R-Spondin Potentiates Wnt/β-Catenin Signaling through Orphan Receptors LGR4 and LGR5

被引：145

作者：

Ruffner, Heinz ^{[1
]}

Sprunger, Joelle ^{[1
]}

Charlat, Olga ^{[2
]}

Leighton-Davies, Juliet ^{[1
]}

Grosshans, Bianka ^{[1
]}

Salathe, Adrian ^{[1
]}

Zietzling, Svenja ^{[1
]}

Beck, Valerie ^{[1
]}

Therier, Maxime ^{[1
]}

Isken, Andrea ^{[1
]}

Xie, Yang ^{[2
]}

Zhang, Yue ^{[2
]}

Hao, Huaixiang ^{[2
]}

Shi, Xiaoying ^{[2
]}

Liu, Dong ^{[2
]}

Song, Qinhui ^{[2
]}

Clay, Ieuan ^{[1
]}

Hintzen, Gabriele ^{[1
]}

Tchorz, Jan ^{[1
]}

Bouchez, Laure C. ^{[1
]}

Michaud, Gregory ^{[2
]}

Finan, Peter ^{[2
]}

Myer, Vic E. ^{[2
]}

Bouwmeester, Tewis ^{[1
]}

Porter, Jeff ^{[2
]}

Hild, Marc ^{[2
]}

Bassilana, Fred ^{[1
]}

Parker, Christian N. ^{[1
]}

Cong, Feng ^{[2
]}

机构：

[1] Novartis Pharma AG, Dev & Mol Pathways, Novartis Inst Biomed Res, Basel, Switzerland

[2] Novartis Inst Biomed Res, Cambridge, MA USA

来源：

PLOS ONE | 2012年 / 7卷 / 07期

关键词：

PANETH CELL-DIFFERENTIATION; STEM-CELLS; IN-VITRO; REDUCED EXPRESSION; DOWN-REGULATION; HAIR FOLLICLE; NULL MICE; R-SPONDIN1; PATHWAY; LRP6;

D O I：

10.1371/journal.pone.0040976

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The Wnt/beta-catenin signaling pathbway controls many important biological processes. R-Spondin (RSPO) proteins are a family of secreted molecules that strongly potentiate Wnt/beta-catenin signaling, however, the molecular mechanism of RSPO action is not yet fully understood. We performed an unbiased siRNA screen to identify molecules specifically required for RSPO, but not Wnt, induced beta-catenin signaling. From this screen, we identified LGR4, then an orphan G protein-coupled receptor (GPCR), as the cognate receptor of RSPO. Depletion of LGR4 completely abolished RSPO-induced beta-catenin signaling. The loss of LGR4 could be compensated by overexpression of LGR5, suggesting that LGR4 and LGR5 are functional homologs. We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5, and that overexpression of LGR4 strongly sensitizes cells to RSPO-activated beta-catenin signaling. Supporting the physiological significance of RSPO-LGR4 interaction, Lgr4(-/-) crypt cultures failed to grow in RSPO-containing intestinal crypt culture medium. No coupling between LGR4 and heterotrimeric G proteins could be detected in RSPO-treated cells, suggesting that LGR4 mediates RSPO signaling through a novel mechanism. Identification of LGR4 and its relative LGR5, an adult stem cell marker, as the receptors of RSPO will facilitate the further characterization of these receptor/ligand pairs in regenerative medicine applications.

引用

页数：13

共 42 条

[1] Identification of stem cells in small intestine and colon by marker gene Lgr5 [J].

Barker, Nick ;

van Es, Johan H. ;

Kuipers, Jeroen ;

Kujala, Pekka ;

van den Born, Maaike ;

Cozijnsen, Miranda ;

Haegebarth, Andrea ;

Korving, Jeroen ;

Begthel, Harry ;

Peters, Peter J. ;

Clevers, Hans .

NATURE, 2007, 449 (7165) :1003-U1

[2] Lgr5+ve Stem Cells Drive Self-Renewal in the Stomach and Build Long-Lived Gastric Units In Vitro [J].

Barker, Nick ;

Huch, Meritxell ;

Kujala, Pekka ;

van de Wetering, Marc ;

Snippert, Hugo J. ;

van Es, Johan H. ;

Sato, Toshiro ;

Stange, Daniel E. ;

Begthel, Harry ;

van den Born, Maaike ;

Danenberg, Esther ;

van den Brink, Stieneke ;

Korving, Jeroen ;

Abo, Arie ;

Peters, Peter J. ;

Wright, Nick ;

Poulsom, Richard ;

Clevers, Hans .

CELL STEM CELL, 2010, 6 (01) :25-36

[3] LITHIUM AMPLIFIES AGONIST-DEPENDENT PHOSPHATIDYLINOSITOL RESPONSES IN BRAIN AND SALIVARY-GLANDS [J].

BERRIDGE, MJ ;

DOWNES, CP ;

HANLEY, MR .

BIOCHEMICAL JOURNAL, 1982, 206 (03) :587-595

[4] R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6 [J].

Binnerts, Minke E. ;

Kim, Kyung-Ah ;

Bright, Jessica M. ;

Patel, Sejal M. ;

Tran, Karolyn ;

Zhou, Mei ;

Leung, John M. ;

Liu, Yi ;

Lomas, Woodrow E., III ;

Dixon, Melissa ;

Hazell, Sophie A. ;

Wagle, Marie ;

Nie, Wen-Sheng ;

Tomasevic, Nenad ;

Williams, Jason ;

Zhan, Xiaoming ;

Levy, Michael D. ;

Funk, Walter D. ;

Abo, Arie .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (37) :14700-14705

[5] PANETH CELL-DIFFERENTIATION IN THE DEVELOPING INTESTINE OF NORMAL AND TRANSGENIC MICE [J].

BRY, L ;

FALK, P ;

HUTTNER, K ;

OUELLETTE, A ;

MIDTVEDT, T ;

GORDON, JI .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (22) :10335-10339

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

Carmon, Kendra S. ;

Gong, Xing ;

Lin, Qiushi ;

Thomas, Anthony ;

Liu, Qingyun .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (28) :11452-11457

[7] Wnt/β-catenin signaling in development and disease [J].

Clevers, Hans .

CELL, 2006, 127 (03) :469-480

[8] Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling [J].

de Lau, Wim ;

Barker, Nick ;

Low, Teck Y. ;

Koo, Bon-Kyoung ;

Li, Vivian S. W. ;

Teunissen, Hans ;

Kujala, Pekka ;

Haegebarth, Andrea ;

Peters, Peter J. ;

van de Wetering, Marc ;

Stange, Daniel E. ;

van Es, Johan E. ;

Guardavaccaro, Daniele ;

Schasfoort, Richard B. M. ;

Mohri, Yasuaki ;

Nishimori, Katsuhiko ;

Mohammed, Shabaz ;

Heck, Albert J. R. ;

Clevers, Hans .

NATURE, 2011, 476 (7360) :293-U57

[9] Targeted disruption of the Wnt regulator Kremen induces limb defects and high bone density [J].

Ellwanger, Kristina ;

Saito, Hiroaki ;

Clement-Lacroix, Philippe ;

Maltry, Nicole ;

Niedermeyer, Joachim ;

Lee, Woon Kyu ;

Baron, Roland ;

Rawadi, Georges ;

Westphal, Heiner ;

Niehrs, Christof .

MOLECULAR AND CELLULAR BIOLOGY, 2008, 28 (15) :4875-4882

[10]

Gao Y, 2006, HOKKAIDO IGAKU ZASSH, V81, P109

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