title: The mitogen-activated protein kinase kinase kinase kinase GCKR positively regulates canonical and noncanonical Wnt signaling in B lymphocytes.
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.
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 10, Room 11B08, 10 Center Dr. MSC 1876, Bethesda, MD 20892, USA.
authors.forename: Chong-Shan
authors.initials: CS
authors.lastname: Shi
authors.forename: Ning-Na
authors.initials: NN
authors.lastname: Huang
authors.forename: Kathleen
authors.initials: K
authors.lastname: Harrison
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.forename: John H
authors.initials: JH
authors.lastname: Kehrl
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D003600:Cytosol / Q000378:metabolism; D000072261:Dishevelled Proteins; D004789:Enzyme Activation; D000081410:Germinal Center Kinases; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000378:metabolism; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation / Q000235:genetics*; D051153:Wnt Proteins / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D017077:Culture Media, Conditioned; D000072261:Dishevelled Proteins; D000081410:Germinal Center Kinases; D020662:Guanine Nucleotide Exchange Factors; D010750:Phosphoproteins; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin; D010768:Phosphoserine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C513658:Map4K5 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D020744:rac GTP-Binding Proteins