LGR6 is a high affinity receptor of R-Spondins and potentially functions as a tumor suppressor

PLoS ONE

Volumn 7, Issue 5, 2012, Pages

  Gong, Xing ^a   Carmon, Kendra S ^a   Lin, Qiushi ^a   Thomas, Anthony ^a   Yi, Jing ^a   Liu, Qingyun ^a  

^a UNIVERSITY OF TEXAS MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BETA CATENIN; HETEROTRIMERIC GUANINE NUCLEOTIDE BINDING PROTEIN; LEUCINE RICH REPEAT CONTAINING G PROTEIN COUPLED RECEPTOR 4; LEUCINE RICH REPEAT CONTAINING G PROTEIN COUPLED RECEPTOR 5; LEUCINE RICH REPEAT CONTAINING G PROTEIN COUPLED RECEPTOR 6; R SPONDIN 1; R SPONDIN 2; R SPONDIN 3; SECRETORY PROTEIN; TUMOR SUPPRESSOR PROTEIN; UNCLASSIFIED DRUG; WNT PROTEIN; WNT3A PROTEIN;

ARTICLE; BINDING AFFINITY; CELL MIGRATION; COLON CANCER; COLON CARCINOGENESIS; CONTROLLED STUDY; GENE OVEREXPRESSION; HELA CELL; HUMAN; HUMAN CELL; LOSS OF FUNCTION MUTATION; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; SIGNAL TRANSDUCTION; SOMATIC MUTATION; WILD TYPE;

BETA CATENIN; CELL MOVEMENT; COLONIC NEOPLASMS; GTP-BINDING PROTEINS; HELA CELLS; HUMANS; INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS; MUTATION; PROTEIN BINDING; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION; THROMBOSPONDINS; TUMOR SUPPRESSOR PROTEINS; WNT PROTEINS;

EID: 84861218349     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0037137     Document Type: Article

References (60)

1. Hsu SY, Kudo M, Chen T, Nakabayashi K, Bhalla A, et al. (2000) The three subfamilies of leucine-rich repeat-containing G protein-coupled receptors (LGR): identification of LGR6 and LGR7 and the signaling mechanism for LGR7. Mol Endocrinol 14: 1257-1271.
2. Barker N, Clevers H, (2010) Leucine-rich repeat-containing G-protein-coupled receptors as markers of adult stem cells. Gastroenterology 138: 1681-1696.
3. Snippert HJ, Haegebarth A, Kasper M, Jaks V, van Es JH, et al. (2010) Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin. Science 327: 1385-1389.
4. Jaks V, Barker N, Kasper M, van Es JH, Snippert HJ, et al. (2008) Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nat Genet 40: 1291-1299.
5. Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, et al. (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449: 1003-1007.
6. Van Schoore G, Mendive F, Pochet R, Vassart G, (2005) Expression pattern of the orphan receptor LGR4/GPR48 gene in the mouse. Histochem Cell Biol 124: 35-50.
7. Mustata RC, Van Loy T, Lefort A, Libert F, Strollo S, et al. (2011) Lgr4 is required for Paneth cell differentiation and maintenance of intestinal stem cells ex vivo. EMBO Rep 12: 558-564.
8. de Lau W, Barker N, Low TY, Koo BK, Li VS, et al. (2011) Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 476: 293-297.
9. Carmon KS, Gong X, Lin Q, Thomas A, Liu Q, (2011) R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling. Proc Natl Acad Sci U S A 108: 11452-11457.
10. Glinka A, Dolde C, Kirsch N, Huang YL, Kazanskaya O, et al. (2011) LGR4 and LGR5 are R-spondin receptors mediating Wnt/beta-catenin and Wnt/PCP signalling. EMBO Rep 12: 1055-1061.
11. Kim KA, Zhao J, Andarmani S, Kakitani M, Oshima T, et al. (2006) R-Spondin proteins: a novel link to beta-catenin activation. Cell Cycle 5: 23-26.
12. Kazanskaya O, Glinka A, del Barco Barrantes I, Stannek P, Niehrs C, et al. (2004) R-Spondin2 is a secreted activator of Wnt/beta-catenin signaling and is required for Xenopus myogenesis. Dev Cell 7: 525-534.
13. Nam JS, Turcotte TJ, Smith PF, Choi S, Yoon JK, (2006) Mouse cristin/R-spondin family proteins are novel ligands for the Frizzled 8 and LRP6 receptors and activate beta-catenin-dependent gene expression. J Biol Chem 281: 13247-13257.
14. MacDonald BT, Tamai K, He X, (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17: 9-26.
15. Niehrs C, Shen J, (2010) Regulation of Lrp6 phosphorylation. Cell Mol Life Sci 67: 2551-2562.
16. Kim KA, Kakitani M, Zhao J, Oshima T, Tang T, et al. (2005) Mitogenic influence of human R-spondin1 on the intestinal epithelium. Science 309: 1256-1259.
17. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, et al. (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314: 268-274.
18. Schuebel KE, Chen W, Cope L, Glockner SC, Suzuki H, et al. (2007) Comparing the DNA hypermethylome with gene mutations in human colorectal cancer. PLoS Genet 3: 1709-1723.
19. Chan TA, Glockner S, Yi JM, Chen W, Van Neste L, et al. (2008) Convergence of mutation and epigenetic alterations identifies common genes in cancer that predict for poor prognosis. PLoS Med 5: e114.
20. Mokarram P, Kumar K, Brim H, Naghibalhossaini F, Saberi-firoozi M, et al. (2009) Distinct high-profile methylated genes in colorectal cancer. PLoS One 4: e7012.
21. Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, et al. (2011) COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res 39: D945-950.
22. Vogelstein B, Kinzler KW, (2004) Cancer genes and the pathways they control. Nat Med 10: 789-799.
23. Ootani A, Li X, Sangiorgi E, Ho QT, Ueno H, et al. (2009) Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat Med 15: 701-706.
24. Binnerts ME, Kim KA, Bright JM, Patel SM, Tran K, et al. (2007) R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6. Proc Natl Acad Sci U S A 104: 14700-14705.
25. Kim KA, Wagle M, Tran K, Zhan X, Dixon MA, et al. (2008) R-Spondin family members regulate the Wnt pathway by a common mechanism. Mol Biol Cell 19: 2588-2596.
26. Wei Q, Yokota C, Semenov MV, Doble B, Woodgett J, et al. (2007) R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and beta-catenin signaling. J Biol Chem 282: 15903-15911.
27. Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, et al. (1997) Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science 275: 1784-1787.
28. Veeman MT, Slusarski DC, Kaykas A, Louie SH, Moon RT, (2003) Zebrafish prickle, a modulator of noncanonical Wnt/Fz signaling, regulates gastrulation movements. Curr Biol 13: 680-685.
29. Mao B, Wu W, Li Y, Hoppe D, Stannek P, et al. (2001) LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature 411: 321-325.
30. Bafico A, Liu G, Yaniv A, Gazit A, Aaronson SA, (2001) Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat Cell Biol 3: 683-686.
31. Semenov MV, Tamai K, Brott BK, Kuhl M, Sokol S, et al. (2001) Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Curr Biol 11: 951-961.
32. Chen S, Bubeck D, MacDonald BT, Liang WX, Mao JH, et al. (2011) Structural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling. Dev Cell 21: 848-861.
33. Cheng Z, Biechele T, Wei Z, Morrone S, Moon RT, et al. (2011) Crystal structures of the extracellular domain of LRP6 and its complex with DKK1. Nat Struct Mol Biol 18: 1204-1210.
34. Bourhis E, Wang W, Tam C, Hwang J, Zhang Y, et al. (2011) Wnt antagonists bind through a short peptide to the first beta-propeller domain of LRP5/6. Structure 19: 1433-1442.
35. Gurevich VV, Gurevich EV, (2008) Rich tapestry of G protein-coupled receptor signaling and regulatory mechanisms. Mol Pharmacol 74: 312-316.
36. Shenoy SK, Lefkowitz RJ, (2011) beta-Arrestin-mediated receptor trafficking and signal transduction. Trends Pharmacol Sci 32: 521-533.
37. Riobo NA, Manning DR, (2005) Receptors coupled to heterotrimeric G proteins of the G12 family. Trends Pharmacol Sci 26: 146-154.
38. Stratton MR, (2011) Exploring the genomes of cancer cells: progress and promise. Science 331: 1553-1558.
39. Yachida S, Jones S, Bozic I, Antal T, Leary R, et al. (2010) Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467: 1114-1117.
40. Mazerbourg S, Bouley DM, Sudo S, Klein CA, Zhang JV, et al. (2004) Leucine-rich repeat-containing, G protein-coupled receptor 4 null mice exhibit intrauterine growth retardation associated with embryonic and perinatal lethality. Mol Endocrinol 18: 2241-2254.
41. Morita H, Mazerbourg S, Bouley DM, Luo CW, Kawamura K, et al. (2004) Neonatal lethality of LGR5 null mice is associated with ankyloglossia and gastrointestinal distension. Mol Cell Biol 24: 9736-9743.
42. Yoon JK, Lee JS, (2012) Cellular signaling and biological functions of R-spondins. Cell Signal 24: 369-377.
43. Rosenbaum DM, Zhang C, Lyons JA, Holl R, Aragao D, et al. (2011) Structure and function of an irreversible agonist-beta(2) adrenoceptor complex. Nature 469: 236-240.
44. Rasmussen SG, DeVree BT, Zou Y, Kruse AC, Chung KY, et al. (2011) Crystal structure of the beta2 adrenergic receptor-Gs protein complex. Nature 477: 549-555.
45. Kobilka B, Schertler GF, (2008) New G-protein-coupled receptor crystal structures: insights and limitations. Trends Pharmacol Sci 29: 79-83.
46. Ben-Shlomo I, Rauch R, Avsian-Kretchmer O, Hsueh AJ, (2007) Matching receptome genes with their ligands for surveying paracrine/autocrine signaling systems. Mol Endocrinol 21: 2009-2014.
47. Luo CW, Dewey EM, Sudo S, Ewer J, Hsu SY, et al. (2005) Bursicon, the insect cuticle-hardening hormone, is a heterodimeric cystine knot protein that activates G protein-coupled receptor LGR2. Proc Natl Acad Sci U S A 102: 2820-2825.
48. Mendive FM, Van Loy T, Claeysen S, Poels J, Williamson M, et al. (2005) Drosophila molting neurohormone bursicon is a heterodimer and the natural agonist of the orphan receptor DLGR2. FEBS Lett 579: 2171-2176.
49. Luo CW, Hsueh AJ, (2006) Genomic analyses of the evolution of LGR genes. Chang Gung Med J 29: 2-8.
50. Glinka A, Wu W, Delius H, Monaghan AP, Blumenstock C, et al. (1998) Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature 391: 357-362.
51. Major MB, Camp ND, Berndt JD, Yi X, Goldenberg SJ, et al. (2007) Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin signaling. Science 316: 1043-1046.
52. Gao Y, Kitagawa K, Hiramatsu Y, Kikuchi H, Isobe T, et al. (2006) Up-regulation of GPR48 induced by down-regulation of p27Kip1 enhances carcinoma cell invasiveness and metastasis. Cancer Res 66: 11623-11631.
53. Tanese K, Fukuma M, Yamada T, Mori T, Yoshikawa T, et al. (2008) G-protein-coupled receptor GPR49 is up-regulated in basal cell carcinoma and promotes cell proliferation and tumor formation. Am J Pathol 173: 835-843.
54. McClanahan T, Koseoglu S, Smith K, Grein J, Gustafson E, et al. (2006) Identification of overexpression of orphan G protein-coupled receptor GPR49 in human colon and ovarian primary tumors. Cancer Biol Ther 5: 419-426.
55. Merlos-Suarez A, Barriga FM, Jung P, Iglesias M, Cespedes MV, et al. (2011) The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell 8: 511-524.
56. Walker F, Zhang HH, Odorizzi A, Burgess AW, (2011) LGR5 is a negative regulator of tumourigenicity, antagonizes Wnt signalling and regulates cell adhesion in colorectal cancer cell lines. PLoS One 6: e22733.
57. de Sousa EMF, Colak S, Buikhuisen J, Koster J, Cameron K, et al. (2011) Methylation of cancer-stem-cell-associated Wnt target genes predicts poor prognosis in colorectal cancer patients. Cell Stem Cell 9: 476-485.
58. De Lorenzi L, Groppetti D, Arrighi S, Pujar S, Nicoloso L, et al. (2008) Mutations in the RSPO1 coding region are not the main cause of canine SRY-negative XX sex reversal in several breeds. Sex Dev 2: 84-95.
59. Bordonaro M, Lazarova DL, Sartorelli AC, (2008) Hyperinduction of Wnt activity: a new paradigm for the treatment of colorectal cancer? Oncol Res 17: 1-9.
60. Segditsas S, Tomlinson I, (2006) Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene 25: 7531-7537.