Shi Chong-Shan, Huang Ning-Na, Harrison Kathleen, Han Sang-Bae, Kehrl John H
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.
Mol Cell Biol. 2006 Sep;26(17):6511-21. doi: 10.1128/MCB.00209-06.
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.
Wnt配体与卷曲蛋白（Fz）家族的受体结合，以控制细胞命运、增殖和极性。经典的Wnt/Fz信号通过使糖原合成酶激酶3β（GSK3β）失活来稳定β-连环蛋白，导致β-连环蛋白易位至细胞核并激活Wnt靶基因。非经典的Wnt/Fz信号激活RhoA和Rac，后者触发c-Jun氨基末端激酶（JNK）的激活。在此，我们表明将B淋巴细胞暴露于Wnt3a条件培养基会激活JNK并提高胞质β-连环蛋白水平。Rac鸟嘌呤核苷酸交换因子Asef和丝裂原活化蛋白激酶激酶激酶激酶生发中心激酶相关酶（GCKR）都是B细胞中Wnt介导的JNK激活所必需的。此外，我们表明GCKR对B细胞中的β-连环蛋白途径有正向影响。GCKR表达的降低会抑制Wnt3a诱导的GSK3β丝氨酸9位点的磷酸化，并减少胞质β-连环蛋白的积累。此外，Wnt信号诱导GCKR与GSK3β之间的相互作用。我们的研究结果表明，GCKR在B淋巴细胞中促进经典和非经典Wnt信号传导。
