G Protein-coupled receptor kinases phosphorylate LRP6 in the Wnt pathway.
Journal Article (Journal Article)
Wnt ligands conduct their functions in canonical Wnt signaling by binding to two receptors, the single transmembrane low density lipoprotein receptor-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 knock-down of GRK5 results in reduced Wnt signaling, analogous to LRP6 knock-down, 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.
Full Text
Duke Authors
Cited Authors
- Chen, M; Philipp, M; Wang, J; Premont, RT; Garrison, TR; Caron, MG; Lefkowitz, RJ; Chen, W
Published Date
- December 11, 2009
Published In
Volume / Issue
- 284 / 50
Start / End Page
- 35040 - 35048
PubMed ID
- 19801552
Pubmed Central ID
- PMC2787365
Electronic International Standard Serial Number (EISSN)
- 1083-351X
Digital Object Identifier (DOI)
- 10.1074/jbc.M109.047456
Language
- eng
Conference Location
- United States