Wnt Signalling

• morphogenic signalling pathways are important for development, specifically planar cell polarity (PCP) which is the local action of morphogens in action -> the polarization of a field of cells within a plane/sheet, not just a single cell

  • PCP can be apical/basal, proximal/distal, etc.

  
• Wnt signalling has very localized action and creates very steep gradients (has impact at high concentrations, not low/moderate since it rapidly dilutes out)

  • Wnt ligands are small proteins and are covalently attached to a lipid tail through palmitoylation at the N terminus so they can't travel far because membrane bound
  • Wnt ligand and Frizzled receptors (type of GPCR) have many different types

  
• absence of Wnt ligand -> protein complex forms to degrade beta-catenin

  • no Wnt ligand -> Frizzled and LRP (co-receptor) and associated protein Dishevelled are unengaged -> destruction complex forms which activates its kinases -> this causes the phosphorylation, ubiquitination, and destruction of beta-catenin protein and the target genes of beta-catenin (Wnt) are further inactivated by Groucho with LEF1/TCF
  • the destruction complex contains -> axin (scaffold), glycogen synthase kinase 3 beta (GSK3B, kinase), CK1 (kinase), APC (scaffold), beta-catenin (target)

  
• presence of Wnt ligand -> destruction complex dissociates, beta-catenin stabilized which leads to transcription

  • Wnt ligand binds Frizzled, LRP recruited and engaged in active complex -> Frizzled GPCR (with TM 5 pulled into cavity) recruits Dishevelled -> Dishevelled dissociate axin and APC from destruction complex -> CK1 and GSK3 kinases can phosphorylate LRP to enhance dissociation -> axin binds Dishevelled and phosphorylated LRP -> beta-catenin escapes degradation and enters the nucleus -> binds to factors and displaces Groucho repressor -> target genes (Wnt) activated for transcription

  
• Frizzled/Wnt in PCP and morphogenesis

  • Frizzled and Dishevelled bound to Wnt -> Vang/Fmi in the same cell will bind to another cell's Frizzled and Dishevelled -> this complex represses response to Wnt/impairs normal activation by Wnt so each cell accepts Wnt signal from ONE side but not the other -> PCP established -> polarization!

  
• polarization causes cells to have a leading edge that are always receptive to Wnt signalling and the other isn't, Frizzled will always be engaged in a protein/protein interaction which either activates (Wnt) or outcompetes for Wnt (Vang)