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PMID:19107203

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Citation

Piao, S, Lee, SH, Kim, H, Yum, S, Stamos, JL, Xu, Y, Lee, SJ, Lee, J, Oh, S, Han, JK, Park, BJ, Weis, WI and Ha, NC (2008) Direct inhibition of GSK3beta by the phosphorylated cytoplasmic domain of LRP6 in Wnt/beta-catenin signaling. PLoS ONE 3:e4046

Abstract

Wnt/beta-catenin signaling plays a central role in development and is also involved in a diverse array of diseases. Binding of Wnts to the coreceptors Frizzled and LRP6/5 leads to phosphorylation of PPPSPxS motifs in the LRP6/5 intracellular region and the inhibition of GSK3beta bound to the scaffold protein Axin. However, it remains unknown how GSK3beta is specifically inhibited upon Wnt stimulation. Here, we show that overexpression of the intracellular region of LRP6 containing a Ser/Thr rich cluster and a PPPSPxS motif impairs the activity of GSK3beta in cells. Synthetic peptides containing the PPPSPxS motif strongly inhibit GSK3beta in vitro only when they are phosphorylated. Microinjection of these peptides into Xenopus embryos confirms that the phosphorylated PPPSPxS motif potentiates Wnt-induced second body axis formation. In addition, we show that the Ser/Thr rich cluster of LRP6 plays an important role in LRP6 binding to GSK3beta. These observations demonstrate that phosphorylated LRP6/5 both recruits and directly inhibits GSK3beta using two distinct portions of its cytoplasmic sequence, and suggest a novel mechanism of activation in this signaling pathway.

Links

PubMed PMC2603313 Online version:10.1371/journal.pone.0004046

Keywords

Amino Acid Motifs/physiology; Amino Acid Sequence; Animals; Cells, Cultured; Cytoplasm/metabolism; Embryo, Nonmammalian; Embryonic Development/drug effects; Glycogen Synthase Kinase 3/antagonists & inhibitors; Humans; LDL-Receptor Related Proteins/chemistry; LDL-Receptor Related Proteins/metabolism; LDL-Receptor Related Proteins/pharmacology; LDL-Receptor Related Proteins/physiology; Low Density Lipoprotein Receptor-Related Protein-5; Low Density Lipoprotein Receptor-Related Protein-6; Molecular Sequence Data; Phosphorylation; Protein Kinases/metabolism; Protein Structure, Tertiary/physiology; Sequence Homology, Amino Acid; Signal Transduction/physiology; Wnt Proteins/physiology; Xenopus/embryology; beta Catenin/physiology

Significance

Annotations

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

MOUSE:AXIN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O75581

F

Seeded From UniProt

complete

HUMAN:LRP6

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O35625

F

Seeded From UniProt

complete

HUMAN:LRP6

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9WV60

F

Seeded From UniProt

complete

HUMAN:LRP6

involved_in

GO:0060070: canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LRP6

involved_in

GO:0071901: negative regulation of protein serine/threonine kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CTNB1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9WV60

F

Seeded From UniProt

complete

MOUSE:GSK3B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q02248

F

Seeded From UniProt

complete

MOUSE:GSK3B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O75581

F

Seeded From UniProt

complete

HUMAN:LRP5

involved_in

GO:0071901: negative regulation of protein serine/threonine kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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