title: Sprouty is a negative regulator of transforming growth factor β-induced epithelial-to-mesenchymal transition and cataract.
abstract: Fibrosis affects an extensive range of organs and is increasingly acknowledged as a major component of many chronic disorders. It is now well accepted that the elevated expression of certain inflammatory cell-derived cytokines, especially transforming growth factor β (TGFβ), is involved in the epithelial-to-mesenchymal transition (EMT) leading to the pathogenesis of a diverse range of fibrotic diseases. In lens, aberrant TGFβ signaling has been shown to induce EMT leading to cataract formation. Sproutys (Sprys) are negative feedback regulators of receptor tyrosine kinase (RTK)-signaling pathways in many vertebrate systems, and in this study we showed that they are important in the murine lens for promoting the lens epithelial cell phenotype. Conditional deletion of Spry1 and Spry2 specifically from the lens leads to an aberrant increase in RTK-mediated extracellular signal-regulated kinase 1/2 phosphorylation and, surprisingly, elevated TGFβ-related signaling in lens epithelial cells, leading to an EMT and subsequent cataract formation. Conversely, increased Spry overexpression in lens cells can suppress not only TGFβ-induced signaling, but also the accompanying EMT and cataract formation. On the basis of these findings, we propose that a better understanding of the relationship between Spry and TGFβ signaling will not only elucidate the etiology of lens pathology, but will also lead to the development of treatments for other fibrotic-related diseases associated with TGFβ-induced EMT.
authors.affiliation: Anatomy and Histology, Bosch Institute & Save Sight Institute, University of Sydney, Sydney, Australia.
authors.forename: Eun Hye H
authors.initials: EH
authors.lastname: Shin
authors.forename: M Albert
authors.initials: MA
authors.lastname: Basson
authors.forename: Michael L
authors.initials: ML
authors.lastname: Robinson
authors.forename: John W
authors.initials: JW
authors.lastname: McAvoy
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Lovicu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002386:Cataract / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D007908:Lens, Crystalline / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; C425468:Spry1 protein, mouse; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse