Cross-regulation of the Wnt signalling pathway: a role of MAP kinases.

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.