Positive feedback between Dia1, LARG, and RhoA regulates cell morphology and invasion (original) (raw)

  1. Thomas M. Kitzing1,4,
  2. Arul S. Sahadevan1,4,
  3. Dominique T. Brandt1,
  4. Helga Knieling1,
  5. Sebastian Hannemann2,
  6. Oliver T. Fackler2,
  7. Jörg Großhans3, and
  8. Robert Grosse1,5
  9. 1 Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany;
  10. 2 Department of Virology, University of Heidelberg, 69120 Heidelberg, Germany;
  11. 3 Zentrum für Molekulare Biologie Heidelberg, University of Heidelberg, 69120 Heidelberg, Germany
  12. ↵4 These authors contributed equally to this work.

Abstract

The RhoA-effector Dia1 controls actin-dependent processes such as cytokinesis, SRF transcriptional activity, and cell motility. Dia1 polymerizes actin through its formin homology (FH) 2 domain. Here we show that Dia1 acts upstream of RhoA independently of its effects on actin assembly. Dia1 binds to the leukemia-associated Rho-GEF (LARG) through RhoA-dependent release of Dia1 autoinhibition. The FH2 domain stimulates the guanine nucleotide exchange activity of LARG in vitro. Our results reveal that Dia1 is necessary for LPA-stimulated Rho/ROCK signaling and bleb-associated cancer cell invasion. Thus, Dia1-dependent RhoA activation constitutes a positive feedback mechanism to modulate cell behavior.

Footnotes