A Canonical Mechanism in a Noncanonical Pathway

Science's STKE  07 Jun 2005:
Vol. 2005, Issue 287, pp. tw214
DOI: 10.1126/stke.2872005tw214

Wnt signals through canonical and noncanonical pathways to regulate many processes during development. Canonical Wnt signaling involves stabilization of β-catenin, which binds to transcriptional repressors of the T cell factor (TCF) family, converting them into transcriptional activators and activating target genes. Noncanonical Wnt pathways, however, appear to function independently of effects on β-catenin stabilization. During Caenorhabditis elegans development, the somatic gonadal precursor divides into asymmetric daughter cells whose fates depend on nuclear abundance of the TCF homolog POP-1; the cell with more nuclear POP-1 adopts a "proximal" fate, whereas that with less nuclear POP-1 adopts a "distal" fate. Noncanonical Wnt and mitogen-activated protein kinase (MAPK) signaling involving the MAPK LIT-1 and the β-catenin WRM-1 are required for reduction in nuclear POP-1 in the distal daughter. Inactivation of the gene sys-1 (symmetrical sisters) leads to adoption of a proximal fate in both daughter cells, despite asymmetric nuclear POP-1 content, and, surprisingly, the absence of POP-1 also leads to a proximal fate (see Bowerman).

Kidd et al. determined that sys-1 encoded a protein containing three armadillo repeats, with an amino acid sequence unlike that of β-catenin. However, transgenic analysis indicated that SYS-1 could substitute for the C. elegans β-catenin BAR-1 in vulval development. Further, SYS-1 bound POP-1 both in a yeast two-hybrid assay and when tagged versions of both proteins were expressed in HEK 293 T cells. Mutational analysis indicated that SYS-1 bound to the POP-1 β-catenin-binding domain. When cotransfected into NCI-H28 cells, SYS-1 coactivated POP-1-dependent transcription. Experiments in which sys-1 dosage was varied supported a model in which SYS-1 acted as a limiting coactivator of POP-1. In this model, abundant nuclear POP-1 is mostly uncomplexed with SYS-1 and acts as a transcriptional repressor (leading to a proximal fate), whereas with low abundance, most POP-1 is complexed with SYS-1 and acts as a transcriptional activator (leading to a distal fate). Thus, the authors proposed that SYS-1 acts as β-catenin does, despite its lack of sequence similarity, and that the SYS-1 pathway represents a new twist on Wnt signaling.

A. R. Kidd III, J. A. Miskowski, K. R. Siegfried, H. Sawa, J. Kimble, A β-catenin identified by functional rather than sequence criteria and its role in Wnt/MAPK signaling. Cell 121, 761-772 (2005). [PubMed]

B. Bowerman, Advocating asymmetry and the POP-1 paradox: Noncanonical Wnt signaling in C. elegans. Cell 121, 662-664 (2005). [PubMed]