PUBLICATION
G protein-coupled receptor kinases phosphorylate LRP6 in the Wnt pathway
- Authors
- Chen, M., Philipp, M., Wang, J., Premont, R.T., Garrison, T.R., Caron, M.G., Lefkowitz, R.J., and Chen, W.
- ID
- ZDB-PUB-091023-18
- 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.
Citation
Chen, M., Philipp, M., Wang, J., Premont, R.T., Garrison, T.R., Caron, M.G., Lefkowitz, R.J., and Chen, W. (2009) G protein-coupled receptor kinases phosphorylate LRP6 in the Wnt pathway. The Journal of biological chemistry. 284(50):35040-35048.
Abstract
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.
Genes / Markers
Probes
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping