LRP6

Summary

LRP6 (LDL receptor related protein 6, HGNC:6698) is a protein-coding gene on chromosome 12p13.2, encoding Low-density lipoprotein receptor-related protein 6 (O75581). Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalosomes.

This gene encodes a member of the low density lipoprotein (LDL) receptor gene family. LDL receptors are transmembrane cell surface proteins involved in receptor-mediated endocytosis of lipoprotein and protein ligands. The protein encoded by this gene functions as a receptor or, with Frizzled, a co-receptor for Wnt and thereby transmits the canonical Wnt/beta-catenin signaling cascade. Through its interaction with the Wnt/beta-catenin signaling cascade this gene plays a role in the regulation of cell differentiation, proliferation, and migration and the development of many cancer types. This protein undergoes gamma-secretase dependent RIP- (regulated intramembrane proteolysis) processing but the precise locations of the cleavage sites have not been determined.

Source: NCBI Gene 4040 — RefSeq curated summary.

At a glance

• Gene–disease (curated): tooth agenesis (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 13
• Clinical variants (ClinVar): 807 total — 62 pathogenic, 18 likely-pathogenic
• Phenotypes (HPO): 76
• Druggable target: yes
• MANE Select transcript: NM_002336

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6698
Approved symbol	LRP6
Name	LDL receptor related protein 6
Location	12p13.2
Locus type	gene with protein product
Status	Approved
Aliases	ADCAD2
Ensembl gene	ENSG00000070018
Ensembl biotype	protein_coding
OMIM	603507
Entrez	4040

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 11 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000261349, ENST00000535731, ENST00000538239, ENST00000540415, ENST00000540527, ENST00000543091, ENST00000545658, ENST00000864647, ENST00000864648, ENST00000864649, ENST00000864650, ENST00000940211, ENST00000940212, ENST00000940213

RefSeq mRNA: 13 — MANE Select: NM_002336 NM_001414244, NM_001414245, NM_001414246, NM_001414247, NM_001414248, NM_001414249, NM_001414250, NM_001414251, NM_001414252, NM_001414253, NM_001414254, NM_001414255, NM_002336

CCDS: CCDS8647

Canonical transcript exons

ENST00000261349 — 23 exons

Exon	Start	End
ENSE00000482178	12135175	12135300
ENSE00000482182	12125296	12125432
ENSE00000721602	12126691	12126921
ENSE00000721632	12138325	12138534
ENSE00000721639	12147366	12147556
ENSE00000721644	12148942	12149153
ENSE00000721649	12150836	12151038
ENSE00000721654	12158829	12159155
ENSE00000721658	12159780	12159964
ENSE00000721663	12162193	12162419
ENSE00000721668	12164273	12164562
ENSE00000721672	12165079	12165295
ENSE00000721676	12179810	12179981
ENSE00000721681	12181043	12181439
ENSE00000721686	12183980	12184111
ENSE00000721689	12186923	12187119
ENSE00000822034	12244262	12244655
ENSE00001141657	12116025	12121420
ENSE00001434043	12266681	12267044
ENSE00003498510	12130783	12130893
ENSE00003579227	12131821	12132057
ENSE00003662790	12124565	12124662
ENSE00003663975	12203203	12203400

Expression profiles

Bgee: expression breadth ubiquitous, 139 present calls, max score 95.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.8799 / max 217.0966, expressed in 1547 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129711	7.7337	1524
129709	1.5272	733
129708	0.1740	53
129712	0.1518	55
129710	0.1210	37
129707	0.1000	51
129706	0.0722	40

Top tissues by expression

141 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	95.58	gold quality
corpus callosum	UBERON:0002336	91.98	gold quality
ventricular zone	UBERON:0003053	91.88	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.79	gold quality
liver	UBERON:0002107	87.37	gold quality
stromal cell of endometrium	CL:0002255	87.29	gold quality
colonic epithelium	UBERON:0000397	86.87	gold quality
embryo	UBERON:0000922	86.87	gold quality
ganglionic eminence	UBERON:0004023	86.87	gold quality
placenta	UBERON:0001987	86.71	gold quality
sural nerve	UBERON:0015488	86.66	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.12	gold quality
cortical plate	UBERON:0005343	84.99	gold quality
endometrium	UBERON:0001295	84.55	gold quality
skeletal muscle tissue	UBERON:0001134	84.13	gold quality
right lobe of liver	UBERON:0001114	83.86	gold quality
uterus	UBERON:0000995	83.54	gold quality
body of uterus	UBERON:0009853	82.98	gold quality
myometrium	UBERON:0001296	82.97	gold quality
adrenal tissue	UBERON:0018303	82.94	gold quality
uterine cervix	UBERON:0000002	82.83	gold quality
islet of Langerhans	UBERON:0000006	82.74	gold quality
muscle tissue	UBERON:0002385	82.72	gold quality
smooth muscle tissue	UBERON:0001135	82.53	gold quality
endocervix	UBERON:0000458	81.68	gold quality
lung	UBERON:0002048	81.62	gold quality
pancreas	UBERON:0001264	81.55	gold quality
descending thoracic aorta	UBERON:0002345	81.41	gold quality
thoracic aorta	UBERON:0001515	81.24	gold quality
ascending aorta	UBERON:0001496	81.17	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.60

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF5, CEBPB, CEBPG, ELAVL1, MYC, NFKBIA

Literature-anchored findings (GeneRIF, showing 40)

• Wnt canonical signaling through LRP6 establishes a novel mechanism for receptor activation which is opposite to the general paradigm of ligand-induced receptor oligomerization (PMID:12897152)
• role for an LDL receptor-related protein in the regulation of vascular smooth muscle cell proliferation and survival through the evolutionary conserved Wnt signaling cascade. (PMID:15271658)
• LRP6 may function as a potential oncogenic protein by modulating Wnt/beta-catenin signaling (PMID:15516984)
• SOST antagonizes Wnt signaling by binding to the extracellular domain of the Wnt coreceptors LRP5 and LRP6 and disrupting Wnt-induced Frizzled-LRP complex formation. (PMID:15908424)
• Together our results show that in addition to serving as a folding chaperone, Mesd can function as a receptor antagonist by inhibiting ligand binding to mature LRP6. (PMID:16263759)
• a direct interaction between LRP6 and GSK3 results in an attenuation of GSK3 activity (PMID:16365045)
• These data suggest that LRP6, VEGF, and VLDLR may play a role in the risk of developing (age-related macular degeneration)AMD. (PMID:16384981)
• active CKIepsilon generation may induce a negative feedback loop by phosphorylation of sites on LRP5/6 that modulate axin binding and hence beta-catenin degradation (PMID:16513652)
• LRP6 is required for anthrax toxin lethality; LRP6 enables toxin internalization by interacting at the cell surface with PA receptors (PMID:16564009)
• Mesd and LRP6 modulate Wnt signaling. (PMID:16989816)
• These findings suggest a novel mechanism for LRP6 in Wnt signaling: induction of ectodomain shedding of LRP6, followed by the gamma-secretase involved proteolytic releasing its intracellular domain. (PMID:17326769)
• results link a mutation in LRP6 which encodes a co-receptor in the Wnt signaling pathway to coronary artery disease and multiple cardiovascular risk factors (PMID:17332414)
• The finding that GRB10 interferes with the binding of Axin to LRP6 indicated a possible molecular mechanism by which the overexpression of GRB10 suppresses Wnt signaling. (PMID:17376403)
• report the association between common LRP6 variants and late-onset Alzheimer’s disease in a multicenter case-control series as well as in a large family-based series ascertained (PMID:17517621)
• it is proposed that Wnts induce coclustering of receptors and Dvl in LRP6-signalosomes, which in turn triggers LRP6 phosphorylation to promote Axin recruitment and beta-catenin stabilization (PMID:17569865)
• Results identify a novel feedback mechanism by which Wnt, including Wnt3a, negatively regulates LRP6 at the mRNA level. (PMID:17698587)
• While secreted Wise either synergizes or inhibits the Wnt signals depending on the partner ligand, ER-retained Wise consistently blocks the Wnt pathway. ER-retained Wise reduces LRP6 on the cell surface, making cells less susceptible to the Wnt signal. (PMID:17765217)
• RSPO1 regulates Wnt signaling by inhibiting internalization of LRP6. (PMID:17804805)
• Both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction. Axin, a key scaffolding protein in the Wnt pathway, is required for Lrp6 phosphorylation via its ability to recruit Gsk3. (PMID:18077588)
• each LRP6 PPPS/TP motif contributes in a combinatorial fashion to activate the canonical Wnt-beta-catenin pathway (PMID:18083125)
• data argue against a human-specific role for LRP6 in anthrax toxin entry and suggest instead that involvement of this protein may be restricted to certain cell types independently of their species of origin (PMID:18350154)
• PPPSP motifs represents a built-in amplifier for Wnt signaling by the LRP6 family of receptors. (PMID:18362152)
• propose that palmitoylation serves to tilt the long, 23-residue transmembrane domain of LRP6 with respect to the plane of membrane to prevent a hydrophobic mismatch and subsequent recognition by the ER quality control (PMID:18378904)
• No association was seen between FRZB, LRP5 and LRP6 variants with radiographic osteoarthritic outcomes in two population-based cohorts (PMID:18406176)
• We found no evidence for a substantial effect of LRP5 or LRP6 SNPs on susceptibility to type 2 diabetes or clinical characteristics of diabetic subjects in Japanese population. (PMID:18493104)
• Kremen may not be essential for Dkk1-mediated Wnt antagonism and Kremen may only play a role when cells express a high level of LRP5/6 (PMID:18502762)
• DKK1 inhibition of LRP6 is independent of LRP6 internalization and degradation (PMID:18505732)
• analysis of the structural basis of the interaction between Dkk and low density lipoprotein receptor-related protein (LRP) 5/6 (PMID:18524778)
• WNT3 and DKK1 regulate distinct internalization pathways of LRP6 to tune the activation of beta catenin signaling. (PMID:18606139)
• The authors show that LRP6 can indeed form a complex with anthrax toxin receptors, and that this interaction plays a role both in Wnt signalling and in anthrax toxin endocytosis. (PMID:18717822)
• Wnt3a stimulates formation of phosphatidylinositol 4,5-bisphosphate through frizzled & dishevelled; in turn PtdIns (4,5)P2 regulated phosphorylation of LRP6 at Thr1479 & Ser1490; study reveals signaling mechanism for Wnt to regulate LRP6 phosphorylation (PMID:18772438)
• BAMBI interacts with Wnt receptor Frizzled5, coreceptor LRP6, and Dishevelled2 and increases the interaction between Frizzled5 and Dishevelled2 (PMID:18838381)
• PTH treatment led to phosphorylation of LRP6 and an increase in amount of beta-catenin in osteoblasts with a concurrent increase in bone formation in rat. Thus, LRP6 coreceptor is a key element of the PTH signaling that regulates osteoblast activity. (PMID:18981475)
• Phosphorylated LRP6/5 both recruits and directly inhibits GSK3beta using two distinct portions of its cytoplasmic sequence. (PMID:19107203)
• propose a working model that Axin recruitment to the phosphorylated LRP6 places GSK3 in the vicinity of multiple phosphorylated PPPSPXS motifs (PMID:19293931)
• These studies reveal unique properties of the LRP6 beta-propeller domains and provide novel tools to understand LRP6 function in ligand binding and Wnt signaling. (PMID:19339249)
• Results identify the first propeller domain as a novel regulatory domain for DKK1 binding to LRP6. (PMID:19477926)
• A common variant in low-density lipoprotein receptor-related protein 6 gene (LRP6) is associated with LDL-cholesterol. (PMID:19667113)
• PPP(S/T)P motif phosphorylation of the free LRP6 intracellular domain is not required to activate the Wnt/beta-catenin pathway and attenuate GSK3beta activity (PMID:19711366)
• Results identify GRK5/6 as novel kinases for the single transmembrane receptor LRP6 during Wnt signaling. (PMID:19801552)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	lrp6	ENSDARG00000100143
mus_musculus	Lrp6	ENSMUSG00000030201
rattus_norvegicus	Lrp6	ENSRNOG00000006338
drosophila_melanogaster	arr	FBGN0000119

Paralogs (14): LRP2 (ENSG00000081479), NID2 (ENSG00000087303), NID1 (ENSG00000116962), LRP1 (ENSG00000123384), LDLR (ENSG00000130164), LRP3 (ENSG00000130881), LRP4 (ENSG00000134569), EGF (ENSG00000138798), LRP12 (ENSG00000147650), VLDLR (ENSG00000147852), LRP8 (ENSG00000157193), LRP5 (ENSG00000162337), LRP1B (ENSG00000168702), LRP10 (ENSG00000197324)

Protein

Protein identifiers

Low-density lipoprotein receptor-related protein 6 — O75581 (reviewed: O75581)

All UniProt accessions (5): O75581, F5H0Z3, F5H7J9, H0YGH0, H0YGW5

UniProt curated annotations — full annotation on UniProt →

Function. Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalosomes. Cell-surface coreceptor of Wnt/beta-catenin signaling, which plays a pivotal role in various processes including retinal angiogenesis and bone formation. The Wnt-induced Fzd/LRP6 coreceptor complex recruits DVL1 polymers to the plasma membrane which, in turn, recruits the AXIN1/GSK3B-complex to the cell surface promoting the formation of signalosomes and inhibiting AXIN1/GSK3-mediated phosphorylation and destruction of beta-catenin. Required for posterior patterning of the epiblast during gastrulation.

Subunit / interactions. Homodimer; disulfide-linked. Forms phosphorylated oligomer aggregates on Wnt-signaling. Forms a WNT-signaling complex formed of a WNT protein, a FZD protein and LRP5 or LRP6. Interacts (via the extracellular domain) with WNT1; the interaction is enhanced by prior formation of the Wnt/Fzd complex. Interacts (via the beta-propeller regions 3 and 4) with WNT3A. Interacts (via the beta-propeller regions 1 and 2) with WNT9B. Interacts with FZD5; the interaction forms a coreceptor complex for Wnt signaling and is inhibited by DKK1 and DRAXIN. Interacts (via beta propeller region) with DKK1; the interaction inhibits FZD5/LRP6 complex formation. Interacts with DKK2. Interacts with C1orf187/DRAXIN; the interaction inhibits Wnt signaling. Interacts (via the phosphorylated PPPSP motifs) with AXIN1; the interaction recruits the AXIN1/GSK3B complex to cell surface LRP6 signalosomes. Interacts with GRB10; the interaction prevents AXIN1 binding, thus negatively regulating the Wnt signaling pathway. Interacts (via the extracellular domain) with RSPO1; the interaction activates Wnt/beta-catenin signaling. Interacts (via the extracellular domain) with RSPO3 (via the cysteine rich domain); the interaction activates Wnt/beta-catenin signaling. Interacts (via the beta-propeller regions 1 and 2) with SOST; the interaction competes with DKK1 for binding for inhibiting beta-catenin signaling. Interacts with MESD; the interaction prevents the formation of LRP6 aggregates and targets LRP6 to the plasma membrane. Interacts (via the cytoplasmic domain) with CSNKIE; the interaction phosphorylates LRP6, binds AXIN1 and inhibits AXIN1/GSK3B-mediated phosphorylation of beta-catenin. Interacts with MACF1. Interacts with DAB2; the interaction involves LRP6 phosphorylation by CK2 and sequesters LRP6 towards clathrin-mediated endocytosis. Interacts with TMEM198. Interacts with CAPRIN2; the interaction promotes LRP6 phosphorylation at Ser-1490. Found in a complex with CAPRIN2, CCNY and CDK14 during G2/M stage; CAPRIN2 functions as a scaffold for the complex by binding to CCNY via its N terminus and to CDK14 via its C terminus. Interacts with LYPD6 (via NxI motif). Forms a ternary complex with DKK1 and KREM1. Interacts with KREM1 in a DKK1-dependent manner. Interacts with MDK: this interaction is calcium dependent. Interacts with LMBR1L. Interacts with GPR37; this interaction promotes LRP6 maturation. Interacts with MEST; this interaction inhibits LRP6 maturation by reducing its glycosylation, preventing proper processing and localization to the cell membrane.

Subcellular location. Cell membrane. Endoplasmic reticulum. Membrane raft.

Tissue specificity. Widely coexpressed with LRP5 during embryogenesis and in adult tissues.

Post-translational modifications. Dual phosphorylation of cytoplasmic PPPSP motifs sequentially by GSK3 and CK1 is required for AXIN1-binding, and subsequent stabilization and activation of beta-catenin via preventing GSK3-mediated phosphorylation of beta-catenin. Phosphorylated, in vitro, by GRK5/6 within and outside the PPPSP motifs. Phosphorylation at Ser-1490 by CDK14 during G2/M phase leads to regulation of the Wnt signaling pathway during the cell cycle. Phosphorylation by GSK3B is induced by RPSO1 binding and inhibited by DKK1. Phosphorylated, in vitro, by casein kinase I on Thr-1479. Undergoes gamma-secretase-dependent regulated intramembrane proteolysis (RIP). The extracellular domain is first released by shedding, and then, through the action of gamma-secretase, the intracellular domain (ICD) is released into the cytoplasm where it is free to bind to GSK3B and to activate canonical Wnt signaling. Palmitoylation on the two sites near the transmembrane domain leads to release of LRP6 from the endoplasmic reticulum. Mono-ubiquitinated which retains LRP6 in the endoplasmic reticulum. Ubiquitinated by ZNRF3, leading to its degradation by the proteasome. N-glycosylation is required for cell surface location.

Disease relevance. Coronary artery disease, autosomal dominant, 2 (ADCAD2) [MIM:610947] A common heart disease characterized by reduced or absent blood flow in one or more of the arteries that encircle and supply the heart. Its most important complication is acute myocardial infarction. The disease is caused by variants affecting the gene represented in this entry. Tooth agenesis, selective, 7 (STHAG7) [MIM:616724] An autosomal dominant form of selective tooth agenesis, a common anomaly characterized by the congenital absence of one or more teeth. Selective tooth agenesis without associated systemic disorders has sometimes been divided into 2 types: oligodontia, defined as agenesis of 6 or more permanent teeth, and hypodontia, defined as agenesis of less than 6 teeth. The number in both cases does not include absence of third molars (wisdom teeth). The disease is caused by variants affecting the gene represented in this entry. Vitreoretinopathy, exudative 8 (EVR8) [MIM:621268] An autosomal dominant form of exudative vitreoretinopathy, a disorder of the retinal vasculature characterized by an abrupt cessation of growth of peripheral capillaries, leading to an avascular peripheral retina. This may lead to compensatory retinal neovascularization, which is thought to be induced by hypoxia from the initial avascular insult. New vessels are prone to leakage and rupture causing exudates and bleeding, followed by scarring, retinal detachment and blindness. Clinical features can be highly variable, even within the same family. Patients with mild forms of the disease are asymptomatic, and their only disease related abnormality is an arc of avascular retina in the extreme temporal periphery. The disease may be caused by variants affecting the gene represented in this entry.

Domain organisation. The YWTD-EGF-like domains 1 and 2 are required for the interaction with Wnt-frizzled complex. The YWTD-EGF-like domains 3 and 4 are required for the interaction with DKK1. The PPPSP motifs play a central role in signal transduction by being phosphorylated, leading to activate the Wnt signaling pathway.

Induction. Decreased levels on WNT3A stimulation.

Similarity. Belongs to the LDLR family.

RefSeq proteins (13): NP_001401173, NP_001401174, NP_001401175, NP_001401176, NP_001401177, NP_001401178, NP_001401179, NP_001401180, NP_001401181, NP_001401182, NP_001401183, NP_001401184, NP_002327* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000033	LDLR_classB_rpt	Repeat
IPR000742	EGF	Domain
IPR002172	LDrepeatLR_classA_rpt	Repeat
IPR011042	6-blade_b-propeller_TolB-like	Homologous_superfamily
IPR017049	LRP5/6	Family
IPR023415	LDLR_class-A_CS	Conserved_site
IPR036055	LDL_receptor-like_sf	Homologous_superfamily
IPR050778

Pfam: PF00057, PF00058, PF14670

UniProt features (278 total): strand 111, turn 38, mutagenesis site 24, disulfide bond 21, repeat 20, sequence variant 13, helix 10, glycosylation site 10, domain 7, region of interest 5, short sequence motif 5, modified residue 5, topological domain 2, lipid moiety-binding region 2, signal peptide 1, chain 1, transmembrane region 1, compositionally biased region 1, cross-link 1

Structure

Experimental structures (PDB)

30 structures.

PDB	Method	Resolution (Å)
3SOV	X-RAY DIFFRACTION	1.27
7NAM	X-RAY DIFFRACTION	1.6
8FFE	X-RAY DIFFRACTION	1.72
3SOB	X-RAY DIFFRACTION	1.9
3SOQ	X-RAY DIFFRACTION	1.9
4A0P	X-RAY DIFFRACTION	1.9
8DVM	X-RAY DIFFRACTION	2
4NM5	X-RAY DIFFRACTION	2.3
4NM7	X-RAY DIFFRACTION	2.3
8DVL	X-RAY DIFFRACTION	2.5
5AIR	X-RAY DIFFRACTION	2.53
8DVN	X-RAY DIFFRACTION	2.53
6H15	X-RAY DIFFRACTION	2.6
9FIX	X-RAY DIFFRACTION	2.78
3S2K	X-RAY DIFFRACTION	2.8
3S8Z	X-RAY DIFFRACTION	2.8
3S94	X-RAY DIFFRACTION	2.8
9FIW	X-RAY DIFFRACTION	2.82
9FIY	X-RAY DIFFRACTION	2.88
21KR	ELECTRON MICROSCOPY	2.9
4DG6	X-RAY DIFFRACTION	2.9
6H16	X-RAY DIFFRACTION	2.9
21KS	ELECTRON MICROSCOPY	3.01
3S8V	X-RAY DIFFRACTION	3.1
21KT	ELECTRON MICROSCOPY	3.33
5FWW	X-RAY DIFFRACTION	3.5
6L6R	X-RAY DIFFRACTION	3.8
8CTG	ELECTRON MICROSCOPY	3.8
8S7C	X-RAY DIFFRACTION	4.7
5GJE	ELECTRON MICROSCOPY	21

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75581-F1	79.87	0.53

Antibody-complex structures (SAbDab): 4 — 3SOB, 6H15, 6H16, 8FFE

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (8): 1420, 1430, 1479, 1490, 1493, 1394, 1399, 1403

Disulfide bonds (21): 286–297, 293–308, 310–323, 592–603, 599–612, 614–627, 893–904, 900–914, 916–929, 1207–1218, 1214–1228, 1230–1243, 1249–1263, 1256–1276, 1270–1285, 1288–1300, 1295–1313, 1307–1322, 1326–1338, 1333–1351 …

Glycosylation sites (10): 42, 81, 281, 433, 486, 692, 859, 865, 926, 1039

Mutagenesis-validated functional residues (24):

Position	Phenotype
1485	no change in the phosphorylation state of pppsp motif. some reduction in wnt/beta-catenin signaling.
1486	no change in the phosphorylation state of pppsp motif. increased wnt/beta-catenin signaling.
1487	no change in the phosphorylation state of pppsp motif a. greatly reduced wnt/beta-catenin signaling.
1488	no change in the phosphorylation state of pppsp motif a. greatly reduced wnt/beta-catenin signaling.
1489	no change in the phosphorylation state of pppsp motif a. greatly reduced wnt/beta-catenin signaling.
1490	greatly reduced phosphorylation of pppsp motif a. greatly reduced wnt/beta-catenin signaling.
1490	some loss of phosphorylation of pppsp motif a. little reduction in wnt/beta-catenin signaling.
1491	greatly reduced phosphorylation of pppsp motif a. greatly reduced wnt/beta-catenin signaling.
1492	no change in the phosphorylation state of pppsp motif a. greatly reduced wnt/beta-catenin signaling.
1493	no change in the phosphorylation state of pppsp motif a. greatly reduced wnt/beta-catenin signaling.
1494	no change in the phosphorylation state of pppsp motif a. little reduction of wnt/beta-catenin signaling.
1495	no change in the phosphorylation state of pppsp motif. no reduction of wnt/beta-catenin signaling.
1529	no effect on the phosphorylation state of pppsp motif b.
1530	abolishes phosphorylation of pppsp motif b. reduced wnt/beta-catenin signaling.
1531	abolishes phosphorylation of pppsp motif b. reduced wnt/beta-catenin signaling.
1572	abolishes wnt/beta-catenin signaling.
1590	abolishes wnt/beta-catenin signaling.
1607	abolishes wnt/beta-catenin signaling.
1394	some reduction of palmitoylation, little change in plasma membrane location in the presence of mesd nor in wnt-signaling
1399	some reduction of palmitoylation, and little change in plasma membrane location in the presence of mesd nor in wnt-signa
1403	abolishes ubiquitination, no change in plasma membrane location in the presence of mesd but greatly reduced wnt-signalin
1420	enhanced axin1 binding and increased beta-catenin activity by 2.2-fold. further enhanced axin1 binding and increases bet
1430	enhanced axin1 binding. further enhanced axin1 binding and increases beta-catenin activity by 3.3-fold; when associated

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-3772470	Negative regulation of TCF-dependent signaling by WNT ligand antagonists
R-HSA-4641262	Disassembly of the destruction complex and recruitment of AXIN to the membrane
R-HSA-4641263	Regulation of FZD by ubiquitination
R-HSA-5340588	Signaling by RNF43 mutants
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-195721	Signaling by WNT
R-HSA-4791275	Signaling by WNT in cancer
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers

MSigDB gene sets: 529 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, YAGI_AML_WITH_INV_16_TRANSLOCATION, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_CELLULAR_RESPONSE_TO_LIPID, CHUANG_OXIDATIVE_STRESS_RESPONSE_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOCC_CELL_SURFACE, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_1, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, MORF_RAD51L3, GOBP_CELL_CELL_SIGNALING

GO Biological Process (26): endocytosis (GO:0006897), positive regulation of cytosolic calcium ion concentration (GO:0007204), chemical synaptic transmission (GO:0007268), nervous system development (GO:0007399), neural crest formation (GO:0014029), neural crest cell differentiation (GO:0014033), Wnt signaling pathway (GO:0016055), negative regulation of smooth muscle cell apoptotic process (GO:0034392), response to peptide hormone (GO:0043434), positive regulation of cell cycle (GO:0045787), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), canonical Wnt signaling pathway (GO:0060070), cellular response to cholesterol (GO:0071397), dopaminergic neuron differentiation (GO:0071542), protein localization to plasma membrane (GO:0072659), cell-cell adhesion (GO:0098609), midbrain dopaminergic neuron differentiation (GO:1904948), regulation of DNA-templated transcription (GO:0006355), tissue development (GO:0009888), vesicle-mediated transport (GO:0016192), midbrain development (GO:0030901), regulation of apoptotic process (GO:0042981), chordate embryonic development (GO:0043009), anatomical structure formation involved in morphogenesis (GO:0048646), transmembrane transport (GO:0055085)

GO Molecular Function (12): low-density lipoprotein particle receptor activity (GO:0005041), signaling receptor binding (GO:0005102), frizzled binding (GO:0005109), coreceptor activity (GO:0015026), Wnt-protein binding (GO:0017147), kinase inhibitor activity (GO:0019210), toxin transmembrane transporter activity (GO:0019534), protein serine/threonine kinase inhibitor activity (GO:0030291), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), Wnt receptor activity (GO:0042813), protein binding (GO:0005515)

GO Cellular Component (15): extracellular region (GO:0005576), endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), cell surface (GO:0009986), cytoplasmic vesicle (GO:0031410), early endosome membrane (GO:0031901), neuronal cell body (GO:0043025), membrane raft (GO:0045121), synapse (GO:0045202), Wnt-Frizzled-LRP5/6 complex (GO:1990851), Wnt signalosome (GO:1990909), early endosome (GO:0005769), Golgi apparatus (GO:0005794), caveola (GO:0005901), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
TCF dependent signaling in response to WNT	3
Signaling by WNT	1
Signaling by WNT in cancer	1
Signal Transduction	1
Diseases of signal transduction by growth factor receptors and second messengers	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	3
cellular anatomical structure	3
cytoplasm	3
DNA-templated transcription	2
Wnt signaling pathway	2
endomembrane system	2
intracellular membrane-bounded organelle	2
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
regulation of biological quality	1
anterograde trans-synaptic signaling	1
system development	1
epithelial to mesenchymal transition	1
chordate embryonic development	1
anatomical structure formation involved in morphogenesis	1
mesenchymal cell differentiation	1
stem cell differentiation	1
cell surface receptor signaling pathway	1
negative regulation of muscle cell apoptotic process	1
smooth muscle cell apoptotic process	1
regulation of smooth muscle cell apoptotic process	1
response to hormone	1
response to nitrogen compound	1
response to oxygen-containing compound	1
cell cycle	1
positive regulation of cellular process	1
regulation of cell cycle	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
cellular response to sterol	1
response to cholesterol	1
cellular response to alcohol	1
neuron differentiation	1
protein localization to membrane	1
protein localization to cell periphery	1

Protein interactions and networks

STRING

2029 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRP6	AXIN1	O15169	999
LRP6	DKK1	O94907	999
LRP6	WNT1	P04628	998
LRP6	WNT3A	P56704	998
LRP6	SOST	Q9BQB4	998
LRP6	DKK2	Q9UBU2	998
LRP6	FZD4	Q9ULV1	996
LRP6	DKK4	Q9UBT3	994
LRP6	DVL1	O14640	994
LRP6	LRP5	O75197	987
LRP6	PTH1R	Q03431	983
LRP6	DVL2	O14641	981
LRP6	WNT7A	O00755	963
LRP6	RSPO1	Q2MKA7	960
LRP6	GSK3B	P49841	955

IntAct

284 interactions, top by confidence:

A	B	Type	Score
LRP6	DKK1	psi-mi:“MI:0407”(direct interaction)	0.960
DKK1	LRP6	psi-mi:“MI:0915”(physical association)	0.960
CSNK1A1	FAM83G	psi-mi:“MI:0914”(association)	0.900
LRP6	SOST	psi-mi:“MI:0407”(direct interaction)	0.890
SOST	LRP6	psi-mi:“MI:0914”(association)	0.890
SOST	LRP4	psi-mi:“MI:0914”(association)	0.790
LRP6	WNT3A	psi-mi:“MI:0407”(direct interaction)	0.770
ETV6	LRP6	psi-mi:“MI:0914”(association)	0.730
LRP6	Wnt3a	psi-mi:“MI:0915”(physical association)	0.710
Wnt3a	LRP6	psi-mi:“MI:0407”(direct interaction)	0.710
LRP6	LRP6	psi-mi:“MI:0407”(direct interaction)	0.680
LRRK2	LRP6	psi-mi:“MI:0915”(physical association)	0.660
GSK3A	LRP6	psi-mi:“MI:0915”(physical association)	0.650
DKK1	LRP5	psi-mi:“MI:0914”(association)	0.640
KLK5	DENND11	psi-mi:“MI:0914”(association)	0.640

BioGRID (212): SERPINF1 (Reconstituted Complex), LRP6 (Affinity Capture-MS), LRP6 (Affinity Capture-MS), LRP6 (Affinity Capture-MS), LRP6 (Affinity Capture-MS), LRP6 (Affinity Capture-MS), LRP6 (Affinity Capture-MS), LRP6 (Affinity Capture-MS), LRP6 (Affinity Capture-MS), GAS8 (Co-fractionation), LRP6 (Proximity Label-MS), LRP6 (Affinity Capture-Western), LRP6 (Proximity Label-MS), LRP6 (Affinity Capture-MS), LRP6 (Affinity Capture-MS)

ESM2 similar proteins: D3ZTD8, O18735, O60568, O75096, O75197, O75581, O88572, P00533, P04626, P06494, P21589, P21860, P31423, P35349, P52850, P55245, P70424, Q01279, Q08C93, Q14833, Q1EGL1, Q1ZZH0, Q2KHZ8, Q3TIW9, Q5E9T6, Q5EZ72, Q5I0K3, Q5NCH9, Q5R6K5, Q5R8E3, Q5RB22, Q5U367, Q60553, Q61526, Q62799, Q68EF4, Q6IS24, Q6UWV6, Q70KH2, Q7TT15

Diamond homologs: A1Z877, O08523, O75443, O75581, O88572, P01131, P20063, P35950, P35951, P35952, Q14114, Q28832, Q5ZQU0, Q6X0I2, Q70E20, Q8TER0, Q91VN0, Q98931, Q99087, Q9JI18, Q9NZR2, Q9YH85, A2AJX4, B3EWZ5, B3EWZ6, B3EX02, C0HL13, P35953, P60755, P60756, P85171, P97435, P98072, P98073, P98074, Q0PMG2, Q0WYX8, Q2PC93, Q5VYJ5, Q7Z553

SIGNOR signaling

85 interactions.

A	Effect	B	Mechanism
LRP6	“down-regulates activity”	AXIN1	relocalization
DKK1	down-regulates	LRP6	binding
Wnt	“up-regulates activity”	LRP6	binding
WNT10A	up-regulates	LRP6	binding
WNT10B	“up-regulates activity”	LRP6	binding
WNT11	“up-regulates activity”	LRP6	binding
WNT16	up-regulates	LRP6	binding
WNT2	up-regulates	LRP6	binding
WNT3	up-regulates	LRP6	binding
WNT3A	“up-regulates activity”	LRP6	binding
WNT4	up-regulates	LRP6	binding
WNT5A	“up-regulates activity”	LRP6	binding
WNT5B	up-regulates	LRP6	binding
WNT7A	“up-regulates activity”	LRP6	binding
WNT8B	up-regulates	LRP6	binding
WNT9A	up-regulates	LRP6	binding
CSNK1G1	up-regulates	LRP6	phosphorylation
CSNK1A1	up-regulates	LRP6	phosphorylation
GSK3B	“up-regulates activity”	LRP6	phosphorylation
CSNK1E	up-regulates	LRP6	phosphorylation
MACF1	up-regulates	LRP6
CAV1	up-regulates	LRP6	binding
DVL1	“up-regulates activity”	LRP6	binding
CDK14	up-regulates	LRP6	phosphorylation
WNT9B	up-regulates	LRP6	binding
CDH1	up-regulates	LRP6	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 170 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Negative regulation of TCF-dependent signaling by WNT ligand antagonists	6	38.2×	1e-06
Regulation of FZD by ubiquitination	7	32.4×	7e-07
Downstream signal transduction	5	17.0×	6e-04
Disassembly of the destruction complex and recruitment of AXIN to the membrane	5	15.9×	8e-04
NCAM signaling for neurite out-growth	5	12.1×	2e-03
Class B/2 (Secretin family receptors)	7	11.9×	2e-04
TCF dependent signaling in response to WNT	11	11.6×	8e-07
Signaling by SCF-KIT	5	11.1×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
viral protein processing	5	18.8×	2e-03
hair follicle development	6	15.8×	8e-04
canonical Wnt signaling pathway	12	12.7×	1e-07
extracellular matrix disassembly	5	12.6×	9e-03
negative regulation of canonical Wnt signaling pathway	14	11.4×	3e-08
Wnt signaling pathway	9	6.2×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

807 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	62
Likely pathogenic	18
Uncertain significance	407
Likely benign	174
Benign	104

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1033503	NM_002336.3(LRP6):c.3394_3395del (p.Ser1132fs)	Pathogenic
1033504	NM_002336.3(LRP6):c.874_875del (p.Gly292fs)	Pathogenic
1199176	NM_002336.3(LRP6):c.845-1G>A	Pathogenic
1296979	NM_002336.3(LRP6):c.2840T>C (p.Met947Thr)	Pathogenic
1296980	NM_002336.3(LRP6):c.1154G>C (p.Arg385Pro)	Pathogenic
1328138	NM_002336.3(LRP6):c.56-2A>T	Pathogenic
1342139	NM_002336.3(LRP6):c.3399del (p.Ala1134fs)	Pathogenic
1452446	NM_002336.3(LRP6):c.3204dup (p.Gly1069fs)	Pathogenic
1456993	NM_002336.3(LRP6):c.3726_3727del (p.Cys1243fs)	Pathogenic
1694660	NM_002336.3(LRP6):c.2182C>T (p.Arg728Ter)	Pathogenic
1697974	NM_002336.3(LRP6):c.1870dup (p.Met624fs)	Pathogenic
1697975	NM_002336.3(LRP6):c.1762+2T>C	Pathogenic
1805121	NM_002336.3(LRP6):c.3332dup (p.Ser1111fs)	Pathogenic
2021101	NM_002336.3(LRP6):c.1276C>T (p.Arg426Ter)	Pathogenic
2034280	NM_002336.3(LRP6):c.573T>G (p.Tyr191Ter)	Pathogenic
218878	NM_002336.3(LRP6):c.1779dup (p.Glu594Ter)	Pathogenic
218880	NM_002336.3(LRP6):c.2224_2225dup (p.Leu742fs)	Pathogenic
225147	NM_002336.3(LRP6):c.4593del (p.Cys1532fs)	Pathogenic
225148	NM_002336.3(LRP6):c.3398-2A>C	Pathogenic
2498545	NM_002336.3(LRP6):c.3888dup (p.Ser1297fs)	Pathogenic
2572177	NM_002336.3(LRP6):c.4093G>T (p.Glu1365Ter)	Pathogenic
2708589	NM_002336.3(LRP6):c.3898del (p.Cys1300fs)	Pathogenic
2722635	NM_002336.3(LRP6):c.3625C>T (p.Gln1209Ter)	Pathogenic
2754681	NM_002336.3(LRP6):c.1417C>T (p.Arg473Ter)	Pathogenic
2755733	NM_002336.3(LRP6):c.4176dup (p.Ile1393fs)	Pathogenic
2762205	NM_002336.3(LRP6):c.1373+1G>A	Pathogenic
2765523	NM_002336.3(LRP6):c.842dup (p.Asn281fs)	Pathogenic
280425	NM_002336.3(LRP6):c.2953C>T (p.Arg985Ter)	Pathogenic
280603	NM_002336.3(LRP6):c.2994+2T>C	Pathogenic
2812056	NM_002336.3(LRP6):c.2523_2531delinsTCTTGGTACTAACTCAGTATCTCAGTAACTTGGTCCAG (p.Gln842_Tyr844delinsLeuGlyThrAsnSerValSerGlnTer)	Pathogenic

SpliceAI

4732 predictions. Top by Δscore:

Variant	Effect	Δscore
12:12124658:AAAAT:A	acceptor_gain	1.0000
12:12124659:AAAT:A	acceptor_gain	1.0000
12:12124660:AAT:A	acceptor_gain	1.0000
12:12124660:AATC:A	acceptor_loss	1.0000
12:12124661:AT:A	acceptor_gain	1.0000
12:12124661:ATCT:A	acceptor_loss	1.0000
12:12124662:TCTAA:T	acceptor_loss	1.0000
12:12124663:C:CA	acceptor_loss	1.0000
12:12124663:C:CC	acceptor_gain	1.0000
12:12125291:CTTA:C	donor_gain	1.0000
12:12125292:TTA:T	donor_loss	1.0000
12:12125294:A:AC	donor_gain	1.0000
12:12125294:ACTG:A	donor_gain	1.0000
12:12125295:C:CG	donor_gain	1.0000
12:12125295:CT:C	donor_gain	1.0000
12:12125295:CTG:C	donor_gain	1.0000
12:12125295:CTGC:C	donor_gain	1.0000
12:12125295:CTGCA:C	donor_gain	1.0000
12:12125428:CATTC:C	acceptor_gain	1.0000
12:12125429:ATTC:A	acceptor_gain	1.0000
12:12125430:TTC:T	acceptor_gain	1.0000
12:12125430:TTCC:T	acceptor_gain	1.0000
12:12125431:TC:T	acceptor_gain	1.0000
12:12125431:TCCT:T	acceptor_gain	1.0000
12:12125432:CC:C	acceptor_gain	1.0000
12:12125433:C:CC	acceptor_gain	1.0000
12:12125438:A:AC	acceptor_gain	1.0000
12:12130777:A:AC	donor_gain	1.0000
12:12130778:C:CC	donor_gain	1.0000
12:12130778:CTT:C	donor_loss	1.0000

AlphaMissense

10617 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:12131964:C:G	C1276S	1.000
12:12131965:A:T	C1276S	1.000
12:12131982:C:G	C1270S	1.000
12:12131983:A:T	C1270S	1.000
12:12135180:C:G	C1243S	1.000
12:12135181:A:T	C1243S	1.000
12:12147411:A:G	W1118R	1.000
12:12147411:A:T	W1118R	1.000
12:12150993:C:G	R946P	1.000
12:12158835:A:G	C929R	1.000
12:12158874:A:G	C916R	1.000
12:12159825:A:G	W807R	1.000
12:12159825:A:T	W807R	1.000
12:12162223:G:T	P750H	1.000
12:12162286:A:T	I729N	1.000
12:12162289:C:G	R728P	1.000
12:12162311:A:G	W721R	1.000
12:12162311:A:T	W721R	1.000
12:12162314:A:C	Y720D	1.000
12:12162341:C:G	A711P	1.000
12:12162415:A:T	I686N	1.000
12:12164293:A:G	W678R	1.000
12:12164293:A:T	W678R	1.000
12:12164296:A:C	Y677D	1.000
12:12164444:G:C	C627W	1.000
12:12164445:C:G	C627S	1.000
12:12164445:C:T	C627Y	1.000
12:12164446:A:G	C627R	1.000
12:12164446:A:T	C627S	1.000
12:12164484:C:T	C614Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000024784 (12:12171644 C>T), RS1000070512 (12:12172657 T>A,C), RS1000071360 (12:12215021 C>T), RS1000080302 (12:12213245 T>G), RS1000082800 (12:12220019 G>T), RS1000086796 (12:12178062 A>G), RS1000132246 (12:12163871 C>G,T), RS1000137650 (12:12166861 G>A,T), RS1000156770 (12:12245637 C>T), RS1000201115 (12:12115688 G>A), RS1000237624 (12:12118925 G>A,C), RS1000258869 (12:12154177 G>A), RS1000268502 (12:12236307 C>T), RS1000300948 (12:12218323 A>T), RS1000322656 (12:12236131 G>C)

Disease associations

OMIM: gene MIM:603507 | disease phenotypes: MIM:616724, MIM:174050, MIM:610947, MIM:106600, MIM:119530, MIM:621268, MIM:305100, MIM:621449, MIM:148300, MIM:610755

GenCC curated gene-disease

Disease	Classification	Inheritance
tooth agenesis	Definitive	Autosomal dominant
tooth agenesis, selective, 7	Strong	Autosomal dominant
coronary artery disease, autosomal dominant 2	Limited	Unknown

Mondo (15): tooth agenesis, selective, 7 (MONDO:0014749), autosomal dominant polycystic liver disease (MONDO:0000447), autosomal dominant polycystic kidney disease (MONDO:0004691), coronary artery disease, autosomal dominant 2 (MONDO:0012586), prostate cancer (MONDO:0008315), tooth agenesis (MONDO:0005486), breast ductal adenocarcinoma (MONDO:0005590), orofacial cleft (MONDO:0000358), exudative vitreoretinopathy 8 (MONDO:0979571), ectodermal dysplasia syndrome (MONDO:0019287), osteopetrosis, autosomal dominant 4 (MONDO:0980938), keratoconus (MONDO:0015486), multiple endocrine neoplasia type 4 (MONDO:0012552), coronary artery disorder (MONDO:0005010), microcephaly (MONDO:0001149)

Orphanet (9): Oligodontia (Orphanet:99798), Isolated polycystic liver disease (Orphanet:2924), Autosomal dominant polycystic kidney disease (Orphanet:730), Familial prostate cancer (Orphanet:1331), Ectodermal dysplasia syndrome (Orphanet:79373), Multiple endocrine neoplasia type 4 (Orphanet:276152), NON RARE IN EUROPE: Hypodontia (Orphanet:2227), OBSOLETE: Keratoconus (Orphanet:156071), NON RARE IN EUROPE: Isolated keratoconus (Orphanet:2335)

HPO phenotypes

76 total (30 of 76 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000132	Menorrhagia
HP:0000164	Abnormality of the dentition
HP:0000202	Orofacial cleft
HP:0000457	Depressed nasal ridge
HP:0000541	Retinal detachment
HP:0000668	Hypodontia
HP:0000670	Carious teeth
HP:0000677	Oligodontia
HP:0000679	Taurodontia
HP:0000682	Abnormal dental enamel morphology
HP:0000684	Delayed eruption of teeth
HP:0000685	Hypoplasia of teeth
HP:0000687	Widely spaced teeth
HP:0000689	Dental malocclusion
HP:0000690	Agenesis of maxillary lateral incisor
HP:0000691	Microdontia
HP:0000696	Delayed eruption of permanent teeth
HP:0000822	Hypertension
HP:0000939	Osteoporosis
HP:0000963	Thin skin
HP:0000964	Eczematoid dermatitis
HP:0000966	Hypohidrosis
HP:0001000	Abnormality of skin pigmentation
HP:0001231	Abnormal fingernail morphology
HP:0001493	Falciform retinal fold
HP:0001645	Sudden cardiac death
HP:0001658	Myocardial infarction
HP:0001952	Glucose intolerance
HP:0001997	Gout

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST002097_24	Coronary artery calcification	6.000000e-06
GCST003055_1	Tandem gait	1.000000e-06
GCST004490_16	Cerebrospinal fluid t-tau:AB1-42 ratio	1.000000e-08
GCST006190_48	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	9.000000e-14
GCST006190_86	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	3.000000e-07
GCST006192_35	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	2.000000e-09
GCST006192_69	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	4.000000e-15
GCST006193_31	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	9.000000e-11
GCST006195_13	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	9.000000e-08
GCST006195_62	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	5.000000e-13
GCST006979_884	Heel bone mineral density	3.000000e-21
GCST006979_885	Heel bone mineral density	3.000000e-11
GCST007002_5	Cerebrospinal fluid t-tau levels in normal cognition	6.000000e-07

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0007708	t-tau:beta-amyloid 1-42 ratio measurement
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement
EFO:0006335	systolic blood pressure
EFO:0009270	heel bone mineral density
EFO:0004760	t-tau measurement

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D003324	Coronary Artery Disease	C14.280.647.250.260; C14.907.137.126.339; C14.907.585.250.260
D004476	Ectodermal Dysplasia	C16.131.077.350; C16.131.831.350; C16.320.850.250; C17.800.804.350; C17.800.827.250
D007640	Keratoconus	C11.204.627
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D016891	Polycystic Kidney, Autosomal Dominant	C12.050.351.968.419.403.875.500; C12.200.777.419.403.875.500; C12.950.419.403.875.500; C16.131.077.717.500; C16.320.184.625.500
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C567045	Coronary Artery Disease, Autosomal Dominant 2 (supp.)
C567059	Multiple Endocrine Neoplasia, Type IV (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3745588 (SINGLE PROTEIN), CHEMBL3885562 (PROTEIN-PROTEIN INTERACTION)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

14 potent at pChembl≥5 of 14 total, top 14 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.33	Kd	470	nM	CHEMBL1162107
5.52	IC50	3000	nM	CHEMBL3747431
5.47	IC50	3380	nM	CHEMBL3764819
5.43	IC50	3740	nM	CHEMBL3764323
5.42	IC50	3770	nM	CHEMBL3765769
5.39	IC50	4060	nM	CHEMBL3764205
5.36	IC50	4330	nM	CHEMBL3765415
5.34	IC50	4610	nM	CHEMBL3765394
5.33	IC50	4710	nM	CHEMBL3765591
5.31	IC50	4870	nM	CHEMBL3763214
5.28	IC50	5230	nM	CHEMBL3764713
5.26	IC50	5500	nM	CHEMBL3763953
5.21	IC50	6160	nM	CHEMBL3764972
5.20	IC50	6380	nM	CHEMBL3747431

PubChem BioAssay actives

14 with measured affinity, of 58 total; 13 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
7-(dimethylamino)-3,4-dioxo-10H-phenoxazine-1-carboxylic acid	1894739: Inhibition of human LRP6-DKK1 interaction by binding to LRP6 incubated for 1 hr by SPR analysis	kd	0.4700	uM
7-(dimethylamino)-3,4-dioxo-10H-phenoxazine-1-carboxylic acid;hydrochloride	1277979: Binding affinity to human LRP6 expressed in HEK293 cells assessed as inhibition of DKK1/LRP6 interaction using compound pre-treated DKK1 conditioned medium	ic50	3.0000	uM
butyl 7-(dimethylamino)-2-[(4-methoxyphenyl)methylamino]-3,4-dioxo-10H-phenoxazine-1-carboxylate	1277976: Binding affinity to human LRP6 expressed in HEK293 cells assessed as inhibition of DKK1/LRP6 interaction using compound pre-treated DKK1 conditioned media after 2 hrs by fluorescence microscopic analysis	ic50	3.3800	uM
methyl 7-(dimethylamino)-2-morpholin-4-yl-3,4-dioxo-10H-phenoxazine-1-carboxylate	1277976: Binding affinity to human LRP6 expressed in HEK293 cells assessed as inhibition of DKK1/LRP6 interaction using compound pre-treated DKK1 conditioned media after 2 hrs by fluorescence microscopic analysis	ic50	3.7400	uM
methyl 7-(dimethylamino)-2-(4-methylanilino)-3,4-dioxo-10H-phenoxazine-1-carboxylate	1277976: Binding affinity to human LRP6 expressed in HEK293 cells assessed as inhibition of DKK1/LRP6 interaction using compound pre-treated DKK1 conditioned media after 2 hrs by fluorescence microscopic analysis	ic50	3.7700	uM
methyl 2-(cyclohexylamino)-7-(dimethylamino)-3,4-dioxo-10H-phenoxazine-1-carboxylate	1277976: Binding affinity to human LRP6 expressed in HEK293 cells assessed as inhibition of DKK1/LRP6 interaction using compound pre-treated DKK1 conditioned media after 2 hrs by fluorescence microscopic analysis	ic50	4.0600	uM
methyl 7-(dimethylamino)-2-[(4-methoxyphenyl)methylamino]-3,4-dioxo-10H-phenoxazine-1-carboxylate	1277976: Binding affinity to human LRP6 expressed in HEK293 cells assessed as inhibition of DKK1/LRP6 interaction using compound pre-treated DKK1 conditioned media after 2 hrs by fluorescence microscopic analysis	ic50	4.3300	uM
methyl 2-(cyclopentylamino)-7-(dimethylamino)-3,4-dioxo-10H-phenoxazine-1-carboxylate	1277976: Binding affinity to human LRP6 expressed in HEK293 cells assessed as inhibition of DKK1/LRP6 interaction using compound pre-treated DKK1 conditioned media after 2 hrs by fluorescence microscopic analysis	ic50	4.6100	uM
methyl 7-(dimethylamino)-2-(4-methoxyanilino)-3,4-dioxo-10H-phenoxazine-1-carboxylate	1277976: Binding affinity to human LRP6 expressed in HEK293 cells assessed as inhibition of DKK1/LRP6 interaction using compound pre-treated DKK1 conditioned media after 2 hrs by fluorescence microscopic analysis	ic50	4.7100	uM
methyl 2-(3,4-dichloroanilino)-7-(dimethylamino)-3,4-dioxo-10H-phenoxazine-1-carboxylate	1277976: Binding affinity to human LRP6 expressed in HEK293 cells assessed as inhibition of DKK1/LRP6 interaction using compound pre-treated DKK1 conditioned media after 2 hrs by fluorescence microscopic analysis	ic50	4.8700	uM
methyl 2-amino-7-(dimethylamino)-3,4-dioxo-10H-phenoxazine-1-carboxylate	1277976: Binding affinity to human LRP6 expressed in HEK293 cells assessed as inhibition of DKK1/LRP6 interaction using compound pre-treated DKK1 conditioned media after 2 hrs by fluorescence microscopic analysis	ic50	5.2300	uM
methyl 7-(dimethylamino)-3,4-dioxo-2-piperidin-1-yl-10H-phenoxazine-1-carboxylate	1277976: Binding affinity to human LRP6 expressed in HEK293 cells assessed as inhibition of DKK1/LRP6 interaction using compound pre-treated DKK1 conditioned media after 2 hrs by fluorescence microscopic analysis	ic50	5.5000	uM
methyl 2-anilino-7-(dimethylamino)-3,4-dioxo-10H-phenoxazine-1-carboxylate	1277976: Binding affinity to human LRP6 expressed in HEK293 cells assessed as inhibition of DKK1/LRP6 interaction using compound pre-treated DKK1 conditioned media after 2 hrs by fluorescence microscopic analysis	ic50	6.1600	uM

CTD chemical–gene interactions

46 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	4
trichostatin A	decreases expression, affects cotreatment	3
sodium arsenite	decreases expression, increases reaction, increases expression, affects cotreatment, increases abundance	3
Niclosamide	decreases expression, decreases phosphorylation	3
Tetrachlorodibenzodioxin	decreases expression, increases expression	3
Valproic Acid	decreases methylation, decreases expression	3
(+)-JQ1 compound	increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	increases expression	1
kojic acid	decreases expression	1
beta-lapachone	increases expression	1
butyraldehyde	decreases expression	1
manganese chloride	increases expression, affects cotreatment, decreases expression, increases abundance	1
4-phenylenediamine	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
FV-429 compound	affects cotreatment, decreases reaction, increases expression	1
Vorinostat	decreases expression	1
Glyphosate	decreases expression	1
Ethanol	decreases response to substance	1
Arbutin	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3768327	Binding	Binding affinity to LRP6 in human SH-SY5Y cells assessed as DKK1/LRP6 interaction-mediated increase in beta-catenin level at 10 uM incubated for 1 hr using compound pre-treated DKK1 conditioned media by Western blot analysis	Discovery of novel phenoxazinone derivatives as DKK1/LRP6 interaction inhibitors: Synthesis, biological evaluation and structure-activity relationships. — Bioorg Med Chem

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B0ZM	Abcam Hep-G2 LRP6 KO	Cancer cell line	Male
CVCL_D7GU	Ubigene HEK293T LRP6 KO	Transformed cell line	Female
CVCL_D9IU	Ubigene HEK293 LRP6 KO	Transformed cell line	Female
CVCL_SV91	HAP1 LRP6 (-) 1	Cancer cell line	Male
CVCL_SV92	HAP1 LRP6 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

174 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00414440	PHASE4	COMPLETED	Efficacy, Safety and Tolerability of Everolimus in Preventing End-stage Renal Disease in Patients With Autosomal Dominant Polycystic Kidney Disease
NCT03273413	PHASE4	ACTIVE_NOT_RECRUITING	Statin Therapy in Patients With Early Stage ADPKD
NCT03949894	PHASE4	COMPLETED	Evaluating the Safety and effectivenesS in Adult KorEaN Patients Treated With Tolvaptan for Management of Autosomal domInAnt poLycystic Kidney Disease
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function