Behrens J
Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, Germany.
J Cell Sci. 2000 Mar;113 ( Pt 6):911-9. doi: 10.1242/jcs.113.6.911.
The Wnt signal transduction pathway regulates various aspects of embryonal development and is involved in cancer formation. Wnts induce the stabilisation of cytosolic (beta)-catenin, which then associates with TCF transcription factors to regulate expression of Wnt-target genes. At various levels the Wnt pathway is subject to cross-regulation by other components. Recent evidence suggests that a specific MAP kinase pathway involving the MAP kinase kinase kinase TAK1 and the MAP kinase NLK counteract Wnt signalling. In particular, homologues of TAK1 and NLK, MOM-4 and LIT-1, negatively regulate Wnt-controlled cell fate decision in the early Caenorhabditis elegans embryo. Moreover, TAK1 activates NLK, which phosphorylates TCFs bound to (beta)-catenin. This blocks nuclear localization and DNA binding of TCFs. Since TAK1 is activated by TGF-(beta) and various cytokines, it might provide an entry point for regulation of the Wnt system by other pathways. In addition, alterations in TAK1-NLK might play a role in cancer.
Wnt信号转导通路调节胚胎发育的各个方面，并参与癌症形成。Wnts诱导胞质（β）-连环蛋白的稳定，然后（β）-连环蛋白与TCF转录因子结合以调节Wnt靶基因的表达。在各个水平上，Wnt通路都受到其他成分的交叉调节。最近的证据表明，涉及丝裂原活化蛋白激酶激酶激酶TAK1和丝裂原活化蛋白激酶NLK的特定丝裂原活化蛋白激酶途径可抵消Wnt信号传导。特别是，TAK1和NLK的同源物MOM-4和LIT-1在秀丽隐杆线虫早期胚胎中对Wnt控制的细胞命运决定起负调节作用。此外，TAK1激活NLK，NLK使与（β）-连环蛋白结合的TCF磷酸化。这会阻止TCF的核定位和DNA结合。由于TAK1被转化生长因子-β（TGF-β）和各种细胞因子激活，它可能为其他途径调节Wnt系统提供一个切入点。此外，TAK1-NLK的改变可能在癌症中起作用。
