Positive feedback between Dia1, LARG, and RhoA regulates cell morphology and invasion.

Thomas M Kitzing, Arul S Sahadevan, Dominique T Brandt, Helga Knieling, Sebastian Hannemann, Oliver T Fackler, Jörg Grosshans, Robert Grosse

Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany.

Genes & development 2007 Jun 15

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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.

Citation

Thomas M Kitzing, Arul S Sahadevan, Dominique T Brandt, Helga Knieling, Sebastian Hannemann, Oliver T Fackler, Jörg Grosshans, Robert Grosse. Positive feedback between Dia1, LARG, and RhoA regulates cell morphology and invasion. Genes & development. 2007 Jun 15;21(12):1478-83