Contribution of protein-protein interactions to the endothelial-barrier-stabilizing function of KRIT1.
Contribution of protein-protein interactions to the endothelial-barrier-stabilizing function of KRIT1.
复制标题
DOI：
10.1242/jcs.258816
复制
发表时间：
2022-01-15
影响因子：
4
通讯作者：
Glading AJ
中科院分区：
文献类型：
--
作者：
Swamy H;Glading AJ
Krev相互作用捕获蛋白1（KRIT 1）是促进粘附连接（AJ）稳定性的内皮支架蛋白。KRIT 1促进屏障稳定的确切机制尚不清楚。我们测试了一组KRIT 1构建体的能力，这些构建体含有抑制Rap 1结合、ICAP 1 α结合、破坏KRIT 1的磷酸酪氨酸结合（PTB）结构域或将KRIT 1引导至质膜的突变，单独或组合，以恢复KRIT 1缺陷内皮细胞的屏障功能。我们发现，切除192 NPAY 195基序或破坏PTB结构域足以恢复AJ蛋白定位和屏障功能的控制水平，无论KRIT 1或Rap 1结合的连接定位。我们的KRIT 1构建体在KRIT 1缺失的内皮细胞中拯救AJ和屏障功能的能力与β1整合素活性降低和皮质肌动蛋白纤维的维持相关。综上所述，我们的研究结果表明，Rap 1结合，ICAP 1 α结合和连接定位是不需要的KRIT 1的能力，以稳定内皮细胞接触，并表明，KRIT 1的能力，以限制整合素活性可能参与屏障稳定。总结：与目前的模型相反，KRIT 1不需要与ICAP 1 α和Rap 1结合或连接定位来稳定内皮屏障。相反，自身相互作用和/或β1整联蛋白激活是KRIT 1信号传导的关键要素。
Krev-interaction trapped protein 1 (KRIT1) is an endothelial scaffold protein that promotes adherens junction (AJ) stability. The precise mechanism by which KRIT1 promotes barrier stabilization is unclear. We tested the ability of a panel of KRIT1 constructs containing mutations that inhibit Rap1 binding, ICAP1α binding, disrupt KRIT1's phosphotyrosine-binding (PTB) domain, or direct KRIT1 to the plasma membrane, either alone or in combination, to restore barrier function in KRIT1-deficient endothelial cells. We found that ablating the 192NPAY195 motif or disrupting the PTB domain was sufficient to restore AJ protein localization and barrier function to control levels, irrespective of the junctional localization of KRIT1 or Rap1 binding. The ability of our KRIT1 constructs to rescue AJ and barrier function in KRIT1-depleted endothelial cells correlated with decreased β1 integrin activity and maintenance of cortical actin fibers. Taken together, our findings indicate that Rap1 binding, ICAP1α binding and junctional localization are not required for the ability of KRIT1 to stabilize endothelial contacts, and suggest that the ability of KRIT1 to limit integrin activity could be involved in barrier stabilization. Summary: Contrary to current models, KRIT1 does not require binding to ICAP1α and Rap1, or junctional localization, to stabilize the endothelial barrier. Instead, self-interaction and/or β1 integrin activation are critical elements of KRIT1 signaling.
登录
查看更多内容
DOI：
10.1161/atvbaha.118.311705
发表时间：
2018-11
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Al-Yafeai Z;Yurdagul A Jr;Peretik JM;Alfaidi M;Murphy PA;Orr AW
通讯作者：
Orr AW
影响因子：
5.3
作者：
DiStefano, Peter V.;Glading, Angela J.
通讯作者：
Glading, Angela J.
影响因子：
5.4
作者：
Dull, T;Zufferey, R;Naldini, L
通讯作者：
Naldini, L
影响因子：
4.8
作者：
DiStefano, Peter V.;Kuebel, Julia M.;Glading, Angela J.
通讯作者：
Glading, Angela J.
影响因子：
4.6
作者：
Goitre L;DiStefano PV;Moglia A;Nobiletti N;Baldini E;Trabalzini L;Keubel J;Trapani E;Shuvaev VV;Muzykantov VR;Sarelius IH;Retta SF;Glading AJ
通讯作者：
Glading AJ