Reactome | RSPOs bind LGRs

RSPOs bind LGRs

Stable Identifier

R-HSA-4641206

Type

Reaction

Species

Homo sapiens

Compartment

plasma membrane, extracellular region

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There are four human RSpondin genes in humans whose products are secreted agonists of canonical and non-canonical WNT signaling (Kim et al, 2005; Glinka et al, 2007; reviewed in Kim et al, 2006). RSPO proteins enhance signaling in the presence of WNT ligand and have been shown to bind to the leucine-rich repeat containing G protein coupled receptors (LGR) 4, 5 and 6 (Kim et al, 2005; Binnerts et al, 2007; Carmon et al, 2011; de Lau et al, 2011). RSPO:LGR complexes are postulated to potentiate WNT-dependent signaling in a number of potentially overlapping mechanisms. RSPO proteins enhance WNT-mediated phosphorylation of LRP6 in HEK293 cells (Wei et al, 2007; Binnerts et al, 2007; Carmon et al, 2011). A recent report suggests that this effect may be mediated in part by downregulating the levels of ZNFR3 at the plasma membrane. ZNFR3 is an E3 ubiquitin ligase that has been shown to ubiquitinate FZD and to promote internalization of FZD and LRP6. In the presence of RSPO:LGR, ZNFR3 itself is targeted for internalization, allowing enhanced signaling through the WNT receptor complex (Yao et al, 2012).

Literature References

PubMed ID	Title	Journal	Year
16109882	Mitogenic influence of human R-spondin1 on the intestinal epithelium Tomizuka, K, Boyle, B, Liu, Y, Emtage, P, Zhao, J, Kakitani, M, Oshima, T, Kim, KA, Tang, T, Funk, WD, Park, E, Binnerts, M	Science	2005
21909076	LGR4 and LGR5 are R-spondin receptors mediating Wnt/?-catenin and Wnt/PCP signalling Boutros, M, Niehrs, C, Cruciat, CM, Ingelfinger, D, Huang, YL, Kirsch, N, Dolde, C, Kazanskaya, O, Glinka, A	EMBO Rep.	2011
16357527	R-Spondin proteins: a novel link to beta-catenin activation Andarmani, S, Tomizuka, K, Abo, A, Zhao, J, Kakitani, M, Oshima, T, Kim, KA, Funk, WD, Binnerts, ME	Cell Cycle	2006
21693646	R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling Gong, X, Lin, Q, Carmon, KS, Liu, Q, Thomas, A	Proc. Natl. Acad. Sci. U.S.A.	2011
17804805	R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6 Wagle, M, Zhou, M, Abo, A, Liu, Y, Bright, JM, Zhan, X, Kim, KA, Leung, JM, Funk, WD, Levy, MD, Tomasevic, N, Nie, WS, Binnerts, ME, Tran, K, Lomas, WE, Dixon, M, Patel, SM, Hazell, SA, Williams, J	Proc. Natl. Acad. Sci. U.S.A.	2007
22575959	ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner Mickanin, C, Zhang, Y, Bouwmeester, T, Zamponi, R, Xie, Y, Liu, D, Charlat, O, Kirschner, MW, Cong, F, Porter, JA, Avello, M, Lei, H, Serluca, FC, Finan, PM, Oster, E, Hao, HX, Ma, Q, Ruffner, H, Mao, X	Nature	2012
17400545	R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and beta-catenin signaling Wei, Q, Semënov, MV, Doble, B, Yokota, C, Woodgett, J, He, X	J. Biol. Chem.	2007
21727895	Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling van De Wetering, M, Clevers, HC, Peters, PJ, Schasfoort, RB, Guardavaccaro, D, Teunissen, H, van Es, JE, Stange, DE, Li, VS, Nishimori, K, Kujala, P, Barker, N, Koo, BK, Heck, AJ, Mohri, Y, Low, TY, Haegebarth, A, Mohammed, S, de Lau, W	Nature	2011