Abstract
Wnt-signal transduction is critical for development and tissue homeostasis in a wide range of animal species and is frequently deregulated in human cancers. Members of the Frat/GBP family of glycogen synthase kinase 3beta (Gsk3b)-binding oncoproteins are recognized as potent activators of the Wnt/beta-catenin pathway in vertebrates. Here, we reveal a novel, Gsk3b-independent function of Frat converging on the activation of JNK and AP-1. Both these have been used as readouts for the noncanonical Frizzled/PCP pathway, which controls polarized cell movements and the establishment of tissue polarity. We find that Frat synergizes with Diversin, the mammalian homolog of the Drosophila PCP protein diego, in the activation of JNK/AP-1 signaling. Importantly, Frat mutants deficient for binding to Gsk3b retain oncogenic activity in vivo, suggesting that Wnt/beta-catenin-independent events contribute to Frat-induced malignant transformation. The observed activities of Frat are reminiscent of the dual function of Dishevelled in the Wnt/beta-catenin and Frizzled/PCP pathways and suggest that Frat may also function to bridge canonical and noncanonical Wnt pathways.
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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Animals
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Blotting, Western
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism
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Dishevelled Proteins
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Drosophila Proteins
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Female
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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JNK Mitogen-Activated Protein Kinases / metabolism
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Lymphoma, T-Cell / genetics
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Lymphoma, T-Cell / metabolism
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Lymphoma, T-Cell / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Phosphorylation
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Proto-Oncogene Proteins
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Signal Transduction*
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Survival Analysis
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TCF Transcription Factors / genetics
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TCF Transcription Factors / metabolism
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Transcription Factor AP-1 / genetics
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Transcription Factor AP-1 / metabolism
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Transfection
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Wnt Proteins / genetics
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Wnt Proteins / metabolism*
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Ankrd6 protein, mouse
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Carrier Proteins
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Cytoskeletal Proteins
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Dishevelled Proteins
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Drosophila Proteins
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Frat1 protein, mouse
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Frat2 protein, mouse
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Intracellular Signaling Peptides and Proteins
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Neoplasm Proteins
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Phosphoproteins
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Proto-Oncogene Proteins
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TCF Transcription Factors
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Transcription Factor AP-1
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Wnt Proteins
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beta Catenin
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dsh protein, Drosophila
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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JNK Mitogen-Activated Protein Kinases
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Glycogen Synthase Kinase 3