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

PloS One
Jeong Eun ParkRenPing Zhou

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 u...Continue Reading

References

Aug 1, 1996·Investigative Ophthalmology & Visual Science·C A McCarty, H R Taylor
Feb 5, 1999·Science·C D ThanosJ U Bowie
Apr 17, 1999·American Journal of Human Genetics·D MackayS Bhattacharya
Oct 16, 1999·American Journal of Human Genetics·E HéonF L Munier
Nov 5, 1999·Protein Science : a Publication of the Protein Society·M SmallaH Oschkinat
Jun 15, 2000·The New England Journal of Medicine·C J HammondC E Gilbert
Feb 13, 2001·Human Molecular Genetics·J A McGrathH van Bokhoven
Jun 1, 2002·Science·Lewis C Cantley
Nov 13, 2002·Archives of Ophthalmology·John Paul SanGiovanniMark A Klebanoff
Nov 26, 2002·Molecular and Cellular Biology·Pamela GhioniLuisa Guerrini
Dec 24, 2002·Trends in Neurosciences·Juha-Pekka Himanen, Dimitar B Nikolov
May 27, 2003·Journal of Dental Research·P N KantaputraJ A McGrath
Jan 27, 2004·Molecular Biology of the Cell·Eui Kyun ParkIra O Daar
May 15, 2004·Molecular and Cellular Biology·Cristina E TognonPoul H B Sorensen
Jul 14, 2004·Biochemical and Biophysical Research Communications·Mark S DuxburyEdward E Whang
Sep 7, 2004·Clinical and Experimental Dermatology·M T SahinS Oztürkcan
May 26, 2005·Investigative Ophthalmology & Visual Science·S Amer RiazuddinJ Fielding Hejtmancik
Jun 2, 2005·Science's STKE : Signal Transduction Knowledge Environment·Feng Qiao, James U Bowie
Jul 30, 2005·The Journal of Biological Chemistry·Matteo ParriPaola Chiarugi
Aug 27, 2005·Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology·Frank PillekampRuediger Koehling
Aug 27, 2005·New Directions for Child and Adolescent Development·Elliot Turiel
Sep 17, 2005·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Dana M Brantley-SiedersJin Chen
Oct 29, 2005·Molecular Cancer Research : MCR·Jill WykoskyWaldemar Debinski
Nov 24, 2005·Eye·A Foster, S Resnikoff
Dec 21, 2005·The Journal of Cell Biology·Hanna Y IrieJoan S Brugge
Jun 24, 2006·Science·Ling QiMarc Montminy

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Citations

Jul 30, 2014·Molecular and Cellular Biochemistry·Vanita VanitaPeter N Robinson
May 31, 2012·Science China. Life Sciences·Alexander I SonRenPing Zhou
Sep 27, 2013·The New England Journal of Medicine·John C ByrdDanelle F James
Jun 27, 2017·Experimental Eye Research·Catherine ChengXiaohua Gong
Jan 1, 2013·Genes·Jeong Eun ParkRenping Zhou
Dec 22, 2017·PloS One·Thomas M BennettAlan Shiels
Aug 30, 2017·Cold Spring Harbor Perspectives in Biology·Ian V BeamishTimothy E Kennedy
Nov 10, 2018·International Journal of Cancer. Journal International Du Cancer·Yuanyuan ShengLunxiu Qin
Oct 12, 2018·Current Medicinal Chemistry·Marian VincenziMarilisa Leone
Oct 19, 2017·Ophthalmic Genetics·Vanita BerryMichel Michaelides
Sep 27, 2013·The New England Journal of Medicine·Stuart A RushworthKristian M Bowles
Dec 7, 2019·The Journal of Biological Chemistry·Rakesh JoshiShawn S C Li
Dec 3, 2016·The Journal of Cell Biology·Thomas NeillRenato V Iozzo
May 26, 2017·Birth Defects Research·Jinyu LiXiaohua Gong
Sep 13, 2013·Development·Catherine ChengXiaohua Gong

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Methods Mentioned

BETA
ubiquitination
transfection
PCR
immunoprecipitation
pull-down

Software Mentioned

ImageJ
NIH
NIH ImageJ
GraphPad
Adobe Photoshop
Prism®

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