Frs2α and Shp2 signal independently of Gab to mediate FGF signaling in lens development

Li, Hongge; Tao, Chenqi; Cai, Zhigang; Hertzler-Schaefer, Kristina; Collins, Tamica N.; Wang, Fen; Feng, Gen‐Sheng; Gotoh, Noriko; Zhang, Xin

doi:10.1242/jcs.134478

Cited by 34 publications

(33 citation statements)

References 50 publications

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“…However, the mechanism by which lens epithelial cells upregulate FGFR expression was previously unclear. Prox1 protein levels are dramatically upregulated in the posterior LV and at the onset of secondary fiber differentiation throughout life (Duncan et al, 2002), a process that is dependent on FGFR signaling in the lens (Li et al, 2014;Zhao et al, 2008). Here, we demonstrate that exogenous FGF is sufficient to stimulate nuclear Prox1 levels in lens explants and that this process requires signaling through the MAPK pathway (see Fig.…”

Section: Prox1 and Fgfrs Form A Novel Regulatory Loop That Regulates supporting

confidence: 51%

Prox1 and fibroblast growth factor receptors form a novel regulatory loop controlling lens fiber differentiation and gene expression

Audette

Anand

et al. 2015

Development

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Lens epithelial cells differentiate into lens fibers (LFs) in response to a fibroblast growth factor (FGF) gradient. This cell fate decision requires the transcription factor Prox1, which has been hypothesized to promote cell cycle exit in differentiating LF cells. However, we find that conditional deletion of Prox1 from mouse lenses results in a failure in LF differentiation despite maintenance of normal cell cycle exit. Instead, RNA-seq demonstrated that Prox1 functions as a global regulator of LF cell gene expression. Intriguingly, Prox1 also controls the expression of fibroblast growth factor receptors (FGFRs) and can bind to their promoters, correlating with decreased downstream signaling through MAPK and AKT in Prox1 mutant lenses. Further, culturing rat lens explants in FGF increased their expression of Prox1, and this was attenuated by the addition of inhibitors of MAPK. Together, these results describe a novel feedback loop required for lens differentiation and morphogenesis, whereby Prox1 and FGFR signaling interact to mediate LF differentiation in response to FGF.

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Section: Prox1 and Fgfrs Form A Novel Regulatory Loop That Regulates supporting

confidence: 51%

Prox1 and fibroblast growth factor receptors form a novel regulatory loop controlling lens fiber differentiation and gene expression

Audette

Anand

et al. 2015

Development

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“…This raises the interesting question: which intracellular molecules mediate the unique activity of FGF in the lens fiber cells? Recent work suggests that the key transmitters of FGF signaling are Frs2, an adaptor protein specific to FGF tyrosine kinase receptors [206], and Shp2, a protein tyrosine phosphatase [144, 207–209]. Constitutively active Ras signaling can compensate for the loss of Frs2 and Shp2 in cell proliferation and differentiation, whereas PI3K signaling rescues an FGF receptor 2 (Fgfr2) deficiency for cell survival, suggesting that FGF signaling employs a compendium of downstream pathways to regulate lens development [146, 207].…”

Section: Reiterative Use Of the Same Genes And Signaling Pathways Dirmentioning

confidence: 99%

Signaling and Gene Regulatory Networks in Mammalian Lens Development

2017

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Ocular lens development represents an advantageous system to study regulatory mechanisms governing cell fate decisions, extracellular signaling, cell and tissue organization, and underlying gene regulatory networks. Spatiotemporaly regulated domains of BMP, FGF, and other signaling molecules in the late gastrula-early neurula stage embryos generate the border region between the neural plate and non-neural ectoderm from which multiple cell types, including lens progenitor cells, emerge and undergo initial tissue formation. Extracellular signaling and DNA-binding transcription factors govern lens and optic cup morphogenesis. Pax6, c-Maf, Hsf4, Prox1, Sox1, and a few additional factors regulate expression of the lens structural proteins, the crystallins. A multitude of cross-talks between a diverse array of signaling pathways control the complexity and order of the lens morphogenetic processes and its transparency.

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“…S1E). We recently showed that FGF signaling requires cooperation between Frs2α and Shp2 to activate Ras signaling in eye development (21,22). This genetic pathway is apparently conserved in skin lesion, as Pten CKO ;Shp2…”

Section: ;Frs2αmentioning

confidence: 99%

Targeting of Ras-mediated FGF signaling suppresses Pten-deficient skin tumor

Mathew

Hannan

Hertzler-Schaefer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Deficiency in PTEN (phosphatase and tensin homolog deleted on chromosome 10) is the underlying cause of PTEN hamartoma tumor syndrome and a wide variety of human cancers. In skin epidermis, we have previously identified an autocrine FGF signaling induced by loss of Pten in keratinocytes. In this study, we demonstrate that skin hyperplasia requires FGF receptor adaptor protein Frs2α and tyrosine phosphatase Shp2, two upstream regulators of Ras signaling. Although the PI3-kinase regulatory subunits p85α and p85β are dispensable, the PI3-kinase catalytic subunit p110α requires interaction with Ras to promote hyperplasia in Pten-deficient skin, thus demonstrating an important crosstalk between Ras and PI3K pathways. Furthermore, genetic and pharmacological inhibition of Ras-MAPK pathway impeded epidermal hyperplasia in Pten animals. These results reveal a positive feedback loop connecting Pten and Ras pathways and suggest that FGF-activated Ras-MAPK pathway is an effective therapeutic target for preventing skin tumor induced by aberrant Pten signaling.

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Frs2α and Shp2 signal independently of Gab to mediate FGF signaling in lens development

Cited by 34 publications

References 50 publications

Prox1 and fibroblast growth factor receptors form a novel regulatory loop controlling lens fiber differentiation and gene expression

Prox1 and fibroblast growth factor receptors form a novel regulatory loop controlling lens fiber differentiation and gene expression

Signaling and Gene Regulatory Networks in Mammalian Lens Development

Targeting of Ras-mediated FGF signaling suppresses Pten-deficient skin tumor

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