Human cataract mutations in EPHA2 SAM domain alter receptor stability and function

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

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The cellular and molecular mechanisms underlying the pathogenesis of cataracts leading to visual impairment remain poorly understood. In recent studies, several mutations in the cytoplasmic sterile-α-motif (SAM) domain of human EPHA2 on chromosome 1p36 have been associated with hereditary cataracts in several families. Here, we have investigated how these SAM domain mutations affect EPHA2 activity. We showed that the SAM domain mutations dramatically destabilized the EPHA2 protein in a proteasome-dependent pathway, as evidenced by the increase of EPHA2 receptor levels in the presence of the proteasome inhibitor MG132. In addition, the expression of wild-type EPHA2 promoted the migration of the mouse lens epithelial αTN4-1 cells in the absence of ligand stimulation, whereas the mutants exhibited significantly reduced activity. In contrast, stimulation of EPHA2 with its ligand ephrin-A5 eradicates the enhancement of cell migration accompanied by Akt activation. Taken together, our studies suggest that the SAM domain of the EPHA2 protein plays critical roles in enhancing the stability of EPHA2 by modulating the proteasome-dependent process. Furthermore, activation of Akt switches EPHA2 from promoting to inhibiting cell migration upon ephrin-A5 binding. Our results provide the first report of multiple EPHA2 cataract mutations contributing to the destabilization of the receptor and causing the loss of cell migration activity.

Original languageEnglish (US)
Article numbere36564
JournalPloS one
Volume7
Issue number5
DOIs
StatePublished - May 3 2012

Fingerprint

Ephrin-A5
cataract
Proteasome Endopeptidase Complex
Cataract
proteasome endopeptidase complex
Chemical activation
cell movement
Ligands
Cell Movement
mutation
Mutation
receptors
Proteasome Inhibitors
Chromosomes
Lenses
Proteins
Switches
Vision Disorders
Lens
pathogenesis

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Park, Jeong Eun ; Son, Alexander I. ; Hua, Rui ; Wang, Lianqing ; Zhang, Xue ; Zhou, Renping. / Human cataract mutations in EPHA2 SAM domain alter receptor stability and function. In: PloS one. 2012 ; Vol. 7, No. 5.
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abstract = "The cellular and molecular mechanisms underlying the pathogenesis of cataracts leading to visual impairment remain poorly understood. In recent studies, several mutations in the cytoplasmic sterile-α-motif (SAM) domain of human EPHA2 on chromosome 1p36 have been associated with hereditary cataracts in several families. Here, we have investigated how these SAM domain mutations affect EPHA2 activity. We showed that the SAM domain mutations dramatically destabilized the EPHA2 protein in a proteasome-dependent pathway, as evidenced by the increase of EPHA2 receptor levels in the presence of the proteasome inhibitor MG132. In addition, the expression of wild-type EPHA2 promoted the migration of the mouse lens epithelial αTN4-1 cells in the absence of ligand stimulation, whereas the mutants exhibited significantly reduced activity. In contrast, stimulation of EPHA2 with its ligand ephrin-A5 eradicates the enhancement of cell migration accompanied by Akt activation. Taken together, our studies suggest that the SAM domain of the EPHA2 protein plays critical roles in enhancing the stability of EPHA2 by modulating the proteasome-dependent process. Furthermore, activation of Akt switches EPHA2 from promoting to inhibiting cell migration upon ephrin-A5 binding. Our results provide the first report of multiple EPHA2 cataract mutations contributing to the destabilization of the receptor and causing the loss of cell migration activity.",
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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, Renping.

In: PloS one, Vol. 7, No. 5, e36564, 03.05.2012.

Research output: Contribution to journalArticle

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