Human Cataract Mutations in EPHA2 SAM Domain Alter Receptor Stability and Function

Park, Jeong Eun; Son, Alexander I.; Hua, Rui; Wang, Lianqing; Zhang, Xue; Zhou, Ran

doi:10.1371/journal.pone.0036564

Cited by 41 publications

(46 citation statements)

References 66 publications

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“…This work is consistent with a recent study revealing disorganized lens cells and altered lens refractive index in Epha2 −/− lenses (Shi et al, 2012). Dysfunction of EphA2 due to mutations and other insults is likely to perturb lens equatorial cell morphogenesis, alters the organization and interaction among lens fiber cells, causes abnormal refractive index and leads to both congenital and age-related cataracts in humans and mice (Jun et al, 2009;Kaul et al, 2010;Park et al, 2012;Shiels et al, 2008;Sundaresan et al, 2012;Tan et al, 2011;Zhang et al, 2009).…”

Section: Research Articlesupporting

confidence: 91%

“…Recent studies, including our work, have reported that EphA2 or ephrin A5 mutations cause cataracts with variable severity or incomplete penetrance in humans and mice (Cheng and Gong, 2011;Cooper et al, 2008;Jun et al, 2009;Kaul et al, 2010;Masoodi et al, 2012;Park et al, 2012;Shi et al, 2012;Shiels et al, 2008;Sundaresan et al, 2012;Tan et al, 2011;Zhang et al, 2009). Bidirectional signals mediated by membrane-anchored ephrins and Eph receptor tyrosine kinases play important roles in a broad range of cell-cell recognition events, including axon pathfinding, early segmentation and organ morphogenesis, by modulating cell repulsive or adhesive signals through multiple downstream proteins, such as Ras/Rho, MAP kinase, Akt or FAK, that are crucial for intracellular signal transduction and cytoskeletal dynamics (Arvanitis and Davy, 2008;Himanen et al, 2007;Kullander and Klein, 2002).…”

Section: Introductionmentioning

confidence: 50%

“…Mutations in EPHA2 cause human congenital dominant (Park et al, 2012;Zhang et al, 2009) and recessive (Kaul et al, 2010) cataracts. In addition, non-synonymous SNPs of EPHA2 have been linked to age-related cortical cataracts in humans (Masoodi et al, 2012;Shiels et al, 2008;Sundaresan et al, 2012;Tan et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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EphA2 and Src regulate equatorial cell morphogenesis during lens development

et al. 2013

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SUMMARYHigh refractive index and transparency of the eye lens require uniformly shaped and precisely aligned lens fiber cells. During lens development, equatorial epithelial cells undergo cell-to-cell alignment to form meridional rows of hexagonal cells. The mechanism that controls this morphogenesis from randomly packed cuboidal epithelial cells to highly organized hexagonal fiber cells remains unknown. In Epha2 −/− mouse lenses, equatorial epithelial cells fail to form precisely aligned meridional rows; moreover, the lens fulcrum, where the apical tips of elongating epithelial cells constrict to form an anchor point before fiber cell differentiation and elongation at the equator, is disrupted. Phosphorylated Src-Y424 and cortactin-Y466, actin and EphA2 cluster at the vertices of wildtype hexagonal epithelial cells in organized meridional rows. However, phosphorylated Src and phosphorylated cortactin are not detected in disorganized Epha2 −/− cells with altered F-actin distribution. E-cadherin junctions, which are normally located at the basallateral ends of equatorial epithelial cells and are diminished in newly differentiating fiber cells, become widely distributed in the apical, lateral and basal sides of epithelial cells and persist in differentiating fiber cells in Epha2 −/− lenses. Src −/− equatorial epithelial cells also fail to form precisely aligned meridional rows and lens fulcrum. These results indicate that EphA2/Src signaling is essential for the formation of the lens fulcrum. EphA2 also regulates Src/cortactin/F-actin complexes at the vertices of hexagonal equatorial cells for cell-to-cell alignment. This mechanistic information explains how EphA2 mutations lead to disorganized lens cells that subsequently contribute to altered refractive index and cataracts in humans and mice.

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Section: Research Articlesupporting

confidence: 91%

Section: Introductionmentioning

confidence: 50%

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EphA2 and Src regulate equatorial cell morphogenesis during lens development

et al. 2013

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“…Altered E-cadherin based cell-cell junctions then result in altered lens function and cataracts (Cheng et al 2013a). Indeed, mutations in EphA2 in humans are linked to congenital cataracts (Zhang et al 2009b;Park et al 2012). In the lens of the developing eye, EphA5 colocalizes with N-cadherin at sites of cell-cell adhesion, maintains N-cadherin at the surface of lens cells and increases the association of N-cadherin with β-catenin (Cooper et al 2008).…”

Section: Eph-ephrin Regulation Of Adherens Junctionsmentioning

confidence: 99%

Making Connections: Guidance Cues and Receptors at Nonneural Cell–Cell Junctions

Beamish

Hinck

Kennedy

2017

Cold Spring Harb Perspect Biol

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The field of axon guidance was revolutionized over the past three decades by the identification of highly conserved families of guidance cues and receptors. These proteins are essential for normal neural development and function, directing cell and axon migration, neuron-glial interactions, and synapse formation and plasticity. Many of these genes are also expressed outside the nervous system in which they influence cell migration, adhesion and proliferation. Because the nervous system develops from neural epithelium, it is perhaps not surprising that these guidance cues have significant nonneural roles in governing the specialized junctional connections between cells in polarized epithelia. The following review addresses roles for ephrins, semaphorins, netrins, slits and their receptors in regulating adherens, tight, and gap junctions in nonneural epithelia and endothelia.

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“…Mutations clustered in the cytoplasmic sterile-alpha-motif domain underlying autosomal dominant cataract have been shown to destabilize the receptor and impair Akt-activated cell migration in vitro. [29][30][31] AGK encodes the mitochondrial membrane protein acylglycerol kinase a key enzyme in membrane-lipid metabolism, and a truncation mutation has been associated with autosomal recessive cataract in a Saudi family. Similar mutations in AGK have also been associated with "syndromic" cataract including Sengers syndrome and infantile mitochondrial disease.…”

Section: Genes Encoding Membrane Proteinsmentioning

confidence: 99%

Molecular Genetics of Cataract

Shiels

Hejtmancik

2014

Encyclopedia of Life Sciences

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Cataract can be defined as any opacity or cloudiness of the crystalline lens. When there is significant variation of the refractive index of the lens over distances approximating the wavelength of the transmitted light scattering occurs, resulting in opacity or cataract. Thus, transparency of the crystalline lens requires both orderly arrangement of lens cells and high density of the lens protein constituents. Breakdown of the lens micro‐architecture such as cellular disarray and vacuole formation can cause large fluctuations in optical density of the lens, with resultant cataract. Significant concentrations of high molecular weight protein aggregates of 1000 Å or more in size can also contribute to light scattering. Because 90% of soluble lens proteins is composed of lens crystallins, their short‐range ordered packing in a homogeneous phase and the homoeostatic systems that maintain their stability are critical for maintaining lens transparency. Thus, it is not surprising that approximately 44% of cataract families for whom the mutant gene is known show mutations in lens crystallins with 16% in connexins, 12% in transcription factors, 4% in intermediate filament proteins, 5% in membrane proteins, 5% in chaperones or protein degradation or proofreading proteins, and 6% in a mixed group of other genes, the remainder being unknown. Key Concepts: Cataracts are opacities of the eye lens that result from light scattering either by aggregated proteins within lens cells or disarray of the lens cells themselves. Pathogenesis of inherited cataracts serves to identify critically important developmental, metabolic and biological pathways and processes in the eye lens. Although general trends can be seen with the expression pattern of the causative gene and inherited cataract morphology, identical mutations in the same gene can cause different cataract morphologies and mutations in different genes can result in identical cataract phenotypes. In general, congenital cataracts tend to be caused by mutations that severely disrupt the gene product's structure or function and are thus inherited as highly penetrant Mendelian traits. Conversely, the underlying genetic contributors to age‐related cataracts tend to be less severe mutations that merely impair stability or function and require additional compromise by environmental or modifying genetic factors to cause opacity, so they tend to be multifactorial in their inheritance. Lens crystallins make up 90% of the soluble protein of the eye lens and are thus frequent targets for mutations that destabilise them and cause cataracts. α‐Crystallins are molecular chaperones and can bind denatured proteins, thus preventing or delaying the onset of cataracts, and especially of age‐related cataract. Many other genes implicated in cataractogenesis encode gap junction proteins, solute and aqueous transport proteins, cytoskeletal proteins, developmental transcription factors, membrane proteins, chaperones, or other proteins participating in salvage processes, all important for lens cell development and homoeostasis. In multiple instances, including GALK, EPHA2 and CRYAA, mutations resulting in dramatic destabilization of loss of activity cause congenital cataracts, whereas milder changes contribute to age‐related cataracts in the presence of additional genetic and environmental insults over time.

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Human Cataract Mutations in EPHA2 SAM Domain Alter Receptor Stability and Function

Cited by 41 publications

References 66 publications

EphA2 and Src regulate equatorial cell morphogenesis during lens development

EphA2 and Src regulate equatorial cell morphogenesis during lens development

Making Connections: Guidance Cues and Receptors at Nonneural Cell–Cell Junctions

Molecular Genetics of Cataract

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