Abstract
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.
Highlights
Wnt signaling is an incredibly complicated and critical controller of a myriad of processes in mammals [1]
Pharmacologic inhibitors, cell culture, real-time PCR, chromatin immunoprecipitation, protein immunoprecipitation, Western blotting, reporter-luciferase, protein purification, site-directed mutagenesis, in vitro phosphorylation and binding assays, and immunofluorescence were utilized. Coordinated integration between both canonical and non-canonical Wnt pathways appears to be crucial in the control of fundamental morphologic processes and in the regulation of normal as well as pathologic events. Such integration between both canonical and non-canonical Wnt signaling is presumably effected via reversible phosphorylation mechanism to regulate differential β -catenin/Kat3 coactivator usage in order to coordinate proliferation with differentiation and adhesion
We have shown that one mechanism accounting for this alteration in β -catenin/coactivator usage depends on phosphorylation of p300 Ser89 by protein kinase C (PKC) whose activation is induced by non-canonical Wnt signaling [66]
Summary
Wnt signaling is an incredibly complicated and critical controller of a myriad of processes in mammals [1]. “Canonical” Wnt signaling (or Wnt/βcatenin signaling) is associated with ß-catenin accumulation. Wnt/catenin signaling is associated with the ability of stem cells to proliferate without differentiation [3], proliferation of neuronal precursors [4] as well as neuronal differentiation and neural development [5]. There exists a significant body of literature on “non-canonical” Wnt signaling, that is, the subset of Wnt signaling which does not involve ß-catenin accumulation in the nucleus [6]. A key initial observation about non-canonical signaling was its capacity to counter canonical Wnt/catenin signaling. The ancient and highly evolutionarily conserved Wnt signaling pathway is critical in most tissues and organs for an organism to develop normally from embryo through adult. Even though designating Wnt signaling as either canonical or noncanonical allows for easier conceptual discourse about this signaling pathway, canonical and non-canonical Wnt crosstalk regulates complex nonlinear networks. Received: November 10, 2018 Revised: January 30, 2019 Accepted: February 06, 2019
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