Convergence of Canonical and Non-canonical Wnt Signal: Differential Kat3 Coactivator Usage

BACKGROUND: The ancient and highly evolutionarily conserved Wnt signaling pathway is criti-cal in nearly all tissues and organs for an organism to develop normally from embryo through adult. Wnt signaling is generally parsed into ƒ?ocanonicalƒ?? or Wnt-Iý catenin-dependent or ƒ?onon-canonicalƒ?? Iý catenin-independent signaling. Even though designating Wnt signaling as either canonical or non-canonical allows for easier conceptual discourse about this signaling pathway, in fact canonical and non-canonical Wnt crosstalk regulates complex nonlinear networks. OBJECTIVE: In this perspective, we discuss the integration of canonical and non-canonical Wnt signaling via differential Kat3 (CBP and p300) coactivator usage, thereby regulating and coordinating gene expression programs associated with both proliferation and cellular differentiation and morphogenesis. Methods: Pharmacologic inhibitors, cell culture, real-time PCR, chromatin immunoprecipitation, protein immuno-precipitation, Western blotting, reporter-luciferase, protein purification, site-directed mutagenesis, in vitro phosphorylation and binding assays, and immunofluorescence were utilized. CONCLUSION: Coordinated integration between both canonical and non-canonical Wnt pathways appears to be crucial not only in the control of fundamental morphologic processes but also in the regulation of nor-mal as well as pathologic events. Such integration between both canonical and non-canonical Wnt signal-ing is presumably effected via reversible phosphorylation mechanism (e.g., protein kinase C) to regulate differential Iý-catenin/Kat3 coactivator usage in order to coordinate proliferation with differentiation and adhesion.