Browsing by Author "Hertzler-Schaefer, Kristina"

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    Frs2α and Shp2 signal independently of Gab to mediate FGF signaling in lens development
    (Company of Biologists, 2014-02-01) Li, Hongge; Tao, Chenqi; Cai, Zhigang; Hertzler-Schaefer, Kristina; Collins, Tamica N.; Wang, Fen; Feng, Gen-Sheng; Gotoh, Noriko; Zhang, Xin; Department of Medical and Molecular Genetics, IU School of Medicine
    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.
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    Pten loss induces autocrine FGF signaling to promote skin tumorigenesis
    (Elsevier, 2014) Hertzler-Schaefer, Kristina; Mathew, Grinu; Somani, Ally-Khan; Tholpady, Sunil; Kadakia, Madhavi P.; Chen, Yiping; Spandau, Dan F.; Zhang, Xin; Dermatology, School of Medicine
    Inactivation of the Pten tumor suppressor negatively regulates the PI3K-mTOR pathway. In a model of cutaneous squamous cell carcinoma (SCC), we demonstrate that deletion of Pten strongly elevates Fgf10 protein levels without increasing Fgf10 transcription in vitro and in vivo. The translational activation of Fgf10 by Pten deletion is reversed by genetic disruption of the mTORC1 complex, which also prevents skin tumorigenesis in Pten mutants. We further show that ectopic expression of Fgf10 causes skin papillomas, whereas Pten deletion-induced skin tumors are inhibited by epidermal deletion of Fgfr2. Collectively, our data identify autocrine activation of FGF signaling as an essential mechanism in promoting Pten-deficient skin tumors.