Positive feedback between Dia1, LARG, and RhoA regulates cell morphology and invasion.
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.
Kitzing
Thomas M
TM
Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany.
Sahadevan
Arul S
AS
Brandt
Dominique T
DT
Knieling
Helga
H
Hannemann
Sebastian
S
Fackler
Oliver T
OT
Grosshans
Jörg
J
Grosse
Robert
R
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D005246:Feedback; D000080865:Formins; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering / Q000235:genetics; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
C577222:ARHGEF12 protein, human; D048868:Adaptor Proteins, Signal Transducing; C108962:DIAPH1 protein, human; D000080865:Formins; D020662:Guanine Nucleotide Exchange Factors; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid; D064067:Rho Guanine Nucleotide Exchange Factors; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein