title: Armus is a Rac1 effector that inactivates Rab7 and regulates E-cadherin degradation.
abstract: 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.
authors.affiliation: Molecular Medicine, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, SW7 2AZ, London, UK.
authors.forename: Marieke A M
authors.initials: MA
authors.lastname: Frasa
authors.forename: Filipe C
authors.initials: FC
authors.lastname: Maximiano
authors.forename: Kasia
authors.initials: K
authors.lastname: Smolarczyk
authors.forename: Richard E
authors.initials: RE
authors.lastname: Francis
authors.forename: Martha E
authors.initials: ME
authors.lastname: Betson
authors.forename: Encarnacion
authors.initials: E
authors.lastname: Lozano
authors.forename: James
authors.initials: J
authors.lastname: Goldenring
authors.forename: Miguel C
authors.initials: MC
authors.lastname: Seabra
authors.forename: Alexey
authors.initials: A
authors.lastname: Rak
authors.forename: M Reza
authors.initials: MR
authors.lastname: Ahmadian
authors.forename: Vania M M
authors.initials: VM
authors.lastname: Braga
mesh_terms: D000818:Animals; D019556:COS Cells; D015820:Cadherins / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002450:Cell Communication; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D008954:Models, Biological; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020691:rab GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D000090802:rab7 GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D015820:Cadherins; D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; C107953:RAC1 protein, human; D011994:Recombinant Proteins; C549113:TBC1D2 protein, human; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D020691:rab GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein