LRP6

LRP6 is a transmembrane low-density lipoprotein receptor that shares a similar structure with LRP5. In each protein, about 85% of its 1600-amino-acid length is extracellular. Each has four YWTD β-propeller motifs at the amino terminal end that alternate with four epidermal growth factor (EGF)-like repeats, followed by three LDLR type A repeats. Most extracellular ligands bind to LRP5 and LRP6 at the β-propellers. Each protein has a single-pass, 22-amino-acid transmembrane helix followed by a 207-amino-acid segment that is internal to the cell.{{cite journal |last1=Cheng |first1=Zhihong |last2=Biechele |first2=Travis |last3=Wei |first3=Zhiyi |last4=Morrone |first4=Seamus |last5=Moon |first5=Randall T |last6=Wang |first6=Liguo |last7=Xu |first7=Wenqing |title=Crystal structures of the extracellular domain of LRP6 and its complex with DKK1 |journal=Nature Structural & Molecular Biology |date=November 2011 |volume=18 |issue=11 |pages=1204–1210 |doi=10.1038/nsmb.2139|pmc=3249237 }}{{cite journal |vauthors=Williams BO, Insogna KL |title=Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone |journal=J. Bone Miner. Res. |volume=24 |issue=2 |pages=171–8 |year=2009 |pmid=19072724 |pmc=3276354 |doi=10.1359/jbmr.081235 }}

LRP6 acts as a co-receptor with LRP5 and the Frizzled protein family members for transducing signals by Wnt proteins through the canonical Wnt pathway.

A LRP6 mutant lacking the intracellular domain is defective in Wnt signaling{{cite journal |last1=Tamai |first1=Keiko |last2=Semenov |first2=Mikhail |last3=Kato |first3=Yoichi |last4=Spokony |first4=Rebecca |last5=Liu |first5=Chunming |last6=Katsuyama |first6=Yu |last7=Hess |first7=Fred |last8=Saint-Jeannet |first8=Jean-Pierre |last9=He |first9=Xi |title=LDL-receptor-related proteins in Wnt signal transduction |journal=Nature |date=September 2000 |volume=407 |issue=6803 |pages=530–535 |doi=10.1038/35035117}} while LRP6 mutant lacking the extracellular domain (but anchored on the membrane) are constitutively active.{{cite journal |last1=Mao |first1=Bingyu |last2=Wu |first2=Wei |last3=Li |first3=Yan |last4=Hoppe |first4=Dana |last5=Stannek |first5=Peter |last6=Glinka |first6=Andrei |last7=Niehrs |first7=Christof |title=LDL-receptor-related protein 6 is a receptor for Dickkopf proteins |journal=Nature |date=17 May 2001 |volume=411 |issue=6835 |pages=321–325 |doi=10.1038/35077108}}

Canonical WNT signals are transduced through Frizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser-9 phosphorylation.{{cite journal |vauthors=Katoh M, Katoh M |title=Cross-talk of WNT and FGF signaling pathways at GSK3beta to regulate beta-catenin and SNAIL signaling cascades |journal=Cancer Biol. Ther. |volume=5 |issue=9 |pages=1059–64 |year=2006 |pmid=16940750 |doi=10.4161/cbt.5.9.3151|doi-access=free }} Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin degradation.{{cite journal |vauthors=Hong JY, Park JI, Cho K, Gu D, Ji H, Artandi SE, McCrea PD |title=Shared molecular mechanisms regulate multiple catenin proteins: canonical Wnt signals and components modulate p120-catenin isoform-1 and additional p120 subfamily members |journal=J. Cell Sci. |volume=123 |issue=Pt 24 |pages=4351–65 |year=2010 |pmid=21098636 |pmc=2995616 |doi=10.1242/jcs.067199 }}

LRP6 is regulated by extracellular proteins in the Dickkopf (Dkk) family (like DKK1{{cite journal |vauthors=Semënov MV, Tamai K, Brott BK, Kühl M, Sokol S, He X |title=Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6 |journal=Curr. Biol. |volume=11 |issue=12 |pages=951–61 |year=2001 |pmid=11448771 |doi= 10.1016/s0960-9822(01)00290-1|s2cid=15702819 |doi-access=free |bibcode=2001CBio...11..951S }}), sclerostin, R-spondins and members of the cysteine-knot-type protein family.

Common genetic variants of LRP6 have been associated with the risks for hyperlipidemia,{{cite journal |last1=Tomaszewski |first1=Maciej |last2=Charchar |first2=Fadi J. |last3=Barnes |first3=Timothy |last4=Gawron-Kiszka |first4=Magdalena |last5=Sedkowska |first5=Agnieszka |last6=Podolecka |first6=Ewa |last7=Kowalczyk |first7=Jacek |last8=Rathbone |first8=Wendy |last9=Kalarus |first9=Zbigniew |last10=Grzeszczak |first10=Wladyslaw |last11=Goodall |first11=Alison H. |last12=Samani |first12=Nilesh J. |last13=Zukowska-Szczechowska |first13=Ewa |title=A Common Variant in Low-Density Lipoprotein Receptor–Related Protein 6 Gene (LRP6) Is Associated With LDL-Cholesterol |journal=Arteriosclerosis, Thrombosis, and Vascular Biology |date=September 2009 |volume=29 |issue=9 |pages=1316–1321 |doi=10.1161/ATVBAHA.109.185355|pmc=2814817 }} atherosclerosis,{{cite journal |last1=Sarzani |first1=R. |last2=Salvi |first2=F. |last3=Bordicchia |first3=M. |last4=Guerra |first4=F. |last5=Battistoni |first5=I. |last6=Pagliariccio |first6=G. |last7=Carbonari |first7=L. |last8=Dessì-Fulgheri |first8=P. |last9=Rappelli |first9=A. |title=Carotid artery atherosclerosis in hypertensive patients with a functional LDL receptor-related protein 6 gene variant |journal=Nutrition, Metabolism and Cardiovascular Diseases |date=February 2011 |volume=21 |issue=2 |pages=150–156 |doi=10.1016/j.numecd.2009.08.004}} coronary disease,{{cite journal |last1=Mani |first1=Arya |last2=Radhakrishnan |first2=Jayaram |last3=Wang |first3=He |last4=Mani |first4=Alaleh |last5=Mani |first5=Mohammad-Ali |last6=Nelson-Williams |first6=Carol |last7=Carew |first7=Khary S. |last8=Mane |first8=Shrikant |last9=Najmabadi |first9=Hossein |last10=Wu |first10=Dan |last11=Lifton |first11=Richard P. |title=LRP6 Mutation in a Family with Early Coronary Disease and Metabolic Risk Factors |journal=Science |date=2 March 2007 |volume=315 |issue=5816 |pages=1278–1282 |doi=10.1126/science.1136370|pmc=2945222 }} and late-onset Alzheimer's disease{{cite journal |last1=De Ferrari |first1=Giancarlo V. |last2=Papassotiropoulos |first2=Andreas |last3=Biechele |first3=Travis |last4=Wavrant De-Vrieze |first4=Fabienne |last5=Avila |first5=Miguel E. |last6=Major |first6=Michael B. |last7=Myers |first7=Amanda |last8=Sáez |first8=Katia |last9=Henríquez |first9=Juan P. |last10=Zhao |first10=Alice |last11=Wollmer |first11=M. Axel |last12=Nitsch |first12=Roger M. |last13=Hock |first13=Christoph |last14=Morris |first14=Chris M. |last15=Hardy |first15=John |last16=Moon |first16=Randall T. |title=Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease |journal=Proceedings of the National Academy of Sciences |date=29 May 2007 |volume=104 |issue=22 |pages=9434–9439 |doi=10.1073/pnas.0603523104|pmc=1890512 }} in the general population.

Loss-of-function mutations or LRP6 in humans lead to increased plasma LDL and triglycerides, hypertension, diabetes and osteoporosis. Similarly, mice with a loss-of-function Lrp6 mutation have low bone mass. LRP6 is critical in bone's anabolic response to parathyroid hormone (PTH) treatment, whereas LRP5 is not involved.{{cite journal |vauthors=Kang KS, Robling AG |title=New Insights into Wnt-Lrp5/6-β-Catenin Signaling in Mechanotransduction |journal=Front Endocrinol (Lausanne) |volume=5 |pages=246 |year=2014 |pmid=25653639 |pmc=4299511 |doi=10.3389/fendo.2014.00246 |doi-access=free }} On the other hand, LRP6 does not appear active in mechanotransduction (bone's response to forces), while LRP5 is critical in that role.

Sclerostin, one of the inhibitors of LRP6, is a promising osteocyte-specific Wnt antagonist in osteoporosis clinical trials.{{Cite journal | vauthors = Baron R, Kneissel M| title = WNT signaling in bone homeostasis and disease: from human mutations to treatments | journal = Nature Medicine | volume = 19 | issue = 2 | pages = 179–192 |date=February 2013 | doi = 10.1038/nm.3074 | pmid = 23389618| s2cid = 19968640 }}{{Cite journal | vauthors = Burgers TA, Williams BO | title = Regulation of Wnt/beta-catenin signaling within and from osteocytes | journal = Bone | volume = 54 | issue = 2 | pages = 244–249 |date=June 2013 | doi = 10.1016/j.bone.2013.02.022 | pmid = 23470835 | pmc=3652284}}

{{reflist|2}}

{{refbegin | 2}}

• {{cite journal | vauthors =He X, Semenov M, Tamai K, Zeng X |title=LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. |journal=Development |volume=131 |issue= 8 |pages= 1663–77 |year= 2004 |pmid= 15084453 |doi= 10.1242/dev.01117 |s2cid=2297859 |doi-access= }}
• {{cite journal |vauthors=Hillier LD, Lennon G, Becker M, etal |title=Generation and analysis of 280,000 human expressed sequence tags. |journal=Genome Res. |volume=6 |issue= 9 |pages= 807–28 |year= 1997 |pmid= 8889549 |doi=10.1101/gr.6.9.807 |doi-access=free }}
• {{cite journal |vauthors=Baens M, Wlodarska I, Corveleyn A, etal |title=A physical, transcript, and deletion map of chromosome region 12p12.3 flanked by ETV6 and CDKN1B: hypermethylation of the LRP6 CpG island in two leukemia patients with hemizygous del(12p). |journal=Genomics |volume=56 |issue= 1 |pages= 40–50 |year= 1999 |pmid= 10036184 |doi= 10.1006/geno.1998.5685 }}
• {{cite journal |vauthors=Tamai K, Semenov M, Kato Y, etal |title=LDL-receptor-related proteins in Wnt signal transduction. |journal=Nature |volume=407 |issue= 6803 |pages= 530–5 |year= 2000 |pmid= 11029007 |doi= 10.1038/35035117 |bibcode=2000Natur.407..530T |s2cid=4400159 }}
• {{cite journal |vauthors=Mao B, Wu W, Li Y, etal |title=LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. |journal=Nature |volume=411 |issue= 6835 |pages= 321–5 |year= 2001 |pmid= 11357136 |doi= 10.1038/35077108 |bibcode=2001Natur.411..321M |s2cid=4323027 }}
• {{cite journal |vauthors=Semënov MV, Tamai K, Brott BK, etal |title=Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. |journal=Curr. Biol. |volume=11 |issue= 12 |pages= 951–61 |year= 2001 |pmid= 11448771 |doi=10.1016/S0960-9822(01)00290-1 |s2cid=15702819 |doi-access=free |bibcode=2001CBio...11..951S }}
• {{cite journal |vauthors=Li L, Mao J, Sun L, etal |title=Second cysteine-rich domain of Dickkopf-2 activates canonical Wnt signaling pathway via LRP-6 independently of dishevelled. |journal=J. Biol. Chem. |volume=277 |issue= 8 |pages= 5977–81 |year= 2002 |pmid= 11742004 |doi= 10.1074/jbc.M111131200 |doi-access= free }}
• {{cite journal |vauthors=Strausberg RL, Feingold EA, Grouse LH, etal |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 |bibcode=2002PNAS...9916899M |doi-access=free }}
• {{cite journal |vauthors=Caricasole A, Ferraro T, Iacovelli L, etal |title=Functional characterization of WNT7A signaling in PC12 cells: interaction with A FZD5 x LRP6 receptor complex and modulation by Dickkopf proteins. |journal=J. Biol. Chem. |volume=278 |issue= 39 |pages= 37024–31 |year= 2003 |pmid= 12857724 |doi= 10.1074/jbc.M300191200 |doi-access= free }}
• {{cite journal | vauthors =Liu G, Bafico A, Harris VK, Aaronson SA |title=A novel mechanism for Wnt activation of canonical signaling through the LRP6 receptor. |journal=Mol. Cell. Biol. |volume=23 |issue= 16 |pages= 5825–35 |year= 2003 |pmid= 12897152 |doi=10.1128/MCB.23.16.5825-5835.2003 | pmc=166321 }}
• {{cite journal | vauthors =Zilberberg A, Yaniv A, Gazit A |title=The low density lipoprotein receptor-1, LRP1, interacts with the human frizzled-1 (HFz1) and down-regulates the canonical Wnt signaling pathway. |journal=J. Biol. Chem. |volume=279 |issue= 17 |pages= 17535–42 |year= 2004 |pmid= 14739301 |doi= 10.1074/jbc.M311292200 |doi-access= free }}
• {{cite journal | vauthors =Wang X, Adhikari N, Li Q, Hall JL |title=LDL receptor-related protein LRP6 regulates proliferation and survival through the Wnt cascade in vascular smooth muscle cells. |journal=Am. J. Physiol. Heart Circ. Physiol. |volume=287 |issue= 6 |pages= H2376–83 |year= 2005 |pmid= 15271658 |doi= 10.1152/ajpheart.01173.2003 }}
• {{cite journal |vauthors=Suzuki Y, Yamashita R, Shirota M, etal |title=Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions. |journal=Genome Res. |volume=14 |issue= 9 |pages= 1711–8 |year= 2004 |pmid= 15342556 |doi= 10.1101/gr.2435604 | pmc=515316 }}
• {{cite journal |vauthors=Gerhard DS, Wagner L, Feingold EA, etal |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 | pmc=528928 }}
• {{cite journal |vauthors=Li Y, Lu W, He X, etal |title=LRP6 expression promotes cancer cell proliferation and tumorigenesis by altering beta-catenin subcellular distribution. |journal=Oncogene |volume=23 |issue= 56 |pages= 9129–35 |year= 2005 |pmid= 15516984 |doi= 10.1038/sj.onc.1208123 |s2cid=11159925 |doi-access= }}
• {{cite journal | vauthors =Semënov M, Tamai K, He X |title=SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. |journal=J. Biol. Chem. |volume=280 |issue= 29 |pages= 26770–5 |year= 2005 |pmid= 15908424 |doi= 10.1074/jbc.M504308200 |doi-access= free }}
• {{cite journal |vauthors=Li Y, Chen J, Lu W, etal |title=Mesd binds to mature LDL-receptor-related protein-6 and antagonizes ligand binding. |journal=J. Cell Sci. |volume=118 |issue= Pt 22 |pages= 5305–14 |year= 2006 |pmid= 16263759 |doi= 10.1242/jcs.02651 |doi-access= free }}
• {{cite journal | vauthors =Mi K, Dolan PJ, Johnson GV |title=The low density lipoprotein receptor-related protein 6 interacts with glycogen synthase kinase 3 and attenuates activity. |journal=J. Biol. Chem. |volume=281 |issue= 8 |pages= 4787–94 |year= 2006 |pmid= 16365045 |doi= 10.1074/jbc.M508657200 |doi-access= free }}

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{{Lipoprotein metabolism}}