Low-density lipoprotein receptor-related protein 6 is a
protein that in humans is encoded by the LRP6gene.[5][6] LRP6 is a key component of the
LRP5/LRP6/
Frizzled co-receptor group that is involved in
canonical Wnt pathway.
Structure
LRP6 is a transmembrane low-density
lipoproteinreceptor that shares a similar structure with
LRP5. In each protein, about 85% of its 1600-
amino-acid length is extracellular. Each has four
β-propeller motifs at the
amino terminal end that alternate with four
epidermal growth factor (EGF)-like repeats. Most extracellular ligands bind to LRP5 and LRP6 at the β-propellers. Each protein has a single-pass, 22-amino-acid segment that crosses the cell membrane and a 207-amino-acid segment that is internal to the cell.[7]
Function
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.[7]
Interactions
Canonical
WNT signals are transduced through
Frizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta (
GSK3B) activity not depending on Ser-9
phosphorylation.[8] Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-
catenin degradation.[9]
LRP6 is regulated by extracellular proteins in the
Dickkopf (Dkk) family (like
DKK1[10]),
sclerostin, R-spondins and members of the cysteine-knot-type protein family.[7]
Clinical significance
Loss-of-function mutations or LRP6 in humans lead to increased plasma LDL and triglycerides, hypertension, diabetes and osteoporosis.[7] Similarly, mice with a loss-of-function Lrp6 mutation have low bone mass.[11] LRP6 is critical in bone's
anabolic response to
parathyroid hormone (PTH) treatment, whereas LRP5 is not involved.[11] On the other hand, LRP6 does not appear active in
mechanotransduction (bone's response to forces), while LRP5 is critical in that role.[11]
Sclerostin, one of the inhibitors of LRP6, is a promising osteocyte-specific Wnt antagonist in osteoporosis clinical trials.[12][13]
^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.
Low-density lipoprotein receptor-related protein 6 is a
protein that in humans is encoded by the LRP6gene.[5][6] LRP6 is a key component of the
LRP5/LRP6/
Frizzled co-receptor group that is involved in
canonical Wnt pathway.
Structure
LRP6 is a transmembrane low-density
lipoproteinreceptor that shares a similar structure with
LRP5. In each protein, about 85% of its 1600-
amino-acid length is extracellular. Each has four
β-propeller motifs at the
amino terminal end that alternate with four
epidermal growth factor (EGF)-like repeats. Most extracellular ligands bind to LRP5 and LRP6 at the β-propellers. Each protein has a single-pass, 22-amino-acid segment that crosses the cell membrane and a 207-amino-acid segment that is internal to the cell.[7]
Function
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.[7]
Interactions
Canonical
WNT signals are transduced through
Frizzled receptor and LRP5/LRP6 coreceptor to downregulate GSK3beta (
GSK3B) activity not depending on Ser-9
phosphorylation.[8] Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-
catenin degradation.[9]
LRP6 is regulated by extracellular proteins in the
Dickkopf (Dkk) family (like
DKK1[10]),
sclerostin, R-spondins and members of the cysteine-knot-type protein family.[7]
Clinical significance
Loss-of-function mutations or LRP6 in humans lead to increased plasma LDL and triglycerides, hypertension, diabetes and osteoporosis.[7] Similarly, mice with a loss-of-function Lrp6 mutation have low bone mass.[11] LRP6 is critical in bone's
anabolic response to
parathyroid hormone (PTH) treatment, whereas LRP5 is not involved.[11] On the other hand, LRP6 does not appear active in
mechanotransduction (bone's response to forces), while LRP5 is critical in that role.[11]
Sclerostin, one of the inhibitors of LRP6, is a promising osteocyte-specific Wnt antagonist in osteoporosis clinical trials.[12][13]
^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.