The tyrosine Y250 2.39 in Frizzled 4 defines a conserved motif important for structural integrity of the receptor and recruitment of Disheveled

Cell Signal. 2017 Oct;38:85-96. doi: 10.1016/j.cellsig.2017.06.018. Epub 2017 Jun 29.

Abstract

Frizzleds (FZDs) are unconventional G protein-coupled receptors, which activate diverse intracellular signaling pathways via the phosphoprotein Disheveled (DVL) and heterotrimeric G proteins. The interaction interplay of FZDs with DVL and G proteins is complex, involves different regions of FZD and the potential dynamics are poorly understood. In the present study, we aimed to characterize the function of a highly conserved tyrosine (Y2502.39) in the intracellular loop 1 (IL1) of human FZD4. We have found Y2502.39 to be crucial for DVL2 interaction and DVL2 translocation to the plasma membrane. Mutant FZD4-Y2502.39F, impaired in DVL2 binding, was defective in both β-catenin-dependent and β-catenin-independent WNT signaling induced in Xenopus laevis embryos. The same mutant maintained interaction with the heterotrimeric G proteins Gα12 and Gα13 and was able to mediate WNT-induced G protein dissociation and G protein-dependent YAP/TAZ signaling. We conclude from modeling and dynamics simulation efforts that Y2502.39 is important for the structural integrity of the FZD-DVL, but not for the FZD-G protein interface and hypothesize that the interaction network of Y2502.39 and H3484.46 plays a role in specifying downstream signaling pathways induced by the receptor.

Keywords: DVL2; Disheveled; FZD(4); Frizzled; GNA12; GNA13.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Conserved Sequence*
  • DNA Mutational Analysis
  • Dishevelled Proteins / chemistry*
  • Dishevelled Proteins / metabolism*
  • Embryo, Nonmammalian / metabolism
  • Frizzled Receptors / chemistry*
  • Frizzled Receptors / metabolism*
  • HEK293 Cells
  • Heterotrimeric GTP-Binding Proteins / metabolism
  • Humans
  • Molecular Dynamics Simulation
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Polymerization
  • Protein Binding
  • Signal Transduction
  • Structural Homology, Protein
  • Structure-Activity Relationship
  • Tyrosine / metabolism*
  • Wnt Signaling Pathway
  • Xenopus laevis / embryology

Substances

  • Dishevelled Proteins
  • Frizzled Receptors
  • Tyrosine
  • Heterotrimeric GTP-Binding Proteins