Duration of ERK1/2 phosphorylation induced by FGF or ocular media determines lens cell fate

Iyengar, Laxmi; Wang, Qian; Rasko, John E.J.; McAvoy, John W.; Lovicu, Frank J.

doi:10.1111/j.1432-0436.2007.00167.x

Cited by 50 publications

(48 citation statements)

References 24 publications

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“…These signaling pathways are in turn regulated by a multitude of intracellular antagonists including members of the Sprouty family (36,79). Given the importance of ERK1/2 signaling in mediating lens cell behavior (80), together with the fact that Sprouty genes display very distinctive spatial expression in the lens (73), we set out to determine whether Sprouty genes are required for normal lens development and growth. Using a Cre-lox approach to conditionally delete Spry1 and Spry2 from the lens, we demonstrate that these genes are important for maintenance of the postnatal lens epithelium by reducing the susceptibility of these cells to ocular factors such as TGFβ,which are known to contribute to lens pathology leading to cataract formation.…”

Section: Discussionmentioning

confidence: 99%

Sprouty Is a Negative Regulator of Transforming Growth Factor β-Induced Epithelial-to-Mesenchymal Transition and Cataract

Shin

Basson

Robinson

et al. 2012

Mol Med

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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.

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Section: Discussionmentioning

confidence: 99%

Sprouty Is a Negative Regulator of Transforming Growth Factor β-Induced Epithelial-to-Mesenchymal Transition and Cataract

Shin

Basson

Robinson

et al. 2012

Mol Med

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“…Consistent with this notion that duration of ERK activity regulates cell behaviour, aqueous humour, which induces lens epithelial cell proliferation but not fibre differentiation, stimulated ERK1/2 phosphorylation for 4 -6 h, whereas vitreous humour induced an extended duration of ERK1/2 phosphorylation (up to 18 h) leading to lens fibre differentiation (figure 2). If the duration of vitreousinduced ERK1/2 activation was prematurely blocked at 6 h (using a selective inhibitor for FGFR signalling), the vitreous lost its ability to induce lens fibre differentiation but retained the ability to induce lens cell proliferation [25]. More recent studies in this same in vitro model have shown that while a prolonged ERK1/2 phosphorylation was associated with and necessary for fibre cell differentiation, it was not sufficient for this process to proceed normally [27].…”

Section: Lens Fibre Differentiationmentioning

confidence: 99%

Understanding the role of growth factors in embryonic development: insights from the lens

Lovicu

McAvoy

Iongh

2011

Phil. Trans. R. Soc. B

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Growth factors play key roles in influencing cell fate and behaviour during development. The epithelial cells and fibre cells that arise from the lens vesicle during lens morphogenesis are bathed by aqueous and vitreous, respectively. Vitreous has been shown to generate a high level of fibroblast growth factor (FGF) signalling that is required for secondary lens fibre differentiation. However, studies also show that FGF signalling is not sufficient and roles have been identified for transforming growth factor-b and Wnt/Frizzled families in regulating aspects of fibre differentiation. In the case of the epithelium, key roles for Wnt/b-catenin and Notch signalling have been demonstrated in embryonic development, but it is not known if other factors are required for its formation and maintenance. This review provides an overview of current knowledge about growth factor regulation of differentiation and maintenance of lens cells. It also highlights areas that warrant future study.

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“…In this study, we describe the role for the lens capsule as an ECM store of FGF-2, a growth factor required for lens epithelial cell proliferation, migration and differentiation (Robinson, 2006), most likely via MAPK signaling Iyengar et al, 2007). The data presented here provide evidence of the protective role of this ECM store of FGF-2 in a simple, well-defined experimental system that mimics the microenvironment of the lens after surgery or injury (Wormstone et al, 1997;Tamiya et al, 2000).…”

Section: The Lens Capsule Generates a Microenvironment Conducive To Ementioning

confidence: 99%

“…(Troussard et al, 1999;Lee et al, 2005), leads to the degradation of HSPGs in the ECM, allowing soluble FGF-2 release into the media. FGF-2 then binds its receptor and activates downstream signaling pathways Chandrasekher and Sailaja, 2003;Iyengar et al, 2007) to promote cell survival. This represents the simplest form of the cycle and does not exclude contributions from other proteinases, cryptogenic ECM sites, and IGF-1 and TGF-␤2 release that can all influence epithelial cell survival.…”

Section: The Lens Capsule Generates a Microenvironment Conducive To Ementioning

confidence: 99%

FGF-2 Release from the Lens Capsule by MMP-2 Maintains Lens Epithelial Cell Viability

Tholozan

Gribbon

et al. 2007

MBoC

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The lens is an avascular tissue, separated from the aqueous and vitreous humors by its own extracellular matrix, the lens capsule. Here we demonstrate that the lens capsule is a source of essential survival factors for lens epithelial cells. Primary and immortalized lens epithelial cells survive in low levels of serum and are resistant to staurosporine-induced apoptosis when they remain in contact with the lens capsule. Physical contact with the capsule is required for maximal resistance to stress. The lens capsule is also a source of soluble factors including fibroblast growth factor 2 (FGF-2) and perlecan, an extracellular matrix component that enhances FGF-2 activity. Matrix metalloproteinase 2 (MMP-2) inhibition as well as MMP-2 pretreatment of lens capsules greatly reduced the protective effect of the lens capsule, although this could be largely reversed by the addition of either conditioned medium or recombinant FGF-2. These data suggest that FGF-2 release from the lens capsule by MMP-2 is essential to lens epithelial cell viability and survival. INTRODUCTIONCell survival requires the continued exposure to specific survival factors. In a classic study (Ishizaki et al., 1993), lens epithelial cells were shown to survive in culture, in the absence of cell-cell contact, as long as the right growth factor cues were available. These factors could be provided exogenously either in the form of conditioned media or in serum supplement (Ishizaki et al., 1993), leading to the widely accepted general hypothesis that cells are programmed to die unless the appropriate signals are received.The recent proposal of the extracellular matrix (ECM) reservoir hypothesis suggests that the ECM itself can act as a reservoir for growth and survival factors (Bergers et al., 2000;Mott and Werb, 2004) that are released via the action of various matrix metalloproteinases (MMPs; reviewed in McCawley and Matrisian, 2001;Mott and Werb, 2004). MMPs have been shown to release fibroblast growth factor (FGF)-2 (MMP-1, -3; Whitelock et al., 1996) and fibroblast growth factor receptor (FGFR)-1 (MMP-2; Levi et al., 1996), activate transforming growth factor (TGF)-␤1/2 (Yu and Stamenkovic, 2000), and to both activate and release insulin-like growth factor (IGF)-1 (MMP-1, -2, -3, and -9;Fowlkes et al., 1994; and MMP-2, -3, and -7;Imai et al., 1997). MMPs are therefore an essential component in this proposed role for the ECM in cell survival and cell proliferation (Ishizuya-Oka et al., 2000;Wiseman et al., 2003). From such data, we can see that the ECM reservoir hypothesis requires three essential components: an ECM, growth factors sequestered by the ECM, and the presence of MMPs to release the growth factors from the ECM. This hypothesis changes our perception of the ECM as it can no longer be considered to solely provide a physical support or appropriate cues for integrin signaling (Hynes, 1992;Adams and Watt, 1993), but is also a source of cell proliferation and survival factors (Klagsbrun, 1990;Taipale and Keski-Oja, 1997;Bergers et al., 2000;...

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Duration of ERK1/2 phosphorylation induced by FGF or ocular media determines lens cell fate

Cited by 50 publications

References 24 publications

Sprouty Is a Negative Regulator of Transforming Growth Factor β-Induced Epithelial-to-Mesenchymal Transition and Cataract

Sprouty Is a Negative Regulator of Transforming Growth Factor β-Induced Epithelial-to-Mesenchymal Transition and Cataract

Understanding the role of growth factors in embryonic development: insights from the lens

FGF-2 Release from the Lens Capsule by MMP-2 Maintains Lens Epithelial Cell Viability

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