Human cataract mutations in EPHA2 SAM domain alter receptor stability and function.
Human cataract mutations in EPHA2 SAM domain alter receptor stability and function.
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人类白内障 EPHA2 SAM 结构域突变改变受体稳定性和功能
DOI：
10.1371/journal.pone.0036564
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Zhou R
中科院分区：
文献类型：
--
作者：
Park JE;Son AI;Hua R;Wang L;Zhang X;Zhou R
白内障致视力损害的细胞和分子机制尚不清楚。在最近的研究中，人类染色体1p36上EPHA2细胞质不育-α-基序（SAM）结构域的几个突变与几个家族的遗传性白内障有关。在这里，我们研究了这些SAM结构域突变如何影响EPHA2活性。我们发现，SAM结构域突变极大地破坏了蛋白酶体依赖途径中EPHA2蛋白的稳定性，在蛋白酶体抑制剂MG132的存在下，EPHA2受体水平增加。此外，在没有配体刺激的情况下，野生型EPHA2的表达促进了小鼠晶状体上皮αTN4-1细胞的迁移，而突变体的活性明显降低。相反，用其配体ephrin-A5刺激EPHA2可消除伴随Akt激活的细胞迁移增强。综上所述，我们的研究表明，EPHA2蛋白的SAM结构域通过调节蛋白酶体依赖性过程，在增强EPHA2的稳定性方面发挥了关键作用。此外，Akt的激活将EPHA2从促进到抑制ephrin-A5结合后的细胞迁移。我们的研究结果首次报道了多个EPHA2白内障突变导致受体不稳定并导致细胞迁移活性丧失。
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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影响因子：
3.7
作者：
Gopal U;Bohonowych JE;Lema-Tome C;Liu A;Garrett-Mayer E;Wang B;Isaacs JS
通讯作者：
Isaacs JS
影响因子：
9.8
作者：
Billingsley, Gail;Santhiya, Sathiyavedu T.;Heon, Elise
通讯作者：
Heon, Elise
影响因子：
9.8
作者：
Berry, V;Francis, P;Quinlan, RA
通讯作者：
Quinlan, RA
影响因子：
4.6
作者：
Dufour, Audrey;Egea, Joaquim;Vanderhaeghen, Pierre
通讯作者：
Vanderhaeghen, Pierre
影响因子：
3.9
作者：
Foster, A;Resnikoff, S
通讯作者：
Resnikoff, S