Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

PNAS 108 (28): 11452-11457

Copyright © 2011 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/β-catenin signaling

Kendra S. Carmon1, Xing Gong1, Qiushi Lin, Anthony Thomas, and Qingyun Liu2

Brown Foundation Institute of Molecular Medicine, and the Texas Therapeutics Institute, University of Texas Health Science Center, Houston, TX 77030

Edited* by C. Thomas Caskey, University of Texas-Houston Health Science Center, Houston, TX, and approved May 25, 2011 (received for review April 15, 2011)

Abstract: The Wnt/β-catenin signaling system plays essential roles in embryonic development and in the self-renewal and maintenance of adult stem cells. R-spondins (RSPOs) are a group of secreted proteins that enhance Wnt/β-catenin signaling and have pleiotropic functions in development and stem cell growth. LGR5, an orphan receptor of the G protein-coupled receptor (GPCR) superfamily, is specifically expressed in stem cells of the intestinal crypt and hair follicle. Knockout of LGR5 in the mouse results in neonatal lethality. LGR4, a receptor closely related to LGR5, also has essential roles in development, as its knockout leads to reduced viability and retarded growth. Overexpression of both receptors has been reported in several types of cancer. Here we demonstrate that LGR4 and LGR5 bind the R-spondins with high affinity and mediate the potentiation of Wnt/β-catenin signaling by enhancing Wnt-induced LRP6 phosphorylation. Interestingly, neither receptor is coupled to heterotrimeric G proteins or to β-arrestin when stimulated by the R-spondins, indicating a unique mechanism of action. The findings provide a basis for stem cell-specific effects of Wnt/β-catenin signaling and for the broad range of functions LGR4, LGR5, and the R-spondins have in normal and malignant growth.

Key Words: cell signaling • stem cell control • gastrointestinal growth • colon cancer

Author contributions: K.S.C., X.G., Q. Lin, and Q. Liu designed research; K.S.C., X.G., Q. Lin, A.T., and Q. Liu performed research; K.S.C., X.G., Q. Lin, and Q. Liu analyzed data; and Q. Liu wrote the paper.

1K.S.C. and X.G. contributed equally to this work.

The authors declare no conflict of interest.

*This Direct Submission article had a prearranged editor.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1106083108/-/DCSupplemental.

2To whom correspondence should be addressed. E-mail: qingyun.liu{at}uth.tmc.edu.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Screening {beta}-Arrestin Recruitment for the Identification of Natural Ligands for Orphan G-Protein-Coupled Receptors.
C. Southern, J. M. Cook, Z. Neetoo-Isseljee, D. L. Taylor, C. A. Kettleborough, A. Merritt, D. L. Bassoni, W. J. Raab, E. Quinn, T. S. Wehrman, et al. (2013)
J Biomol Screen 18, 599-609
   Abstract »    Full Text »    PDF »
Lgr4/Gpr48 Negatively Regulates TLR2/4-associated Pattern Recognition and Innate Immunity by Targeting CD14 Expression.
B. Du, W. Luo, R. Li, B. Tan, H. Han, X. Lu, D. Li, M. Qian, D. Zhang, Y. Zhao, et al. (2013)
J. Biol. Chem. 288, 15131-15141
   Abstract »    Full Text »    PDF »
International Union of Basic and Clinical Pharmacology. LXXXVIII. G Protein-Coupled Receptor List: Recommendations for New Pairings with Cognate Ligands.
A. P. Davenport, S. P. H. Alexander, J. L. Sharman, A. J. Pawson, H. E. Benson, A. E. Monaghan, W. C. Liew, C. P. Mpamhanga, T. I. Bonner, R. R. Neubig, et al. (2013)
Pharmacol. Rev. 65, 967-986
   Abstract »    Full Text »    PDF »
LGR5 promotes survival in human colorectal adenoma cells and is upregulated by PGE2: implications for targeting adenoma stem cells with NSAIDs.
M. R. A. Al-Kharusi, H. J. M. Smartt, A. Greenhough, T. J. Collard, E. D. Emery, A. C. Williams, and C. Paraskeva (2013)
Carcinogenesis 34, 1150-1157
   Abstract »    Full Text »    PDF »
Lgr4-mediated Wnt/{beta}-catenin signaling in peritubular myoid cells is essential for spermatogenesis.
Y. Qian, S. Liu, Y. Guan, H. Pan, X. Guan, Z. Qiu, L. Li, N. Gao, Y. Zhao, X. Li, et al. (2013)
Development 140, 1751-1761
   Abstract »    Full Text »    PDF »
Constitutive Internalization of the Leucine-rich G Protein-coupled Receptor-5 (LGR5) to the Trans-Golgi Network.
J. C. Snyder, L. K. Rochelle, H. K. Lyerly, M. G. Caron, and L. S. Barak (2013)
J. Biol. Chem. 288, 10286-10297
   Abstract »    Full Text »    PDF »
Lgr4 Gene Deficiency Increases Susceptibility and Severity of Dextran Sodium Sulfate-induced Inflammatory Bowel Disease in Mice.
S. Liu, Y. Qian, L. Li, G. Wei, Y. Guan, H. Pan, X. Guan, L. Zhang, X. Lu, Y. Zhao, et al. (2013)
J. Biol. Chem. 288, 8794-8803
   Abstract »    Full Text »    PDF »
Secreted and Transmembrane Wnt Inhibitors and Activators.
C.-M. Cruciat and C. Niehrs (2013)
Cold Spring Harb Perspect Biol 5, a015081
   Abstract »    Full Text »    PDF »
Celebrating 30 Years of Wnt Signaling.
F. Verkaar, K. M. Cadigan, and R. van Amerongen (2012)
Science Signaling 5, mr2
   Abstract »    Full Text »    PDF »
WNT4 and RSPO1 together are required for cell proliferation in the early mouse gonad.
A.-A. Chassot, S. T. Bradford, A. Auguste, E. P. Gregoire, E. Pailhoux, D. G. de Rooij, A. Schedl, and M.-C. Chaboissier (2012)
Development 139, 4461-4472
   Abstract »    Full Text »    PDF »
In vitro organogenesis in three dimensions: self-organising stem cells.
Y. Sasai, M. Eiraku, and H. Suga (2012)
Development 139, 4111-4121
   Abstract »    Full Text »    PDF »
Wnt Signaling in Mammary Glands: Plastic Cell Fates and Combinatorial Signaling.
C. M. Alexander, S. Goel, S. A. Fakhraldeen, and S. Kim (2012)
Cold Spring Harb Perspect Biol 4, a008037
   Abstract »    Full Text »    PDF »
Two anatomically distinct niches regulate stem cell activity.
H. Ema and T. Suda (2012)
Blood 120, 2174-2181
   Abstract »    Full Text »    PDF »
Wnt Proteins.
K. Willert and R. Nusse (2012)
Cold Spring Harb Perspect Biol 4, a007864
   Abstract »    Full Text »    PDF »
LGR5 Interacts and Cointernalizes with Wnt Receptors To Modulate Wnt/{beta}-Catenin Signaling.
K. S. Carmon, Q. Lin, X. Gong, A. Thomas, and Q. Liu (2012)
Mol. Cell. Biol. 32, 2054-2064
   Abstract »    Full Text »    PDF »
Wnt Signaling, Stem Cells, and Cancer of the Gastrointestinal Tract.
A. Schepers and H. Clevers (2012)
Cold Spring Harb Perspect Biol 4, a007989
   Abstract »    Full Text »    PDF »
GPR48 Increases Mineralocorticoid Receptor Gene Expression.
J. Wang, X. Li, Y. Ke, Y. Lu, F. Wang, N. Fan, H. Sun, H. Zhang, R. Liu, J. Yang, et al. (2012)
J. Am. Soc. Nephrol. 23, 281-293
   Abstract »    Full Text »    PDF »
Dissection of Aberrant GPCR Signaling in Tumorigenesis - A Systems Biology Approach.
J. Wu, N. Xie, X. Zhao, E. C. Nice, and C. Huang (2012)
Cancer Genomics Proteomics 9, 37-50
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882