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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Cell Line
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Cell Line, Tumor
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Feedback
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Formins
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Guanine Nucleotide Exchange Factors / genetics
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Guanine Nucleotide Exchange Factors / metabolism*
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Humans
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Models, Biological
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Mutation
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Neoplasm Invasiveness
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RNA, Small Interfering / genetics
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Receptors, Lysophosphatidic Acid / genetics
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Receptors, Lysophosphatidic Acid / metabolism
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Rho Guanine Nucleotide Exchange Factors
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Signal Transduction
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rhoA GTP-Binding Protein / genetics
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rhoA GTP-Binding Protein / metabolism*
Substances
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ARHGEF12 protein, human
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Adaptor Proteins, Signal Transducing
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DIAPH1 protein, human
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Formins
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Guanine Nucleotide Exchange Factors
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RNA, Small Interfering
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Receptors, Lysophosphatidic Acid
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Rho Guanine Nucleotide Exchange Factors
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RHOA protein, human
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rhoA GTP-Binding Protein