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Molecular and Cellular Biology, September 2006, p. 6511-6521, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.00209-06

The Mitogen-Activated Protein Kinase Kinase Kinase Kinase GCKR Positively Regulates Canonical and Noncanonical Wnt Signaling in B Lymphocytes

Chong-Shan Shi, Ning-Na Huang, Kathleen Harrison, Sang-Bae Han, and John H. Kehrl^*

Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

Received 6 February 2006/ Returned for modification 9 March 2006/ Accepted 13 June 2006

Wnt ligands bind receptors of the Frizzled (Fz) family to control cell fate, proliferation, and polarity. Canonical Wnt/Fz signaling stabilizes ß-catenin by inactivating GSK3ß, leading to the translocation of ß-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 ß-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 ß-catenin pathway in B cells. Reduction of GCKR expression inhibits Wnt3a-induced phosphorylation of GSK3ß at serine 9 and decreases the accumulation of cytosolic ß-catenin. Furthermore, Wnt signaling induces an interaction between GCKR and GSK3ß. Our findings demonstrate that GCKR facilitates both canonical and noncanonical Wnt signaling in B lymphocytes.

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* Corresponding author. Mailing address: 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. Phone: (301) 402-4852. Fax: (301) 402-0070. E-mail: jkehrl{at}niaid.nih.gov.

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Molecular and Cellular Biology, September 2006, p. 6511-6521, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.00209-06

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