May 2004
Volume 45, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2004
Src Kinases Signal Formation of Cataract through a Mechanism Involving Caspase Activation, Cadherin Cleavage and the Induction of Apoptosis
Author Affiliations & Notes
  • S. Menko
    Pathology, Anatomy & Cell Biology, Thomas Jefferson University, Philadelphia, PA
  • J. Zhou
    Pathology, Anatomy & Cell Biology, Thomas Jefferson University, Philadelphia, PA
  • Footnotes
    Commercial Relationships  S. Menko, None; J. Zhou, None.
  • Footnotes
    Support  NIH Grants EY10577 and EY014258 to A.S.M and ARVO/Alcon Laboratories Research Fellowship to J.Z.
Investigative Ophthalmology & Visual Science May 2004, Vol.45, 3505. doi:
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      S. Menko, J. Zhou; Src Kinases Signal Formation of Cataract through a Mechanism Involving Caspase Activation, Cadherin Cleavage and the Induction of Apoptosis . Invest. Ophthalmol. Vis. Sci. 2004;45(13):3505.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Abstract: : Purpose. To investigate the mechanism by which activation of Src kinases induces formation of lens cataract. Methods. Cataracts were induced in embryonic lenses by culturing in Media 199 containing 10% FBS, and prevented by attenuation of Src kinase activity with the inhibitor PP1. Apoptosis was determined by TUNEL assay and caspase 3 activation by CaspACE assay. Immunoblot analysis was performed to examine the proteolytic cleavage of N–cadherin. Cadherin junctional organization was determined by immunostaining for ß–catenin. Results. We discovered that lenses induced to form cortical cataracts in our culture model had a high incidence of apoptotic cells in the lens epithelium. This result is consistent with the long held view that epithelial cell dysfunction leads to cataract formation. Epithelial cell apoptosis was coincident with activation of the death inducing protease, caspase 3. Both these phenomena were Src kinase dependent. When Src kinase activity was attenuated, lens epithelial cells resisted the external stresses that otherwise would have led to apoptosis; caspase 3 was not activated, apoptosis was prevented and the lenses remained clear. These results suggest that activation of Src kinases led to formation of cortical cataract by inducing apoptosis in the lens epithelium through a mechanism involving the activation of apoptotic–inducing proteases. Since cadherin junctions are essential to the establishment and maintenance of epithelial cell polarity, conferring them with resistance to apoptosis, we examined whether N–cadherin was targeted by proteases in the epithelium of the cataractous lenses. We found a diminution in N–cadherin with the induction of cataract, coincident with the increased generation of an N–cadherin cytoplasmic domain cleavage product. This was accompanied by destabilization of cadherin junctions in the cataract cultures, as demonstrated by decreased immunostaining for the cadherin junctional protein, ß–catenin. This result is consistent with the ability of caspase 3 to remove the domain of N–cadherin responsible for ß–catenin binding. The Src kinase inhibitor attenuated N–cadherin proteolysis and maintained the integrity of cadherin junctions, preventing apoptosis and blocking the development of lens cataract. Conclusions. Our results suggest that the activation of Src kinases induces cataract formation through a pathway involving activation of caspase 3 and the cleavage of N–cadherin, disassembling cadherin junctions to destabilize cells of the lens epithelium and cause their apoptotic cell death.

Keywords: apoptosis/cell death • cataract • cell adhesions/cell junctions 
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