title: Frs2α and Shp2 signal independently of Gab to mediate FGF signaling in lens development.
abstract: Fibroblast growth factor (FGF) signaling requires a plethora of adaptor proteins to elicit downstream responses, but the functional significances of these docking proteins remain controversial. In this study, we used lens development as a model to investigate Frs2α and its structurally related scaffolding proteins, Gab1 and Gab2, in FGF signaling. We show that genetic ablation of Frs2α alone has a modest effect, but additional deletion of tyrosine phosphatase Shp2 causes a complete arrest of lens vesicle development. Biochemical evidence suggests that this Frs2α-Shp2 synergy reflects their epistatic relationship in the FGF signaling cascade, as opposed to compensatory or parallel functions of these two proteins. Genetic interaction experiments further demonstrate that direct binding of Shp2 to Frs2α is necessary for activation of ERK signaling, whereas constitutive activation of either Shp2 or Kras signaling can compensate for the absence of Frs2α in lens development. By contrast, knockout of Gab1 and Gab2 failed to disrupt FGF signaling in vitro and lens development in vivo. These results establish the Frs2α-Shp2 complex as the key mediator of FGF signaling in lens development.
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Hongge
authors.initials: H
authors.lastname: Li
authors.forename: Chenqi
authors.initials: C
authors.lastname: Tao
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Cai
authors.forename: Kristina
authors.initials: K
authors.lastname: Hertzler-Schaefer
authors.forename: Tamica N
authors.initials: TN
authors.lastname: Collins
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Feng
authors.forename: Noriko
authors.initials: N
authors.lastname: Gotoh
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases; D005123:Eye / Q000254:growth & development*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D007908:Lens, Crystalline / Q000254:growth & development / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics*; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C488187:FRS2alpha protein, mouse; C490897:Gab1 protein, mouse; C490894:Gab2 protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D005346:Fibroblast Growth Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: FGF; Frs2; Gab; Lens; Ras; Shp2