Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3-independent-catenin degradation

Topol L, Jiang X, Choi H, Garrett-Beal L, Carolan PJ and Yang Y
J Cell Biol (2003) 162(5): 899-908
Research Area:
Cancer Research/Cell Biology
Cells used in publication:
Species: human
Tissue Origin: colon
The human colon cancer cell lines SW48 and SW480 were co-transfected by nucleofection in different combinations with the following plasmids: two reporter plasmids for a luciferase-based assay, expression plasmids for Wnt-5a, for dominant negative forms of Siah1 or Siah2 (homologs 1 and 2 of Drosophila seven in absentia), and for the tumor suppressor protein APC (Adenomatous Polyposis Coli).
Wnts are secreted signaling molecules that can transduce their signals through several different pathways. Wnt-5a is considered a noncanonical Wnt as it does not signal by stabilizing beta-catenin in many biological systems. We have uncovered a new noncanonical pathway through which Wnt-5a antagonizes the canonical Wnt pathway by promoting the degradation of beta-catenin. This pathway is Siah2 and APC dependent, but GSK-3 and beta-TrCP independent. Furthermore, we provide evidence that Wnt-5a also acts in vivo to promote beta-catenin degradation in regulating mammalian limb development and possibly in suppressing tumor formation.