|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.
|Source:||The Journal of biological chemistry 284(50): 35040-35048 (Journal)|
|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|
|PubMed:||19801552 Full text @ J. Biol. Chem.|
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.
ABSTRACTWnt 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.