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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.
The Journal of biological chemistry
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
Amino Acid Sequence
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*
Low Density Lipoprotein Receptor-Related Protein-6
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.
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.