Comparison of LRP5 and LRP6 26. Holmen SL, Salic A, Zylstra CR, Kirschner MW, Williams BO (2002) A novel set of Wnt-Frizzled fusion proteins identifies receptor components that activate beta -catenin-dependent signaling. J Biol Chem 277: 34727–34735. 27. Mi K, Johnson GV (2005) Role of the intracellular domains of LRP5 and LRP6 in activating the Wnt canonical pathway. J Cell Biochem 95: 328–338. 28. MacDonald BT, Yokota C, Tamai K, Zeng X, He X (2008) Wnt signal amplification via activity, cooperativity, and regulation of multiple intracellular PPPSP motifs in the Wnt co-receptor LRP6. J Biol Chem 283: 16115–16123. 29. Wolf J, Palmby TR, Gavard J, Williams BO, Gutkind JS (2008) Multiple PPPS/ TP motifs act in a combinatorial fashion to transduce Wnt signaling through LRP6. FEBS Lett 582: 255–261. 30. Mao J, Wang J, Liu B, Pan W, Farr GH, III, et al. (2001) Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell 7: 801–809. 31. Tolwinski NS, Wehrli M, Rives A, Erdeniz N, DiNardo S, et al. (2003) Wg/Wnt signal can be transmitted through arrow/LRP5,6 and Axin independently of Zw3/Gsk3beta activity. Dev Cell 4: 407–418. 32. Liu G, Bafico A, Harris VK, Aaronson SA (2003) A novel mechanism for Wnt activation of canonical signaling through the LRP6 receptor. Mol Cell Biol 23: 5825–5835. 33. Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F, et al. (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461: 614–620. 34. Mi K, Dolan PJ, Johnson GV (2006) The low density lipoprotein receptor- related protein 6 interacts with glycogen synthase kinase 3 and attenuates activity. J Biol Chem 281: 4787–4794. 35. Wu G, Huang H, Garcia Abreu J, He X (2009) Inhibition of GSK3 phosphorylation of beta-catenin via phosphorylated PPPSPXS motifs of Wnt coreceptor LRP6. PLoS ONE 4: e4926. 36. Piao S, Lee SH, Kim H, Yum S, Stamos JL, et al. (2008) Direct inhibition of GSK3beta by the phosphorylated cytoplasmic domain of LRP6 in Wnt/beta- catenin signaling. PLoS ONE 3: e4046. 37. Yum S, Lee SJ, Piao S, Xu Y, Jung J, et al. (2009) The role of the Ser/Thr cluster in the phosphorylation of PPPSP motifs in Wnt coreceptors. Biochem Biophys Res Commun 381: 345–349. 38. Balemans W, Van Hul W (2007) The genetics of low-density lipoprotein receptor-related protein 5 in bone: a story of extremes. Endocrinology 148: 2622–2629. 39. Baig-Lewis S, Peterson-Nedry W, Wehrli M (2007) Wingless/Wnt signal transduction requires distinct initiation and amplification steps that both depend on Arrow/LRP. Dev Biol 306: 94–111. 40. Zeng X, Huang H, Tamai K, Zhang X, Harada Y, et al. (2008) Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions. Development 135: 367–375. 41. Wan M, Li J, Herbst K, Zhang J, Yu B, et al. (2011) LRP6 Mediates cAMP Generation by G Protein-Coupled Receptors Through Regulating the Membrane Targeting of G{alpha}s. Sci Signal 4: ra15. 42. Garnier J, Osguthorpe DJ, Robson B (1978) Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. J Mol Biol 120: 97–120. PLoS ONE | www.plosone.org 11 August 2011 | Volume 6 | Issue 8 | e23537