ZFIN ID: ZDB-PUB-091023-18
G protein-coupled receptor kinases phosphorylate LRP6 in the Wnt pathway
Chen, M., Philipp, M., Wang, J., Premont, R.T., Garrison, T.R., Caron, M.G., Lefkowitz, R.J., and Chen, W.
Date: 2009
Source: The Journal of biological chemistry   284(50): 35040-35048 (Journal)
Registered Authors:
Keywords: G PROTEINS/Coupled Receptors (GPCR), SIGNAL TRANSDUCTION/Protein Kinases, G Protein-coupled Receptor Kinase (GRK), Kinase Phosphorylation, Low-density-lipoprotein-Related Protein 6 (LRP6), Wnt Signaling
MeSH Terms:
  • Amino Acid Sequence
  • Animals
  • Axin Protein
  • Cells, Cultured
  • Fibroblasts/cytology
  • Fibroblasts/physiology
  • Frizzled Receptors/genetics
  • Frizzled Receptors/metabolism
  • G-Protein-Coupled Receptor Kinase 5/genetics
  • G-Protein-Coupled Receptor Kinase 5/metabolism*
  • G-Protein-Coupled Receptor Kinases/genetics
  • G-Protein-Coupled Receptor Kinases/metabolism*
  • HeLa Cells
  • Homeodomain Proteins/genetics
  • Homeodomain Proteins/metabolism
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Oligonucleotides, Antisense/genetics
  • Oligonucleotides, Antisense/metabolism
  • Phosphorylation
  • Receptors, LDL/genetics
  • Receptors, LDL/metabolism*
  • Repressor Proteins/genetics
  • Repressor Proteins/metabolism
  • Signal Transduction/physiology
  • Wnt Proteins/genetics
  • Wnt Proteins/metabolism*
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • beta Catenin/genetics
  • beta Catenin/metabolism
PubMed: 19801552 Full text @ J. Biol. Chem.
Wnt ligands conduct their functions in canonical Wnt signaling by binding to two receptors, the single-transmembrane low-density-lipoprotein-related proteins 5 and 6 (LRP5/6) and seven-transmembrane (7TM) Frizzled receptors. Subsequently, phosphorylation of Serine/Threonine residues within five repeating signature PPPSP motifs on LRP6 is responsible for LRP6 activation. GSK3beta, a cytosolic kinase for phosphorylation of a downstream effector beta-catenin, was proposed to participate in such LRP6 phosphorylation. Here we report a new class of membrane-associated kinases for LRP6 phosphorylation. We found that G protein-coupled receptor kinases 5 and 6 (GRK5/6), traditionally known to phosphorylate and desensitize 7TM G protein-coupled receptors, directly phosphorylate the PPPSP motifs on single-transmembrane LRP6 and regulate Wnt/LRP6 signaling. GRK5/6 induced LRP6 activation is inhibited by the LRP6 antagonist Dickkopf. Depletion of GRK5 markedly reduces Wnt3A-stimulated LRP6 phosphorylation in cells. In zebrafish, functional knockdown of GRK5 results in reduced Wnt signaling, analogous to LRP6 knockdown, as assessed by decreased abundance of beta-catenin and lowered expression of the Wnt target genes cdx4, vent and axin2. Expression of GRK5 rescues the diminished beta-catenin and axin2 response caused by GRK5 depletion. Thus, our findings identify GRK5/6 as novel kinases for the single transmembrane receptor LRP6 during Wnt signaling.