R-spondin1 Is a High Affinity Ligand for LRP6 and Induces LRP6 Phosphorylation and β-Catenin Signaling

R-spondin proteins are newly identified secreted molecules that activate β-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 (Kd = 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. R-spondin proteins are newly identified secreted molecules that activate β-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 (Kd = 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. The Wnt/β-catenin signaling pathway plays pivotal roles in developmental processes and diseases (1Nusse R. Cell Res. 2005; 15: 28-32Crossref PubMed Scopus (811) Google Scholar). Wnt proteins are secreted and lipid-modified molecules (2Willert K. Brown J.D. Danenberg E. Duncan A.W. Weissman I.L. Reya T. Yates III, J.R. Nusse R. Nature. 2003; 423: 448-452Crossref PubMed Scopus (1815) Google Scholar). Depending on the cell type and receptor complement present, Wnt proteins can activate the “canonical” β-catenin-dependent signaling or β-catenin-independent signaling, including the Wnt/Ca2+ pathway and the planar cell polarity pathway (3Strutt D. Development (Camb.). 2003; 130: 4501-4513Crossref PubMed Scopus (213) Google Scholar). The canonical Wnt signaling operates via stabilization of the transcriptional co-activator β-catenin. In the absence of Wnt stimulation, cytosolic β-catenin is sequentially phosphorylated by casein kinase Iα and glycogen synthase kinase 3 (GSK3) 3The abbreviations used are: GSK3, glycogen synthase kinase 3; h, human; Fz, Frizzled; MEF, mouse embryonic fibroblast; RT, reverse transcriptase; CM, conditioned medium; AP, alkaline phosphatase; HA, hemagglutinin; TCF, T-cell factor. in a complex composed of the scaffolding protein Axin and the tumor suppressor protein APC (4Ikeda S. Kishida S. Yamamoto H. Murai H. Koyama S. Kikuchi A. 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Zhang K. Nathans J. Cell. 2004; 116: 883-895Abstract Full Text Full Text PDF PubMed Scopus (694) Google Scholar). On the other hand, Dickkopf-1, Wise, and SOST antagonize Wnt/β-catenin signaling through direct interaction with LRP5/6 (23Li X. Zhang Y. Kang H. Liu W. Liu P. Zhang J. Harris S.E. Wu D. J. Biol. Chem. 2005; 280: 19883-19887Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar, 24Semenov M.V. Tamai K. Brott B.K. Kuhl M. Sokol S. He X. Curr. Biol. 2001; 11: 951-961Abstract Full Text Full Text PDF PubMed Scopus (598) Google Scholar, 25Semenov M. Tamai K. He X. J. Biol. Chem. 2005; 280: 26770-26775Abstract Full Text Full Text PDF PubMed Scopus (608) Google Scholar, 26Bafico A. Liu G. Yaniv A. Gazit A. Aaronson S.A. Nat. Cell Biol. 2001; 3: 683-686Crossref PubMed Scopus (671) Google Scholar, 27Mao B. Wu W. Li Y. Hoppe D. P. A. C. Nature. 2001; PubMed Scopus Google Scholar, N. S. A. P.M. R. Development (Camb.). 2003; 130: PubMed Scopus Google Scholar). and of with the receptor complement in the roles of Wnt/β-catenin signaling in embryonic and of in family of secreted to as R-spondin T. K. M. M. Takada S. H. 2004; PubMed Scopus Google Scholar, O. A. I. P. C. Wu W. Dev. Cell. 2004; 7: Full Text Full Text PDF PubMed Scopus Google has been identified that activate β-catenin signaling M. J. T. T. M. Liu Y. B. E. P. K. Science. 2005; PubMed Scopus (443) Google Scholar, S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). R-spondin proteins in which similarity to the Wnt family of identified as a in mouse that is in the and its Wnt T. K. M. M. Takada S. H. 2004; PubMed Scopus Google Scholar). In in a for molecules that can activate a in O. A. I. P. C. Wu W. Dev. Cell. 2004; 7: Full Text Full Text PDF PubMed Scopus Google Scholar). in Xenopus R-spondin genes are with and by Wnt genes (hRspo1) identified by of its to upon in of M. J. T. T. M. Liu Y. B. E. P. K. Science. 2005; PubMed Scopus (443) Google Scholar). hRspo1 to be in by in a mouse M. J. T. T. M. Liu Y. B. E. P. K. Science. 2005; PubMed Scopus (443) Google Scholar). of hRspo1 with its to β-catenin accumulation and activation of enhancer target the and the mechanism by which the R-spondin family of proteins activates β-catenin signaling is fully understood. It has been that the complex as R-spondin of an of or interaction O. A. I. P. C. Wu W. Dev. Cell. 2004; 7: Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. T. T. M. Liu Y. B. E. P. K. Science. 2005; PubMed Scopus (443) Google Scholar). However, a study that can be with the extracellular of either or LRP6 S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In an to for in R-spondin signaling, we that is a high affinity receptor for hRspo1 (Kd = 1.2 nm). In and Xenopus LRP6 synergizes with hRspo1 to β-catenin signaling. hRspo1 induces LRP6 phosphorylation, which is a in the activation of Wnt/β-catenin signaling. Cell and and in and in For the and in and to the assays to with in the of for 3 with hRspo1 for Cell for R-spondin1 human by as O. A. I. P. C. Wu W. Dev. Cell. 2004; 7: Full Text Full Text PDF PubMed Scopus Google Scholar). The by and for in It for in transcription to used in Xenopus and LRP6 used as K. Semenov M. Kato Y. Spokony R. Liu C. Katsuyama Y. Hess F. Saint-Jeannet J.P. He X. Nature. 2000; 407: 530-535Crossref PubMed Scopus (1095) Google Scholar, 24Semenov M.V. Tamai K. Brott B.K. Kuhl M. Sokol S. He X. Curr. Biol. 2001; 11: 951-961Abstract Full Text Full Text PDF PubMed Scopus (598) Google Scholar, A. Smallwood P.M. Nathans J. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: PubMed Scopus Google Scholar). of the the or the the of the LRP6 extracellular by and of the human in proteins as or the of the Frizzled5 in the of other Frizzled the by and downstream of the and and and or and and stabilization as (18Tamai K. Zeng X. Liu C. Zhang X. Harada Y. Chang Z. He X. Mol. Cell. 2004; 13: 149-156Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar). For by and the and 3 For conditioned with with conditioned with or and The with protein for and with with and by a or and hRspo1 by as human alkaline DKK1, or by of hRspo1 in a in the with and in in the hRspo1 protein sequentially through a and affinity hRspo1 and further by The of hRspo1 and to of and The of the hRspo1 protein as by protein through a and and surface binding as M. Q. P. 2000; PubMed Scopus Google Scholar). for with conditioned or with conditioned with in with and for in in with the with and and an binding affinity as M.V. Tamai K. Brott B.K. Kuhl M. Sokol S. He X. Curr. Biol. 2001; 11: 951-961Abstract Full Text Full Text PDF PubMed Scopus (598) Google Scholar). Xenopus and for and assays as Y. Y. He X. J. 1999; 19: PubMed Google Scholar). and as Y. Y. He X. J. 1999; 19: PubMed Google Scholar). used as of The used as S. Y. P. Development (Camb.). PubMed Google Scholar). of by for of hRspo1 or hRspo1 and Xenopus O. A. I. P. C. Wu W. Dev. Cell. 2004; 7: Full Text Full Text PDF PubMed Scopus Google or mouse T. K. M. M. Takada S. H. 2004; PubMed Scopus Google of hRspo1 proteins in CM, and of the on hRspo1 We the of hRspo1 and type or hRspo1 to activate β-catenin signaling in mouse hRspo1 of cytosolic β-catenin in as O. A. I. P. C. Wu W. Dev. Cell. 2004; 7: Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). However, hRspo1 and to β-catenin although either low of hRspo1 or to β-catenin, hRspo1 and β-catenin. with on Xenopus and mouse O. A. I. P. C. Wu W. Dev. Cell. 2004; 7: Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google the of hRspo1 by of the the that the the of hRspo1 to activate β-catenin signaling. We that hRspo1 proteins with as or human AP, are as by the induction of β-catenin hRspo1 we a affinity to hRspo1 protein with mouse to to S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google we hRspo1 sequentially through affinity and affinity which in hRspo1 with the and and shown in hRspo1 to cytosolic β-catenin, and with to accumulation of β-catenin in hRspo1 with LRP6 to in that Xenopus and mouse have the to activate transcription O. A. I. P. C. Wu W. Dev. Cell. 2004; 7: Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). further hRspo1-induced signaling, in a hRspo1 via the hRspo1 and LRP6 hRspo1 with with Frizzled5 and to a with and to of hRspo1 with or further and The of proteins as by that LRP6 and a Frizzled proteins in hRspo1 signaling. Cell of to shown in protein secreted and of β-catenin signaling the as the type with for and with for other cell including and a the secreted protein of the and The be to binding of to the extracellular to that of which to the extracellular of a of P. M. Wang Y. J.P. D. Nathans J. Nusse R. Nature. PubMed Scopus Google or be to the binding of to in We used to binding to receptors have been used for binding M. Q. P. 2000; PubMed Scopus Google Scholar). We the binding to the and degradation of shown in binding to with LRP6 to the and binding with the of protein which the In and show binding the and that or can with hRspo1 in signaling that LRP6 is a binding receptor for the binding affinity of hRspo1 to we a binding in which of with with A. Smallwood P.M. Nathans J. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: PubMed Scopus Google or extracellular with K. Semenov M. Kato Y. Spokony R. Liu C. Katsuyama Y. Hess F. Saint-Jeannet J.P. He X. Nature. 2000; 407: 530-535Crossref PubMed Scopus (1095) Google Scholar). shown in to and the binding In to to or with low with the of to Frizzled the binding a binding affinity 1.2 LRP6 is a high affinity receptor for further the interaction between hRspo1 and we secreted of the extracellular of and 3 which are with the human proteins, to secreted as by and or shown in hRspo1 with or with hRspo1 binding to to be to either or as or in of hRspo1 as that hRspo1 with hRspo1 LRP6 have shown that phosphorylation of LRP6 is for signaling by the Wnt family of which is in the LRP6 is sequentially phosphorylated by and casein kinase upon Wnt induction (18Tamai K. Zeng X. Liu C. Zhang X. Harada Y. Chang Z. He X. Mol. Cell. 2004; 13: 149-156Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar, 19Zeng X. Tamai K. Doble B. Li S. Huang H. Habas R. Okamura H. Woodgett J. He X. Nature. 2005; 438: 873-877Crossref PubMed Scopus (661) Google Scholar). of the of LRP6 with the scaffolding protein Axin, thereby the extracellular Wnt (18Tamai K. Zeng X. Liu C. Zhang X. Harada Y. Chang Z. He X. Mol. Cell. 2004; 13: 149-156Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar, 19Zeng X. Tamai K. Doble B. Li S. Huang H. Habas R. Okamura H. Woodgett J. He X. Nature. 2005; 438: 873-877Crossref PubMed Scopus (661) Google Scholar, 20Mao J. Wang J. Liu B. Pan W. Farr III, G.H. Flynn C. Yuan H. Takada S. Kimelman D. Li L. Wu D. Mol. Cell. 2001; 7: 801-809Abstract Full Text Full Text PDF PubMed Scopus (694) Google Scholar). mechanism is in signaling, we with shown in phosphorylation of the LRP6 of to as by a phosphorylated (18Tamai K. Zeng X. Liu C. Zhang X. Harada Y. Chang Z. He X. Mol. Cell. 2004; 13: 149-156Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar). The of phosphorylation to be between and hRspo1 stimulation, a that to LRP6 phosphorylation in hRspo1 LRP6 phosphorylation in a to of hRspo1 further the of LRP6 phosphorylation We have that hRspo1 synergizes with to the accumulation of β-catenin is with LRP6 phosphorylation with with or shown in phosphorylation of the LRP6 in a In the of a induction of LRP6 phosphorylation further we the of to a that LRP6 phosphorylation on its the of with hRspo1 in a of LRP6 phosphorylation with of either or hRspo1 that hRspo1 is of LRP6 phosphorylation and has the to with to LRP6 phosphorylation. Our study that Wnt-induced phosphorylation of the LRP6 is by X. Tamai K. Doble B. Li S. Huang H. Habas R. Okamura H. Woodgett J. He X. Nature. 2005; 438: 873-877Crossref PubMed Scopus (661) Google Scholar). we is for hRspo1-induced phosphorylation of LRP6. with of or hRspo1 a in the phosphorylation of the in However, by the of the LRP6 phosphorylation on the The LRP6 phosphorylation with the which be to of the by of Wnt family of proteins, hRspo1-induced LRP6 phosphorylation is by of LRP6 by is a high affinity ligand of LRP6 (Kd = and binding of to LRP6 Wnt/β-catenin signaling M.V. Tamai K. Brott B.K. Kuhl M. Sokol S. He X. Curr. Biol. 2001; 11: 951-961Abstract Full Text Full Text PDF PubMed Scopus (598) Google Scholar, 26Bafico A. Liu G. Yaniv A. Gazit A. Aaronson S.A. Nat. Cell Biol. 2001; 3: 683-686Crossref PubMed Scopus (671) Google Scholar, 27Mao B. Wu W. Li Y. Hoppe D. P. A. C. Nature. 2001; PubMed Scopus Google Scholar). has on hRspo1-induced LRP6 phosphorylation, with hRspo1 in the or absence of In the of of DKK1, phosphorylation of the LRP6 by hRspo1 inhibit by for LRP6 as binds to as as Y. Wang Y. Li X. Zhang J. J. Li Z. J. Li L. Harris S. Wu D. Mol. Cell. Biol. 2004; PubMed Scopus Google by LRP6 B. Wu W. G. J. Li M. H. Hoppe D. P. C. A. C. Nature. 2002; PubMed Scopus Google Scholar). hRspo1 with Frizzled5 and LRP6 to in Xenopus of β-catenin signaling in Xenopus induces the of the embryonic axis K. Semenov M. Kato Y. Spokony R. Liu C. Katsuyama Y. Hess F. Saint-Jeannet J.P. He X. Nature. 2000; 407: 530-535Crossref PubMed Scopus (1095) Google Scholar, N. F. P. J. Cell Biol. PubMed Scopus Google Scholar). We hRspo1 and its with LRP6 or Frizzled in the activation of the β-catenin pathway in in We that Xenopus or mouse O. A. I. P. C. Wu W. Dev. Cell. 2004; 7: Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google to axis its and However, of for hRspo1 and LRP6 of a axis in of and a axis in of and that LRP6 by axis or a high and and of hRspo1 and the of a direct downstream target of signaling in Xenopus R. S.C. Grosschedl R. Dev. Biol. PubMed Scopus (213) Google Scholar). hRspo1 and LRP6 to activate β-catenin signaling in Xenopus with in and with that LRP6 is a receptor for of the Frizzled receptors we and to the of the axis by and and However, of hRspo1 and of the other of a axis in of and a axis in of and with the axis hRspo1 and Frizzled5 of hRspo1 and or that hRspo1 and Frizzled5 to activate the β-catenin signaling pathway in Xenopus hRspo1 that hRspo1 can Frizzled we hRspo1 is of phosphorylation, which is a for Frizzled activation A. S. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, U. S.E. EMBO J. 2000; 19: PubMed Google Scholar, Brennan Brown Mol. Cell. Biol. 2004; PubMed Scopus Google Scholar). shown in of with an of the of with the of the and of the the the phosphorylated of A. S. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google and hRspo1 phosphorylation in a R-spondin proteins are secreted signaling molecules that are in and T. K. M. M. Takada S. H. 2004; PubMed Scopus Google Scholar, O. A. I. P. C. Wu W. Dev. Cell. 2004; 7: Full Text Full Text PDF PubMed Scopus Google Scholar, Wang S. R. E. Y. K. Y. Mol. Biol. 2002; PubMed Scopus Google Scholar). Xenopus is in embryonic O. A. I. P. C. Wu W. Dev. Cell. 2004; 7: Full Text Full Text PDF PubMed Scopus Google in hRspo1 is a and for and in the of by M. J. T. T. M. Liu Y. B. E. P. K. Science. 2005; PubMed Scopus (443) Google Scholar). in and in R-spondin proteins have been shown to have the to cytosolic β-catenin and to activate β-catenin signaling O. A. I. P. C. Wu W. Dev. Cell. 2004; 7: Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. T. T. M. Liu Y. B. E. P. K. Science. 2005; PubMed Scopus (443) Google Scholar, J. S. M. T. A. K. Cell 5: PubMed Google Scholar). However, the mechanism by which R-spondin proteins activate the β-catenin signaling pathway is understood. In we demonstrate that hRspo1 is a high affinity ligand for the Wnt co-receptor LRP6 and induces LRP6 We show that hRspo1 has a interaction with in and induces the phosphorylation of Dishevelled, a Frizzled downstream signaling Our study reveals and interesting between R-spondin and Wnt signaling. hRspo1 proteins an a that is composed of a and a in Our demonstrate Xenopus and S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google the the the is for the activation of β-catenin signaling Xenopus and T. K. M. M. Takada S. H. 2004; PubMed Scopus Google Scholar, O. A. I. P. C. Wu W. Dev. Cell. 2004; 7: Full Text Full Text PDF PubMed Scopus Google which are secreted in we and M. J. T. T. M. Liu Y. B. E. P. K. Science. 2005; PubMed Scopus (443) Google have that hRspo1 is secreted upon in we that hRspo1 is in Wnt proteins, which are lipid-modified and are in the (2Willert K. Brown J.D. Danenberg E. Duncan A.W. Weissman I.L. Reya T. Yates III, J.R. Nusse R. Nature. 2003; 423: 448-452Crossref PubMed Scopus (1815) Google we that hRspo1 is and in the and in in the absence of and on we have a affinity and a hRspo1 LRP6 a for to the mechanism by which R-spondin activates β-catenin signaling have In to binding between Xenopus with LRP6 or Frizzled proteins O. A. I. P. C. Wu W. Dev. Cell. 2004; 7: Full Text Full Text PDF PubMed Scopus Google Scholar). of with the extracellular of either LRP6 or S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Our that LRP6 is a binding and receptor for hRspo1 binds to that are with we have the binding affinity between hRspo1 and LRP6 to be 1.2 hRspo1 induces LRP6 phosphorylation the a of LRP6 activation (18Tamai K. Zeng X. Liu C. Zhang X. Harada Y. Chang Z. He X. Mol. Cell. 2004; 13: 149-156Abstract Full Text Full Text PDF PubMed Scopus (447) Google and hRspo1-induced LRP6 phosphorylation is by the LRP6 with the between R-spondin proteins and LRP6 in and and O. A. I. P. C. Wu W. Dev. Cell. 2004; 7: Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google for a relationship between R-spondin proteins and LRP6. Our study further that hRspo1 can to LRP6 extracellular that are composed of the between R-spondin and Frizzled show that hRspo1 binds to LRP6 with high affinity binds to Frizzled receptors on the cell surface and in 3 and are in with a study that the extracellular of LRP6 R-spondin proteins that of S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In of LRP6 with Frizzled5 or in to hRspo1 binding LRP6 that Frizzled5 or binding to hRspo1 remains in the of LRP6. However, we between R-spondin and Frizzled proteins, Frizzled5 and in the activation of in O. A. I. P. C. Wu W. Dev. Cell. 2004; 7: Full Text Full Text PDF PubMed Scopus Google Scholar). In Xenopus hRspo1 and Frizzled5 other Frizzled including activate β-catenin signaling axis induction The the interaction and the between and Xenopus is the of a relationship is that hRspo1 induces phosphorylation, which is of Frizzled to binding and the a binding that is and the of or which be in and in and to R-spondin and Frizzled between R-spondin and Wnt in with M. J. T. T. M. Liu Y. B. E. P. K. Science. 2005; PubMed Scopus (443) Google Scholar, S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google to between R-spondin and Wnt signaling. R-spondin or Wnt is to the β-catenin and activate transcriptional LRP6 as a binding and signaling LRP6 via be by can to a Frizzled receptor or and can phosphorylation. a mechanism for R-spondin and Wnt signaling. In hRspo1 induction of phosphorylation the R-spondin can activate However, are between R-spondin and Wnt with to the receptor Wnt binds to Frizzled receptors with high affinity to A. Smallwood P.M. Nathans J. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: PubMed Scopus Google Scholar, Wu Nusse R. Mol. Cell. 2000; Full Text Full Text PDF PubMed Google Wnt binding to LRP6 is in X. Semenov M. Tamai K. Zeng X. Development (Camb.). 2004; 131: 1663-1677Crossref PubMed Scopus (864) Google and in to Nusse R. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). R-spondin binds to LRP6 with high affinity binds to Frizzled to a S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google or be to the We that hRspo1 to be as as that of in LRP6 phosphorylation and β-catenin further with R-spondin and Wnt proteins is to It is that hRspo1 and of show in LRP6 phosphorylation and β-catenin stabilization and In Xenopus and mouse of R-spondin genes with and in on the of Wnt genes T. K. M. M. Takada S. H. 2004; PubMed Scopus Google Scholar, O. A. I. P. C. Wu W. Dev. Cell. 2004; 7: Full Text Full Text PDF PubMed Scopus Google Scholar). R-spondin proteins that Wnt signaling We of the He for and

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