The scaffold protein Ajuba suppresses CdGAP activity in epithelia to maintain stable cell-cell contacts.
The scaffold protein Ajuba suppresses CdGAP activity in epithelia to maintain stable cell-cell contacts.
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脚手架蛋白Ajuba抑制上皮中的CDGAP活性，以维持稳定的细胞接触。
DOI：
10.1038/s41598-017-09024-4
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发表时间：
2017-08-23
影响因子：
4.6
通讯作者：
Braga VMM
中科院分区：
文献类型：
--
作者：
McCormack JJ;Bruche S;Ouadda ABD;Ishii H;Lu H;Garcia-Cattaneo A;Chávez-Olórtegui C;Lamarche-Vane N;Braga VMM
活性Rac 1在上皮连接的水平部分调制通过与Ajuba，肌动蛋白结合和支架蛋白的相互作用。在这里，我们表明，筋骨草相互作用的Cdc 42 GTdR激活蛋白CdGAP，一个GAP的Rac 1和Cdc 42，在细胞-细胞接触。CdGAP招聘路口不需要筋骨草，而筋骨草似乎控制CdGAP居住在网站的细胞-细胞粘附。CdGAP表达有力地干扰连接，而筋骨草结合抑制CdGAP活性。筋骨草通过不同的结构域与Rac 1和CdGAP相互作用，并可能使它们在连接处非常接近，以促进活性调节。在功能上，CdGAP-筋骨草相互作用在体内平衡和疾病中维持连接完整性：（i）在亚当斯-奥利弗综合征患者中发现的功能获得性CdGAP突变体强烈地破坏细胞-细胞接触的稳定性，以及（ii）CdGAP mRNA水平与不同癌症中的E-钙粘蛋白蛋白表达呈负相关。我们提出了概念上的见解，如何筋骨草可以整合CdGAP结合和灭活与时空调控的Rac 1活动在路口。Ajuba提供了一种新的机制，因为它能够通过不同的结构域与CdGAP和Rac 1结合，并影响这两种蛋白质的激活状态。这种功能相互作用可能有助于在稳态和不同病理状态下保护上皮组织结构。
Levels of active Rac1 at epithelial junctions are partially modulated via interaction with Ajuba, an actin binding and scaffolding protein. Here we demonstrate that Ajuba interacts with the Cdc42 GTPase activating protein CdGAP, a GAP for Rac1 and Cdc42, at cell-cell contacts. CdGAP recruitment to junctions does not require Ajuba; rather Ajuba seems to control CdGAP residence at sites of cell-cell adhesion. CdGAP expression potently perturbs junctions and Ajuba binding inhibits CdGAP activity. Ajuba interacts with Rac1 and CdGAP via distinct domains and can potentially bring them in close proximity at junctions to facilitate activity regulation. Functionally, CdGAP-Ajuba interaction maintains junctional integrity in homeostasis and diseases: (i) gain-of-function CdGAP mutants found in Adams-Oliver Syndrome patients strongly destabilize cell-cell contacts and (ii) CdGAP mRNA levels are inversely correlated with E-cadherin protein expression in different cancers. We present conceptual insights on how Ajuba can integrate CdGAP binding and inactivation with the spatio-temporal regulation of Rac1 activity at junctions. Ajuba provides a novel mechanism due to its ability to bind to CdGAP and Rac1 via distinct domains and influence the activation status of both proteins. This functional interplay may contribute towards conserving the epithelial tissue architecture at steady-state and in different pathologies.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
5.5
作者：
de Moura, J.;Felicori, L.;Chavez-Olortegui, C.
通讯作者：
Chavez-Olortegui, C.
影响因子：
4.8
作者：
Lamarche-Vane, N;Hall, A
通讯作者：
Hall, A
影响因子：
11.8
作者：
Langer, Ellen M.;Feng, Yunfeng;Longmore, Gregory D.
通讯作者：
Longmore, Gregory D.
影响因子：
4.8
作者：
Marie, H;Pratt, SJ;Braga, VMM
通讯作者：
Braga, VMM