Abstract
Wnt ligands bind receptors of the Frizzled (Fz) family to control cell fate, proliferation, and polarity. Canonical Wnt/Fz signaling stabilizes beta-catenin by inactivating GSK3beta, leading to the translocation of beta-catenin to the nucleus and the activation of Wnt target genes. Noncanonical Wnt/Fz signaling activates RhoA and Rac, and the latter triggers the activation of c-Jun N-terminal kinase (JNK). Here, we show that exposure of B-lymphocytes to Wnt3a-conditioned media activates JNK and raises cytosolic beta-catenin levels. Both the Rac guanine nucleotide exchange factor Asef and the mitogen-activated protein kinase kinase kinase kinase germinal center kinase-related enzyme (GCKR) are required for Wnt-mediated JNK activation in B cells. In addition, we show that GCKR positively affects the beta-catenin pathway in B cells. Reduction of GCKR expression inhibits Wnt3a-induced phosphorylation of GSK3beta at serine 9 and decreases the accumulation of cytosolic beta-catenin. Furthermore, Wnt signaling induces an interaction between GCKR and GSK3beta. Our findings demonstrate that GCKR facilitates both canonical and noncanonical Wnt signaling in B lymphocytes.
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Adenomatous Polyposis Coli Protein / metabolism
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Animals
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B-Lymphocytes / cytology
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B-Lymphocytes / enzymology*
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Cells, Cultured
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Culture Media, Conditioned
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Cytosol / metabolism
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Dishevelled Proteins
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Enzyme Activation
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Germinal Center Kinases
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Guanine Nucleotide Exchange Factors / metabolism
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism
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Mice
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Mice, Inbred C57BL
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Phosphoproteins / metabolism
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Phosphoserine / metabolism
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Protein Binding
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Protein Serine-Threonine Kinases / metabolism*
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Signal Transduction*
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Up-Regulation / genetics*
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Wnt Proteins / metabolism*
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Wnt3 Protein
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Wnt3A Protein
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beta Catenin / metabolism
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rac GTP-Binding Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Adenomatous Polyposis Coli Protein
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Culture Media, Conditioned
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Dishevelled Proteins
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Germinal Center Kinases
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Guanine Nucleotide Exchange Factors
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Phosphoproteins
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WNT3A protein, human
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Wnt Proteins
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Wnt3 Protein
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Wnt3A Protein
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Wnt3a protein, mouse
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beta Catenin
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Phosphoserine
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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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Map4K5 protein, mouse
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Protein Serine-Threonine Kinases
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JNK Mitogen-Activated Protein Kinases
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Glycogen Synthase Kinase 3
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rac GTP-Binding Proteins