Abstract
Mixed lineage kinase 3 (MLK3) is a MAP3K that activates the JNK-dependent MAPK pathways. Here, we show that MLK3 is required for cell migration in a manner independent of its role as a MAP3K or MLK3 kinase activity. Rather, MLK3 functions in a regulated way to limit levels of the activated GTPase Rho by binding to the Rho activator, p63RhoGEF/GEFT, which, in turn, prevents its activation by Galphaq. These findings demonstrate a scaffolding role for MLK3 in controlling the extent of Rho activation that modulates cell migration. Moreover, they suggest that MLK3 functions as a network hub that links a number of signaling pathways.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Cell Line
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Cell Movement / physiology
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Cytoskeleton / ultrastructure
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Focal Adhesions / ultrastructure
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GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism*
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Guanine Nucleotide Exchange Factors / metabolism*
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Humans
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In Vitro Techniques
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MAP Kinase Kinase Kinases / antagonists & inhibitors
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism*
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MAP Kinase Signaling System
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Mitogen-Activated Protein Kinase Kinase Kinase 11
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Models, Biological
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Protein Binding
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Pseudopodia / ultrastructure
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RNA, Small Interfering / genetics
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Receptors, G-Protein-Coupled / metabolism
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Recombinant Fusion Proteins / metabolism
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Rho Guanine Nucleotide Exchange Factors
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Serum Response Factor / metabolism
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Signal Transduction
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rhoA GTP-Binding Protein / metabolism*
Substances
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ARHGEF25 protein, human
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Guanine Nucleotide Exchange Factors
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RNA, Small Interfering
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Receptors, G-Protein-Coupled
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Recombinant Fusion Proteins
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Rho Guanine Nucleotide Exchange Factors
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SRF protein, human
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Serum Response Factor
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RHOA protein, human
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MAP Kinase Kinase Kinases
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GTP-Binding Protein alpha Subunits, Gq-G11
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rhoA GTP-Binding Protein