VANGL2 protein stability is regulated by integrin αv and the extracellular matrix.
VANGL2 protein stability is regulated by integrin αv and the extracellular matrix.
复制标题
VANGL2 蛋白稳定性受整合素 αv 和细胞外基质调节。
DOI：
10.1016/j.yexcr.2018.11.017
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发表时间：
2019
影响因子：
3.7
通讯作者：
Jessen,JasonR
中科院分区：
文献类型：
--
作者：
Jessen,TammyN;Jessen,JasonR
van -like 2 （VANGL2）是胚胎发育中多种极化细胞行为所必需的四代跨膜蛋白。最近的数据显示，人类VANGL2与整合素αv相互作用，控制细胞对细胞外基质蛋白的粘附。本研究的目的是进一步明确整合素αv与VANGL2之间的功能关系。我们证明整合素αv在体外和斑马鱼胚胎中调节VANGL2蛋白水平。虽然整合素αv的下调降低了膜室中VANGL2的表达，但不影响VANGL2的转录。敲低整合素β5，而不敲低β1或β3，也会降低VANGL2蛋白水平。用环己亚胺抑制蛋白质翻译表明，整合素αv敲低的细胞增加了VANGL2的降解，而干扰蛋白酶体或溶酶体的功能可以恢复VANGL2。我们进一步证明整合素激活和使用mncl2刺激细胞-基质粘附不能影响VANGL2。然而，mncl2处理在环己亚胺存在下稳定了VANGL2蛋白的表达水平。在相反的实验中，使用环状RGD肽阻断整合素介导的细胞基质粘附导致VANGL2蛋白水平降低。总之，我们的研究结果支持一个模型，即整合素αv和细胞与细胞外基质的相互作用是维持VANGL2蛋白水平和在质膜上起作用所必需的。
Vang-like 2 (VANGL2) is a four-pass transmembrane protein required for a variety of polarized cell behaviors underlying embryonic development. Recent data show human VANGL2 interacts with integrin αv to control cell adhesion to extracellular matrix proteins. The goal of this study was to further define the functional relationship between integrin αv and VANGL2. We demonstrate integrin αv regulates VANGL2 protein levels both in vitro and in the zebrafish embryo. While integrin αv knockdown reduces VANGL2 expression at membrane compartments, it does not affectVANGL2transcription. Knockdown of integrin β5, but not β1 or β3, also decreases VANGL2 protein levels. Inhibition of protein translation using cycloheximide demonstrates that integrin αv knockdown cells have increased VANGL2 degradation while interference with either proteasome or lysosome function restores VANGL2. We further show integrin activation and stimulation of cell-matrix adhesion using MnCl2fails to influence VANGL2. However, MnCl2treatment stabilizes VANGL2 protein expression levels in the presence of cycloheximide. In the converse experiment, blockage of integrin-mediated cell-matrix adhesion using a cyclic RGD peptide causes a reduction in VANGL2 protein levels. Together, our findings support a model where integrin αv and cellular interactions with the extracellular matrix are required to maintain VANGL2 protein levels and thus function at the plasma membrane.