Human cataract mutations in EPHA2 SAM domain alter receptor stability and function.
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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3343017?pdf=render |
| _version_ | 1818164281674301440 |
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| author | Jeong Eun Park Alexander I Son Rui Hua Lianqing Wang Xue Zhang Renping Zhou |
| author_facet | Jeong Eun Park Alexander I Son Rui Hua Lianqing Wang Xue Zhang Renping Zhou |
| author_sort | Jeong Eun Park |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T17:02:58Z |
| format | Article |
| id | doaj.art-48a72f288dfd4378873bd86c32b3c242 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T17:02:58Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-48a72f288dfd4378873bd86c32b3c2422022-12-22T00:57:47ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0175e3656410.1371/journal.pone.0036564Human cataract mutations in EPHA2 SAM domain alter receptor stability and function.Jeong Eun ParkAlexander I SonRui HuaLianqing WangXue ZhangRenping ZhouThe 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.http://europepmc.org/articles/PMC3343017?pdf=render |
| spellingShingle | Jeong Eun Park Alexander I Son Rui Hua Lianqing Wang Xue Zhang Renping Zhou Human cataract mutations in EPHA2 SAM domain alter receptor stability and function. PLoS ONE |
| title | Human cataract mutations in EPHA2 SAM domain alter receptor stability and function. |
| title_full | Human cataract mutations in EPHA2 SAM domain alter receptor stability and function. |
| title_fullStr | Human cataract mutations in EPHA2 SAM domain alter receptor stability and function. |
| title_full_unstemmed | Human cataract mutations in EPHA2 SAM domain alter receptor stability and function. |
| title_short | Human cataract mutations in EPHA2 SAM domain alter receptor stability and function. |
| title_sort | human cataract mutations in epha2 sam domain alter receptor stability and function |
| url | http://europepmc.org/articles/PMC3343017?pdf=render |
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