Armus Is a Rac1 Effector that Inactivates Rab7 and Regulates E-Cadherin Degradation

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. We find that a TBC/RabGAP protein, Armus, integrates signali...

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Published in:	Current biology Vol. 20; no. 3; pp. 198 - 208
Main Authors:	Frasa, Marieke A.M., Maximiano, Filipe C., Smolarczyk, Kasia, Francis, Richard E., Betson, Martha E., Lozano, Encarnacion, Goldenring, James, Seabra, Miguel C., Rak, Alexey, Ahmadian, M. Reza, Braga, Vania M.M.
Format:	Journal Article
Language:	English
Published:	England Elsevier Inc 09-02-2010
Subjects:	Animals Cadherins - metabolism Carrier Proteins - genetics Carrier Proteins - metabolism Cell Communication CELLBIO Cells, Cultured Chlorocebus aethiops COS Cells GTPase-Activating Proteins - genetics GTPase-Activating Proteins - metabolism Humans Intercellular Junctions - metabolism Keratinocytes - metabolism Models, Biological rab GTP-Binding Proteins - antagonists & inhibitors rac1 GTP-Binding Protein - metabolism Recombinant Proteins - genetics Recombinant Proteins - metabolism Signal Transduction CELLBIO
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Summary:	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. 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. 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. ► Armus is a TBC/RabGAP protein that interacts with active Rac1 to inactivate Rab7 ► EGF-dependent scattering requires Rac1, Armus, and Rab7 to perturb junctions ► Armus facilitates transport of E-cadherin complexes to lysosomes for degradation ► Armus mediates direct cross-talk between Rac1 and Rab7 in intracellular trafficking
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-9822 1879-0445
DOI:	10.1016/j.cub.2009.12.053