ARHGAP18-ezrin functions as an autoregulatory module for RhoA in the assembly of distinct actin-based structures.
ARHGAP18-ezrin functions as an autoregulatory module for RhoA in the assembly of distinct actin-based structures.
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DOI：
10.7554/elife.83526
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发表时间：
2024-01-09
期刊：
影响因子：
7.7
通讯作者：
Bretscher A
中科院分区：
文献类型：
--
作者：
Lombardo AT;Mitchell CAR;Zaman R;McDermitt DJ;Bretscher A
不同的肌动蛋白基结构的位置在很大程度上是由Rho GTPases通过特定的效应器调节的。我们使用上皮细胞的顶端作为模型系统来研究RhoA如何被局部调节以促进两种不同的相邻的基于肌动蛋白的结构。末端网中非肌球蛋白-2丝的组装依赖于RhoA活性，微绒毛的组装也需要RhoA活性来磷酸化和激活ezrin。我们发现，ARHGAP18通过结合活性微绒毛ezrin来定位RhoGAP，这种相互作用增强了ARHGAP18的RhoGAP活性。我们提出了一个模型，其中ezrin-ARHGAP18作为负自我调节模块，在微绒毛中局部降低RhoA活性。与该模型一致，ARHGAP18的缺失导致微绒毛和终端网之间的区别被破坏，包括在微绒毛内形成肌球蛋白-2丝的异常组装。因此，ARHGAP18通过ezrin的招募和激活，微调了RhoA的局部水平，从而允许微绒毛和终端网络之间适当分布基于肌动蛋白的结构。由于RhoGAPs数量远远超过Rho GTPases，这可能代表了一种通用机制，即单个Rho效应物驱动特定的基于动作蛋白的结构。
The location of different actin-based structures is largely regulated by Rho GTPases through specific effectors. We use the apical aspect of epithelial cells as a model system to investigate how RhoA is locally regulated to contribute to two distinct adjacent actin-based structures. Assembly of the non-muscle myosin-2 filaments in the terminal web is dependent on RhoA activity, and assembly of the microvilli also requires active RhoA for phosphorylation and activation of ezrin. We show that the RhoGAP, ARHGAP18, is localized by binding active microvillar ezrin, and this interaction enhances ARHGAP18’s RhoGAP activity. We present a model where ezrin-ARHGAP18 acts as a negative autoregulatory module to locally reduce RhoA activity in microvilli. Consistent with this model, loss of ARHGAP18 results in disruption of the distinction between microvilli and the terminal web including aberrant assembly of myosin-2 filaments forming inside microvilli. Thus, ARHGAP18, through its recruitment and activation by ezrin, fine-tunes the local level of RhoA to allow for the appropriate distribution of actin-based structures between the microvilli and terminal web. As RhoGAPs vastly outnumber Rho GTPases, this may represent a general mechanism whereby individual Rho effectors drive specific actin-based structures.
DOI：
10.1083/jcb.200604046
发表时间：
2006-12-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hanono A;Garbett D;Reczek D;Chambers DN;Bretscher A
通讯作者：
Bretscher A
DOI：
10.1083/jcb.201204008
发表时间：
2012-07-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Garbett D;Bretscher A
通讯作者：
Bretscher A
DOI：
10.1083/jcb.108.3.921
发表时间：
1989-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bretscher A
通讯作者：
Bretscher A