Low-density lipoprotein receptor-related protein 6 is aprotein that in humans is encoded by theLRP6gene.[5][6] LRP6 is a key component of theLRP5/LRP6/Frizzled co-receptor group that is involved incanonical Wnt pathway.
LRP6 is a transmembrane low-densitylipoproteinreceptor that shares a similar structure withLRP5. In each protein, about 85% of its 1600-amino-acid length is extracellular. Each has fourYWTDβ-propeller motifs at theamino terminal end that alternate with fourepidermal growth factor (EGF)-like repeats, followed by threeLDLR type A repeats. Most extracellular ligands bind to LRP5 and LRP6 at the β-propellers. Each protein has a single-pass, 22-amino-acidtransmembrane helix followed by a 207-amino-acid segment that is internal to the cell.[7][8]
LRP6 acts as a co-receptor with LRP5 and theFrizzled protein family members for transducing signals byWnt proteins through thecanonical Wnt pathway.[8]
A LRP6 mutant lacking the intracellular domain is defective in Wnt signaling[9] while LRP6 mutant lacking the extracellular domain (but anchored on the membrane) are constitutively active.[10]
CanonicalWNT signals are transduced throughFrizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser-9phosphorylation.[11] Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin degradation.[12]
LRP6 is regulated by extracellular proteins in theDickkopf (Dkk) family (likeDKK1[13]),sclerostin, R-spondins and members of the cysteine-knot-type protein family.[8]
Common genetic variants of LRP6 have been associated with the risks for hyperlipidemia,[14] atherosclerosis,[15] coronary disease,[16] and late-onset Alzheimer's disease[17] in the general population.
Loss-of-function mutations or LRP6 in humans lead to increased plasma LDL and triglycerides, hypertension, diabetes and osteoporosis.[8] Similarly, mice with a loss-of-function Lrp6 mutation have low bone mass.[18] LRP6 is critical in bone'sanabolic response toparathyroid hormone (PTH) treatment, whereas LRP5 is not involved.[18] On the other hand, LRP6 does not appear active inmechanotransduction (bone's response to forces), while LRP5 is critical in that role.[18] Sclerostin, one of the inhibitors of LRP6, is a promising osteocyte-specific Wnt antagonist in osteoporosis clinical trials.[19][20]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Brown SD, Twells RC, Hey PJ, Cox RD, Levy ER, Soderman AR, Metzker ML, Caskey CT, Todd JA, Hess JF (1998). "Isolation and characterization of LRP6, a novel member of the low density lipoprotein receptor gene family".Biochem. Biophys. Res. Commun.248 (3):879–88.doi:10.1006/bbrc.1998.9061.PMID9704021.
^Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint-Jeannet JP, He X (September 2000). "LDL-receptor-related proteins in Wnt signal transduction".Nature.407 (6803):530–535.doi:10.1038/35035117.
^Mao B, Wu W, Li Y, Hoppe D, Stannek P, Glinka A, Niehrs C (17 May 2001). "LDL-receptor-related protein 6 is a receptor for Dickkopf proteins".Nature.411 (6835):321–325.doi:10.1038/35077108.
^Sarzani R, Salvi F, Bordicchia M, Guerra F, Battistoni I, Pagliariccio G, Carbonari L, Dessì-Fulgheri P, Rappelli A (February 2011). "Carotid artery atherosclerosis in hypertensive patients with a functional LDL receptor-related protein 6 gene variant".Nutrition, Metabolism and Cardiovascular Diseases.21 (2):150–156.doi:10.1016/j.numecd.2009.08.004.
^Baron R, Kneissel M (February 2013). "WNT signaling in bone homeostasis and disease: from human mutations to treatments".Nature Medicine.19 (2):179–192.doi:10.1038/nm.3074.PMID23389618.S2CID19968640.
He X, Semenov M, Tamai K, Zeng X (2004). "LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way".Development.131 (8):1663–77.doi:10.1242/dev.01117.PMID15084453.S2CID2297859.
Baens M, Wlodarska I, Corveleyn A, et al. (1999). "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)".Genomics.56 (1):40–50.doi:10.1006/geno.1998.5685.PMID10036184.
Wang X, Adhikari N, Li Q, Hall JL (2005). "LDL receptor-related protein LRP6 regulates proliferation and survival through the Wnt cascade in vascular smooth muscle cells".Am. J. Physiol. Heart Circ. Physiol.287 (6): H2376–83.doi:10.1152/ajpheart.01173.2003.PMID15271658.
Li Y, Lu W, He X, et al. (2005). "LRP6 expression promotes cancer cell proliferation and tumorigenesis by altering beta-catenin subcellular distribution".Oncogene.23 (56):9129–35.doi:10.1038/sj.onc.1208123.PMID15516984.S2CID11159925.
