RNF43 and ZNRF3 in Wnt Signaling - A Master Regulator at the Membrane

Abstract

The Wnt β-catenin signaling pathway is a highly conserved mechanism that plays a critical role from embryonic development and adult stem cell homeostasis. However, dysregulation of the Wnt pathway has been implicated in various diseases, including cancer. Therefore, multiple layers of regulatory mechanisms tightly control the activation and suppression of the Wnt signal. The E3 ubiquitin ligases RNF43 and ZNRF3, which are known negative regulators of the Wnt pathway, are critical component of Wnt signaling regulation. These E3 ubiquitin ligases control Wnt signaling by targeting the Wnt receptor Frizzled to induce ubiquitination-mediated endo-lysosomal degradation, thus controlling the activation of the Wnt signaling pathway. We also discuss the regulatory mechanisms, interactors, and evolution of RNF43 and ZNRF3. This review article summarizes recent findings on RNF43 and ZNRF3 and their potential implications for the development of therapeutic strategies to target the Wnt signaling pathway in various diseases, including cancer.

Keywords: RNF43; Stem cell; Wnt signaling; ZNRF3.

Fig. 1

Overview of Wnt/βcatenin signaling pathway. The absence of Wnt ligands induces the phosphorylation of β-catenin by the destruction complex. The complex comprises the scaffold protein AXIN, APC, and the GSK3β and CK1α. Without Wnt ligands, β-catenin undergoes GSK3β mediated phosphorylation, followed by ubiquitination facilitated by β-TrCP for proteasomal degradation. Therefore, target genes of Wnt signaling are not activated. Activation of the canonical pathway ensues upon the binding of secreted canonical Wnt ligands to FZD receptors and LRP co-receptors. Subsequently, CK1α and GSK3β phosphorylate LRP receptors, facilitating the recruitment of DVL proteins to the plasma membrane. As a result, β-catenin experiences stabilization and accumulation, and subsequently translocates into the nucleus. Within the nucleus, β-catenin forms an active complex with LEF/TCF proteins by displacing TLE/Gaucho complexes and recruiting co-activators involved in histone modification. This transcriptional switch triggers a multitude of alterations in cellular processes.

Fig. 2

PA-TM-RING family genes. (a) Domain architecture of PA-TM-RING family genes. (b) Amino acid sequence alignment of human PA-TM-RING family.