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RESEARCH COMMUNICATION

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

¹ Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany; ² Department of Virology, University of Heidelberg, 69120 Heidelberg, Germany; ³ Zentrum für Molekulare Biologie Heidelberg, University of Heidelberg, 69120 Heidelberg, Germany

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.

[Keywords: Diaphanous-related formins; RhoA; LARG; actin polymerization; LPA; Rho-kinase]

Received January 11, 2007; revised version accepted May 8, 2007.

⁵ Corresponding author.

E-MAIL robert.grosse{at}pharma.uni-heidelberg.de; FAX 49-06221-548549.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.424807

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