SnapShot: Wnt/β-Catenin Signaling

Abstract

Molecules labeled in green and blue play positive and negative roles in Wnt/β-catenin signaling, respectively. Molecules that are labeled in both colors have dual roles.(Top left) Wnt biogenesis. A lipid modification is added to Wnt ligands by Porc in the endoplasmic reticulum (ER). Wnt ligands are glycosylated in the ER and Golgi and require Wls (also known as Evi) to traffic through the Golgi to the plasma membrane. The retromer complex is also important for Wnt secretion, particularly for long-range signaling. Mature Wnt ligands may interact with lipoprotein particles. Proteoglycans Dally and Kny/Glypican may also facilitate Wnt distribution.(Bottom right) Wnt receptor biogenesis. In cells that respond to Wnt the ER protein MESD is required for folding and trafficking of the Wnt receptor LRP5/6 to the plasma membrane, and the ER protein Shisa prevents folding and trafficking of the Fz protein to the plasma membrane.(Right) Wnt/β-catenin signaling OFF. sFRP and WIF1 directly bind Wnt ligands and prevent Wnts from binding to receptors. SOST/WISE, CTGF/Cyr61 bind to LRP6 (CTGF may also bind to Fz) to prevent the formation of the Wnt-Fz-LRP5/6 receptor complex. DKK binds to and inhibits LRP5/6 in cooperation with the KRM receptor. In the absence of Wnt signaling, the scaffolding protein Axin and tumor suppressor APC form a β-catenin destruction complex that binds cytosolic β-catenin and facilitates sequential phos-phorylation of β-catenin by CK1 (at S45) and GSK3 (at S33/S37/T41). The tumor suppressor WTX may also reside in this complex. Phosphorylated β-catenin is recognized by β-Trcp and ubiquitinated for degradation by the proteasome. In the nucleus, TCF assembles a transcriptional repressor complex to silence Wnt target genes via recruiting Gro, CtBP, and HDACs. Residual β-catenin is exported from the nucleus by RanBP3 and APC or bound by CBY or ICAT that prevents β-catenin association with TCF/LEF.(Left) Wnt/β-catenin signaling ON. The Wnt ligand binds to Fz and LRP5/6 receptors to form a Fz-LRP5/6 complex. Dally and Kny can also bind Wnt and enrich Wnt concentration locally or help Wnt gradient distribution. Rspo proteins and Norrin are secreted agonists that bind to LRP5/6 and/or Fz to activate Wnt/β-catenin signaling. Formation of the Fz-LRP6 complex via Dvl promotes LRP6 phosphorylation by GSK3 and CK1γ and other CK1. Fz binds Dvl and phosphorylated LRP6 recruits Axin to the plasma membrane, resulting in inhibition of β-catenin phosphorylation/degradation by an as yet unknown mechanism. Fz-LRP6-Dvl aggregation may be involved. LRP6 association with caveolin may promote its endocytosis and signaling. Translocation of Axin is facilitated by MACF1. Trimeric G proteins may act between Fz and Dvl, and β-arrestin may associate with Dvl and Axin. Stabilized β-catenin is translocated to the nucleus where it binds TCF/LEF and recruits coactivators such as the Lgs/Pygo complex, CBP/p300, Brahma, MED12/Mediator, and the PAF1/Hyrax complex to initiate RNA transcription and elongation. TCF/β-catenin controls the expression of many genes that affect cell proliferation (i.e.,