R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and beta-catenin signaling.
R-spondin proteins are newly identified secreted molecules that activate beta-catenin signaling. However, the mechanism of R-spondin action and its relationship with Wnt signaling remain unclear. Here we show that human R-spondin1 (hRspo1) is a high affinity ligand for the Wnt co-receptor LRP6 (K(d) = 1.2 nm). hRspo1 induces glycogen synthase kinase 3-dependent phosphorylation and activation of LRP6. DKK1, an LRP6 antagonist, inhibits hRspo1-induced LRP6 phosphorylation. We further demonstrate that hRspo1 synergizes with Frizzled5 in Xenopus axis induction assays and induces the phosphorylation of Dishevelled, a cytoplasmic component downstream of Frizzled function. Our study reveals interesting similarity and distinction between Wnt and R-spondin signaling.
Wei
Qiou
Q
Program of Neurobiology, Children's Hospital Boston, Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Yokota
Chika
C
Semenov
Mikhail V
MV
Doble
Brad
B
Woodgett
Jim
J
He
Xi
X
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D000072261:Dishevelled Proteins; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008024:Ligands; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D019699:Thrombospondins / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism; D014982:Xenopus laevis; D051176:beta Catenin / Q000378:metabolism*; D000098907:R-Spondins
D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D038362:Glycogen Synthase Kinase 3; D036341:Intercellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; D008024:Ligands; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D010750:Phosphoproteins; D019699:Thrombospondins; D051153:Wnt Proteins; D051176:beta Catenin; C501126:DKK1 protein, human; C555475:LRP6 protein, human; C503243:RSPO1 protein, human; D000098907:R-Spondins