Armus is a Rac1 effector that inactivates Rab7 and regulates E-cadherin degradation

Curr Biol. 2010 Feb 9;20(3):198-208. doi: 10.1016/j.cub.2009.12.053. Epub 2010 Jan 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cadherins / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Communication
  • Cells, Cultured
  • Chlorocebus aethiops
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Humans
  • Intercellular Junctions / metabolism
  • Keratinocytes / metabolism
  • Models, Biological
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • rab GTP-Binding Proteins / antagonists & inhibitors*
  • rac1 GTP-Binding Protein / metabolism*

Substances

  • Cadherins
  • Carrier Proteins
  • GTPase-Activating Proteins
  • RAC1 protein, human
  • Recombinant Proteins
  • TBC1D2 protein, human
  • rab7 protein
  • rab GTP-Binding Proteins
  • rac1 GTP-Binding Protein