R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6.
The R-Spondin (RSpo) family of secreted proteins act as potent activators of the Wnt/beta-catenin signaling pathway. We have previously shown that RSpo proteins can induce proliferative effects on the gastrointestinal epithelium in mice. Here we provide a mechanism whereby RSpo1 regulates cellular responsiveness to Wnt ligands by modulating the cell-surface levels of the coreceptor LRP6. We show that RSpo1 activity critically depends on the presence of canonical Wnt ligands and LRP6. Although RSpo1 does not directly activate LRP6, it interferes with DKK1/Kremen-mediated internalization of LRP6 through an interaction with Kremen, resulting in increased LRP6 levels on the cell surface. Our results support a model in which RSpo1 relieves the inhibition DKK1 imposes on the Wnt pathway.
Binnerts
Minke E
ME
Nuvelo, Inc., 201 Industrial Road, Suite 310, San Carlos, CA 94070-6211, USA.
Kim
Kyung-Ah
KA
Bright
Jessica M
JM
Patel
Sejal M
SM
Tran
Karolyn
K
Zhou
Mei
M
Leung
John M
JM
Liu
Yi
Y
Lomas
Woodrow E
WE
Dixon
Melissa
M
Hazell
Sophie A
SA
Wagle
Marie
M
Nie
Wen-Sheng
WS
Tomasevic
Nenad
N
Williams
Jason
J
Zhan
Xiaoming
X
Levy
Michael D
MD
Funk
Walter D
WD
Abo
Arie
A
D000818:Animals; D002460:Cell Line; D004330:Drosophila / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000166:cytology; D026502:LDL-Receptor Related Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008024:Ligands; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000098907:R-Spondins