Armus Is a Rac1 Effector that Inactivates Rab7 and Regulates E-Cadherin Degradation
Armus Is a Rac1 Effector that Inactivates Rab7 and Regulates E-Cadherin Degradation
复制标题
DOI：
10.1016/j.cub.2009.12.053
复制
发表时间：
2010-02-09
期刊：
影响因子：
9.2
通讯作者：
Braga, Vania M. M.
中科院分区：
文献类型：
--
作者：
Frasa, Marieke A. M.;Maximiano, Filipe C.;Braga, Vania M. M.
背景：细胞间黏附和细胞内转运由Rho、Arf和Rab亚家族的小GTP酶信号通路调节。结果：我们发现TBC/RabGAP蛋白Armus在连接分解过程中整合了Arf6、rac1和Rab7之间的信号。Armus与激活的rac1特异结合，其C端TBC/RabGAP结构域使Rab7失活。因此，Armus是一种新的rac1效应器，也是Rab7在体外和体内的真正缺口，这是一种独特的、以前未见报道的组合。ARF6的激活有效地破坏了细胞与细胞之间的接触，并已知激活了rac1和Rab7。ARF6诱导的E-钙粘素降解可被Armus C-末端结构域的表达或Armus RNAL与显性阴性的Rab7或rac1共表达后有效地阻断，并抑制连接的解离。重要的是，Armus RabGAP的表达也阻止了EGF诱导的角质形成细胞中的散射，这一过程需要Arf6、rac1和Rab7的功能。据我们所知，这是首次证实了rac1和Rab7之间的分子和功能联系。结论：我们的数据表明，活性的rac1招募Armus局部灭活Rab7，并促进溶酶体中E-钙粘附素的降解。因此，ARMUS对rac1和Rab7活性的整合为E-钙粘附素的周转和细胞间接触的稳定性提供了一个重要的调节节点。
Background: Cell-cell adhesion and intracellular trafficking are regulated by signaling pathways from small GTPases of the Rho, Arf, and Rab subfamilies. How signaling from distinct small GTPases are integrated in a given process is poorly understood.Results: We find that a TBC/RabGAP protein, Armus, integrates signaling between Arf6, Rac1, and Rab7 during junction disassembly. Armus binds specifically to activated Rac1 and its C-terminal TBC/RabGAP domain inactivates Rab7. Thus, Armus is a novel Rac1 effector and a bona fide GAP for Rab7 in vitro and in vivo, a unique and previously unreported combination. Arf6 activation efficiently disrupts cell-cell contacts and is known to activate Rac1 and Rab7. Arf6-induced E-cadherin degradation is efficiently blocked by expression of Armus C-terminal domain or after Armus RNAL Coexpression of Arf6 with dominant-negative Rab7 or Rac1 also inhibits junction disassembly. Importantly, Armus RabGAP expression also prevents EGF-induced scattering in keratinocytes, a process shown here to require Arf6, Rac1, and Rab7 function. To our knowledge, this is the first report to demonstrate a molecular and functional link between Rac1 and Rab7.Conclusions: Our data indicate that active Rac1 recruits Armus to locally inactivate Rab7 and facilitate E-cadherin degradation in lysosomes. Thus, the integration of Rac1 and Rab7 activities by Armus provides an important regulatory node for E-cadherin turnover and stability of cell-cell contacts.