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Armus is a Rac1 effector that inactivates Rab7 and regulates E-cadherin degradation
Marieke A M Frasa1, Filipe C Maximiano, Kasia Smolarczyk
1Molecular Medicine, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, SW7 2AZ, London, UK.
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 RNAi. 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.
Insights
Armus protein integrates signaling between Arf6, Rac1, and Rab7 GTPases to regulate cell-cell adhesion. This novel Rac1 effector inactivates Rab7, facilitating E-cadherin degradation and controlling cell-cell contact stability.
Area of Science:
- Cell Biology
- Molecular Signaling
Background:
- Cell-cell adhesion and intracellular trafficking rely on small GTPases like Rho, Arf, and Rab.
- Mechanisms integrating signaling from distinct small GTPases remain poorly understood.
Purpose of the Study:
- To investigate how signaling from distinct small GTPases is integrated during cellular processes.
- To identify novel effectors and regulatory mechanisms in cell-cell adhesion and trafficking.
Main Methods:
- Investigated the role of the TBC/RabGAP protein Armus in integrating small GTPase signaling.
- Utilized techniques including protein binding assays, in vitro and in vivo GAP activity assays, RNA interference (RNAi), and dominant-negative protein expression.
- Examined the impact of Armus on E-cadherin degradation and cell scattering induced by Arf6 and EGF.
Main Results:
- Armus was identified as a novel effector of Rac1 and a GTPase-activating protein (GAP) for Rab7, integrating signaling between Arf6, Rac1, and Rab7.
- Armus specifically binds activated Rac1 and inactivates Rab7, playing a key role in junction disassembly.
- Arf6-induced E-cadherin degradation and EGF-induced keratinocyte scattering were significantly blocked by Armus manipulation, highlighting its function in these processes.
- Demonstrated a molecular and functional link between Rac1 and Rab7, previously unreported.
Conclusions:
- Active Rac1 recruits Armus to inactivate Rab7, promoting lysosomal degradation of E-cadherin.
- Armus acts as a crucial regulatory node, integrating Rac1 and Rab7 activities to control E-cadherin turnover and cell-cell contact stability.
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