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PMID:19801552

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Citation

Chen, M, Philipp, M, Wang, J, Premont, RT, Garrison, TR, Caron, MG, Lefkowitz, RJ and Chen, W (2009) G Protein-coupled receptor kinases phosphorylate LRP6 in the Wnt pathway. J. Biol. Chem. 284:35040-8

Abstract

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.

Links

PubMed PMC2787365 Online version:10.1074/jbc.M109.047456

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:A0A2R8Q9H5

involved_in

GO:0060070: canonical Wnt signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100308-2

P

Seeded From UniProt

complete

DANRE:A9JRC5

involved_in

GO:0030177: positive regulation of Wnt signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100308-3

P

Seeded From UniProt

complete

DANRE:D0EWS1

involved_in

GO:0060070: canonical Wnt signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100308-2

P

Seeded From UniProt

complete

DANRE:D0EWS2

involved_in

GO:0030177: positive regulation of Wnt signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100308-3

P

Seeded From UniProt

complete

DANRE:F1QTJ4

involved_in

GO:0060070: canonical Wnt signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100308-2

P

Seeded From UniProt

complete

DANRE:F1R0T6

involved_in

GO:0030177: positive regulation of Wnt signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100308-3

P

Seeded From UniProt

complete

DANRE:F1RAR9

involved_in

GO:0030177: positive regulation of Wnt signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100308-3

P

Seeded From UniProt

complete


See also

References

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