A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation.
Signalling by the Wnt family of secreted lipoproteins has essential functions in development and disease. The canonical Wnt/beta-catenin pathway requires a single-span transmembrane receptor, low-density lipoprotein (LDL)-receptor-related protein 6 (LRP6), whose phosphorylation at multiple PPPSP motifs is induced upon stimulation by Wnt and is critical for signal transduction. The kinase responsible for LRP6 phosphorylation has not been identified. Here we provide biochemical and genetic evidence for a 'dual-kinase' mechanism for LRP6 phosphorylation and activation. Glycogen synthase kinase 3 (GSK3), which is known for its inhibitory role in Wnt signalling through the promotion of beta-catenin phosphorylation and degradation, mediates the phosphorylation and activation of LRP6. We show that Wnt induces sequential phosphorylation of LRP6 by GSK3 and casein kinase 1, and this dual phosphorylation promotes the engagement of LRP6 with the scaffolding protein Axin. We show further that a membrane-associated form of GSK3, in contrast with cytosolic GSK3, stimulates Wnt signalling and Xenopus axis duplication. Our results identify two key kinases mediating Wnt co-receptor activation, reveal an unexpected and intricate logic of Wnt/beta-catenin signalling, and illustrate GSK3 as a genuine switch that dictates both on and off states of a pivotal regulatory pathway.
Zeng
Xin
X
Neurobiology Program, Children's Hospital Boston, Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Tamai
Keiko
K
Doble
Brad
B
Li
Shitao
S
Huang
He
H
Habas
Raymond
R
Okamura
Heidi
H
Woodgett
Jim
J
He
Xi
X
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D060466:Axin Protein; D019521:Body Patterning; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011973:Receptors, LDL / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D013379:Substrate Specificity; D051820:TCF Transcription Factors / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D029867:Xenopus Proteins; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D060466:Axin Protein; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D011973:Receptors, LDL; D012097:Repressor Proteins; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D029867:Xenopus Proteins; C555454:axin1 protein, Xenopus; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3