, mouse; D008565:Membrane Proteins; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051418:Focal Adhesion Kinase 2; C496053:Ptk2b protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D051966:Phospholipase C gamma