LRP5 and LRP6 in development and disease

Trends in Endocrinology and Metabolism

Volumn 24, Issue 1, 2013, Pages 31-39

  Joiner, Danese M ^a   Ke, Jiyuan ^a   Zhong, Zhendong ^a   Xu, H Eric ^a   Williams, Bart O ^a  

^a VAN ANDEL RESEARCH INSTITUTE   (United States)

Author keywords

Crystal structure; Development; Disease; LRP5 6; Wnt catenin

Indexed keywords

BETA CATENIN; DICKKOPF 1 PROTEIN; LOW DENSITY LIPOPROTEIN RECEPTOR RELATED PROTEIN 5; LOW DENSITY LIPOPROTEIN RECEPTOR RELATED PROTEIN 6; SCLEROSTIN; WNT PROTEIN;

ALZHEIMER DISEASE; AORTA VALVE DISEASE; ARTHROPATHY; BONE MASS; CORONARY ARTERY DISEASE; CRYSTAL STRUCTURE; DRUG RESEARCH; DRUG TARGETING; GENE DELETION; GENE EXPRESSION; GENE MUTATION; HUMAN; NONHUMAN; PARATHYROID TUMOR; PHENOTYPE; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; REVIEW; VASCULARIZATION;

ANIMALS; HUMANS; LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN-5; LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN-6; MODELS, BIOLOGICAL; WNT SIGNALING PATHWAY;

EID: 84871665280     PISSN: 10432760     EISSN: 18793061     Source Type: Journal    
DOI: 10.1016/j.tem.2012.10.003     Document Type: Review

References (100)

1. Dieckmann M., et al. Lipoprotein receptors - an evolutionarily ancient multifunctional receptor family. Biol. Chem. 2010, 391:1341-1363.
2. MacDonald B.T., et al. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev. Cell 2009, 17:9-26.
3. Williams B.O., Insogna K.L. Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone. J. Bone Miner. Res. 2009, 24:171-178.
4. Gong Y., et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 2001, 107:513-523.
5. Toomes C., et al. Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. Am. J. Hum. Genet. 2004, 74:721-730.
6. Hardy J., Selkoe D.J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002, 297:353-356.
7. De Ferrari G.V., et al. Common genetic variation within the low-density lipoprotein receptor-related protein 6 and late-onset Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A. 2007, 104:9434-9439.
8. Alberti K.G., et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009, 120:1640-1645.
9. Mani A., et al. LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 2007, 315:1278-1282.
10. Gessert S., Kuhl M. The multiple phases and faces of wnt signaling during cardiac differentiation and development. Circ. Res. 2010, 107:186-199.
11. Rajamannan N.M., et al. Calcific aortic valve disease: not simply a degenerative process: a review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: calcific aortic valve disease - 2011 update. Circulation 2011, 124:1783-1791.
12. Towler D.A., et al. Osteogenic regulation of vascular calcification. Ann. N.Y. Acad. Sci. 2006, 1068:327-333.
13. Rajamannan N.M. The role of Lrp5/6 in cardiac valve disease: LDL-density-pressure theory. J. Cell. Biochem. 2011, 112:2222-2229.
14. -/- mice. J. Cell. Biochem. 2011, 112:2987-2991.
15. Smith A.J., et al. Haplotypes of the low-density lipoprotein receptor-related protein 5 (LRP5) gene: are they a risk factor in osteoarthritis?. Osteoarthritis Cartilage 2005, 13:608-613.
16. Velasco J., et al. Wnt pathway genes in osteoporosis and osteoarthritis: differential expression and genetic association study. Osteoporos. Int. 2010, 21:109-118.
17. Papathanasiou I., et al. Low-density lipoprotein receptor-related protein 5 (LRP5) expression in human osteoarthritic chondrocytes. J. Orthop. Res. 2010, 28:348-353.
18. Bjorklund P., et al. An LRP5 receptor with internal deletion in hyperparathyroid tumors with implications for deregulated WNT/beta-catenin signaling. PLoS Med. 2007, 4:e328.
19. Bjorklund P., et al. The internally truncated LRP5 receptor presents a therapeutic target in breast cancer. PLoS ONE 2009, 4:e4243.
20. Lindvall C., et al. The Wnt signaling receptor Lrp5 is required for mammary ductal stem cell activity and Wnt1-induced tumorigenesis. J. Biol. Chem. 2006, 281:35081-35087.
21. Fujino T., et al. Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion. Proc. Natl. Acad. Sci. U.S.A. 2003, 100:229-234.
22. Magoori K., et al. Severe hypercholesterolemia, impaired fat tolerance, and advanced atherosclerosis in mice lacking both low density lipoprotein receptor-related protein 5 and apolipoprotein E. J. Biol. Chem. 2003, 278:11331-11336.
23. Pinson K.I., et al. An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 2000, 407:535-538.
24. Holmen S.L., et al. Decreased BMD and limb deformities in mice carrying mutations in both Lrp5 and Lrp6. J. Bone Miner. Res. 2004, 19:2033-2040.
25. Zhou C.J., et al. Neuronal production and precursor proliferation defects in the neocortex of mice with loss of function in the canonical Wnt signaling pathway. Neuroscience 2006, 142:1119-1131.
26. Zhou C.J., et al. Severe defects in dorsal thalamic development in low-density lipoprotein receptor-related protein-6 mutants. J. Neurosci. 2004, 24:7632-7639.
27. Zhou C.J., et al. Wnt signaling mutants have decreased dentate granule cell production and radial glial scaffolding abnormalities. J. Neurosci. 2004, 24:121-126.
28. Lindvall C., et al. The Wnt co-receptor Lrp6 is required for normal mouse mammary gland development. PLoS ONE 2009, 4:e5813.
29. Song L., et al. Cardiac neural crest and outflow tract defects in Lrp6 mutant mice. Dev. Dyn. 2010, 239:200-210.
30. Kelly O.G., et al. The Wnt co-receptors Lrp5 and Lrp6 are essential for gastrulation in mice. Development 2004, 131:2803-2815.
31. Kokubu C., et al. Skeletal defects in ringelschwanz mutant mice reveal that Lrp6 is required for proper somitogenesis and osteogenesis. Development 2004, 131:5469-5480.
32. Kubota T., et al. Lrp6 hypomorphic mutation affects bone mass through bone resorption in mice and impairs interaction with Mesd. J. Bone Miner. Res. 2008, 23:1661-1671.
33. Gray J.D., et al. Functional interactions between the LRP6 WNT co-receptor and folate supplementation. Hum. Mol. Genet. 2010, 19:4560-4572.
34. Carter M., et al. Crooked tail (Cd) model of human folate-responsive neural tube defects is mutated in Wnt coreceptor lipoprotein receptor-related protein 6. Proc. Natl. Acad. Sci. U.S.A. 2005, 102:12843-12848.
35. Yadav V.K., et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 2008, 135:825-837.
36. Cui Y., et al. Lrp5 functions in bone to regulate bone mass. Nat. Med. 2011, 17:684-691.
37. Zhong Z., et al. Lrp5 and Lrp6 play compensatory roles in mouse intestinal development. J. Cell. Biochem. 2011, 113:31-38.
38. Joeng K.S., et al. Lrp5 and Lrp6 redundantly control skeletal development in the mouse embryo. Dev. Biol. 2011, 359:222-229.
39. Zhou C.J., et al. Generation of Lrp6 conditional gene-targeting mouse line for modeling and dissecting multiple birth defects/congenital anomalies. Dev. Dyn. 2010, 239:318-326.
40. Glantschnig H., et al. A rate-limiting role for Dickkopf-1 in bone formation and the remediation of bone loss in mouse and primate models of postmenopausal osteoporosis by an experimental therapeutic antibody. J. Pharmacol. Exp. Ther. 2011, 338:568-578.
41. Tian E., et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N. Engl. J. Med. 2003, 349:2483-2494.
42. Yaccoby S., et al. Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood 2007, 109:2106-2111.
43. Heath D.J., et al. Inhibiting Dickkopf-1 (Dkk1) removes suppression of bone formation and prevents the development of osteolytic bone disease in multiple myeloma. J. Bone Miner. Res. 2009, 24:425-436.
44. Diarra D., et al. Dickkopf-1 is a master regulator of joint remodeling. Nat. Med. 2007, 13:156-163.
45. Weng L.H., et al. Control of Dkk-1 ameliorates chondrocyte apoptosis, cartilage destruction, and subchondral bone deterioration in osteoarthritic knees. Arthritis Rheum. 2010, 62:1393-1402.
46. Paszty C., et al. Sclerostin: a gem from the genome leads to bone-building antibodies. J. Bone Miner. Res. 2010, 25:1897-1904.
47. Ominsky M.S., et al. Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J. Bone Miner. Res. 2010, 25:948-959.
48. Li X., et al. Increased bone formation and bone mass induced by sclerostin antibody is not affected by pretreatment or cotreatment with alendronate in osteopenic, ovariectomized rats. Endocrinology 2011, 152:3312-3322.
49. Li X., et al. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J. Bone Miner. Res. 2009, 24:578-588.
50. Tian X., et al. Sclerostin antibody increases bone mass by stimulating bone formation and inhibiting bone resorption in a hindlimb-immobilization rat model. Bone 2011, 48:197-201.
51. Li X., et al. Inhibition of sclerostin by monoclonal antibody increases bone formation, bone mass, and bone strength in aged male rats. J. Bone Miner. Res. 2010, 25:2647-2656.
52. Eddleston A., et al. A short treatment with an antibody to sclerostin can inhibit bone loss in an ongoing model of colitis. J. Bone Miner. Res. 2009, 24:1662-1671.
53. Padhi D., et al. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J. Bone Miner. Res. 2011, 26:19-26.
54. Ominsky M.S., et al. Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones. J. Bone Miner. Res. 2011, 26:1012-1021.
55. Agholme F., et al. Sclerostin antibody treatment enhances metaphyseal bone healing in rats. J. Bone Miner. Res. 2010, 25:2412-2418.
56. Ettenberg S.A., et al. Inhibition of tumorigenesis driven by different Wnt proteins requires blockade of distinct ligand-binding regions by LRP6 antibodies. Proc. Natl. Acad. Sci. U.S.A. 2010, 107:15473-15478.
57. Gong Y., et al. Wnt isoform-specific interactions with coreceptor specify inhibition or potentiation of signaling by LRP6 antibodies. PLoS ONE 2010, 5:e12682.
58. Cheng Z., et al. Crystal structures of the extracellular domain of LRP6 and its complex with DKK1. Nat. Struct. Mol. Biol. 2011, 18:1204-1210.
59. Chen S., et al. Structural and functional studies of LRP6 ectodomain reveal a platform for Wnt signaling. Dev. Cell 2011, 21:848-861.
60. Ahn V.E., et al. Structural basis of Wnt signaling inhibition by Dickkopf binding to LRP5/6. Dev. Cell 2011, 21:862-873.
61. Bourhis E., et al. Wnt antagonists bind through a short peptide to the first beta-propeller domain of LRP5/6. Structure 2011, 19:1433-1442.
62. Liu C.C., et al. Cooperative folding and ligand-binding properties of LRP6 beta-propeller domains. J. Biol. Chem. 2009, 284:15299-15307.
63. Janda C.Y., et al. Structural basis of Wnt recognition by Frizzled. Science 2012, 337:59-64.
64. Kim D.H., et al. A new low density lipoprotein receptor related protein, LRP5, is expressed in hepatocytes and adrenal cortex, and recognizes apolipoprotein E. J. Biochem. 1998, 124:1072-1076.
65. Li V.S., et al. Wnt signaling through inhibition of beta-catenin degradation in an intact Axin1 complex. Cell 2012, 149:1245-1256.
66. Hao H.X., et al. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature 2012, 485:195-200.
67. Xu Q., et al. Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell 2004, 116:883-895.
68. Naito A.T., et al. Complement c1q activates canonical wnt signaling and promotes aging-related phenotypes. Cell 2012, 149:1298-1313.
69. de Lau W.B., et al. The R-spondin protein family. Genome Biol. 2012, 13:242.
70. Mao B., et al. Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature 2002, 417:664-667.
71. Ellwanger K., et al. Targeted disruption of the Wnt regulator Kremen induces limb defects and high bone density. Mol. Cell Biol. 2008, 28:4875-4882.
72. Schulze J., et al. Negative regulation of bone formation by the transmembrane Wnt antagonist Kremen-2. PLoS ONE 2010, 5:e10309.
73. Wang K., et al. Characterization of the Kremen-binding site on Dkk1 and elucidation of the role of Kremen in Dkk-mediated Wnt antagonism. J. Biol. Chem. 2008, 283:23371-23375.
74. Hassler C., et al. Kremen is required for neural crest induction in Xenopus and promotes LRP6-mediated Wnt signaling. Development 2007, 134:4255-4263.
75. Fass D., et al. Molecular basis of familial hypercholesterolaemia from structure of LDL receptor module. Nature 1997, 388:691-693.
76. Liu W., et al. Mutation in EGFP domain of LDL receptor-related protein 6 impairs cellular LDL clearance. Circ. Res. 2008, 103:1280-1288.
77. Ye Z.J., et al. LRP6 protein regulates low density lipoprotein (LDL) receptor-mediated LDL uptake. J. Biol. Chem. 2012, 287:1335-1344.
78. Berendsen A.D., et al. Modulation of canonical Wnt signaling by the extracellular matrix component biglycan. Proc. Natl. Acad. Sci. U.S.A. 2011, 108:17022-17027.
79. Ohazama A., et al. Lrp4: a novel modulator of extracellular signaling in craniofacial organogenesis. Am. J. Med. Genet. A 2010, 152A:2974-2983.
80. Pan W., et al. Wnt3a-mediated formation of phosphatidylinositol 4,5-bisphosphate regulates LRP6 phosphorylation. Science 2008, 321:1350-1353.
81. Niehrs C., Shen J. Regulation of Lrp6 phosphorylation. Cell. Mol. Life Sci. 2010, 67:2551-2562.
82. Keller H., Kneissel M. SOST is a target gene for PTH in bone. Bone 2005, 37:148-158.
83. Kulkarni N.H., et al. Effects of parathyroid hormone on Wnt signaling pathway in bone. J. Cell. Biochem. 2005, 95:1178-1190.
84. Tobimatsu T., et al. Parathyroid hormone increases beta-catenin levels through Smad3 in mouse osteoblastic cells. Endocrinology 2006, 147:2583-2590.
85. Suzuki A., et al. PTH/cAMP/PKA signaling facilitates canonical Wnt signaling via inactivation of glycogen synthase kinase-3beta in osteoblastic Saos-2 cells. J. Cell. Biochem. 2008, 104:304-317.
86. Wan M., et al. Parathyroid hormone signaling through low-density lipoprotein-related protein 6. Genes Dev. 2008, 22:2968-2979.
87. Wan M., et al. LRP6 mediates cAMP generation by G protein-coupled receptors through regulating the membrane targeting of Galpha(s). Sci. Signal. 2011, 4:ra15.
88. Castellone M.D., et al. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science 2005, 310:1504-1510.
89. Haq S., et al. Stabilization of beta-catenin by a Wnt-independent mechanism regulates cardiomyocyte growth. Proc. Natl. Acad. Sci. U.S.A. 2003, 100:4610-4615.
90. Fujino H., et al. Cellular conditioning and activation of beta-catenin signaling by the FPB prostanoid receptor. J. Biol. Chem. 2002, 277:48786-48795.
91. Farias G.G., et al. M1 muscarinic receptor activation protects neurons from beta-amyloid toxicity. A role for Wnt signaling pathway. Neurobiol. Dis. 2004, 17:337-348.
92. Yang M., et al. G protein-coupled lysophosphatidic acid receptors stimulate proliferation of colon cancer cells through the β-catenin pathway. Proc. Natl. Acad. Sci. U.S.A. 2005, 102:6027-6032.
93. Gardner S., et al. Nuclear stabilization of beta-catenin and inactivation of glycogen synthase kinase-3beta by gonadotropin-releasing hormone: targeting Wnt signaling in the pituitary gonadotrope. Mol. Endocrinol. 2007, 21:3028-3038.
94. Unson C.G. Molecular determinants of glucagon receptor signaling. Biopolymers 2002, 66:218-235.
95. Li X.C., Zhuo J.L. Targeting glucagon receptor signalling in treating metabolic syndrome and renal injury in type 2 diabetes: theory versus promise. Clin. Sci. (Lond.) 2007, 113:183-193.
96. Ke J., et al. Modulation of beta-catenin signaling by glucagon receptor activation. PLoS ONE 2012, 7:e33676.
97. Bryja V., et al. The extracellular domain of Lrp5/6 inhibits noncanonical Wnt signaling in vivo. Mol. Biol. Cell 2009, 20:924-936.
98. Andersson E.R., et al. Genetic interaction between Lrp6 and Wnt5a during mouse development. Dev. Dyn. 2010, 239:237-245.
99. Rey J.P., Ellies D.L. Wnt modulators in the biotech pipeline. Dev. Dyn. 2010, 239:102-114.
100. Holdsworth G., et al. Characterization of the interaction of sclerostin with the low density lipoprotein receptor-related protein (LRP) family of Wnt co-receptors. J. Biol. Chem. 2012, 287:26464-26477.