RSPOs bind LGRs

Stable Identifier
Homo sapiens
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

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, Sem├źnov, 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
Orthologous Events
Cite Us!