Association between Gαi2 and ELMO1/Dock180 connects chemokine signalling with Rac activation and metastasis

Nat Commun. 2013;4:1706. doi: 10.1038/ncomms2680.

Abstract

The chemokine CXCL12 and its G-protein-coupled receptor CXCR4 control the migration, invasiveness and metastasis of breast cancer cells. Binding of CXCL12 to CXCR4 triggers activation of heterotrimeric Gi proteins that regulate actin polymerization and migration. However, the pathways linking chemokine G-protein-coupled receptor/Gi signalling to actin polymerization and cancer cell migration are not known. Here we show that CXCL12 stimulation promotes interaction between Gαi2 and ELMO1. Gi signalling and ELMO1 are both required for CXCL12-mediated actin polymerization, migration and invasion of breast cancer cells. CXCL12 triggers a Gαi2-dependent membrane translocation of ELMO1, which associates with Dock180 to activate small G-proteins Rac1 and Rac2. In vivo, ELMO1 expression is associated with lymph node and distant metastasis, and knocking down ELMO1 impairs metastasis to the lung. Our findings indicate that a chemokine-controlled pathway, consisting of Gαi2, ELMO1/Dock180, Rac1 and Rac2, regulates the actin cytoskeleton during breast cancer metastasis.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Sequence
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Chemokine CXCL12 / metabolism*
  • Chemotaxis
  • Enzyme Activation
  • Female
  • GTP-Binding Protein alpha Subunit, Gi2 / chemistry
  • GTP-Binding Protein alpha Subunit, Gi2 / metabolism*
  • Humans
  • Molecular Sequence Data
  • Neoplasm Invasiveness
  • Receptors, CXCR4 / metabolism*
  • Signal Transduction*
  • rac GTP-Binding Proteins / chemistry
  • rac GTP-Binding Proteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Chemokine CXCL12
  • DOCK1 protein, human
  • ELMO1 protein, human
  • Receptors, CXCR4
  • GTP-Binding Protein alpha Subunit, Gi2
  • rac GTP-Binding Proteins