Human Gene LRP6 (uc001rah.4) Description and Page Index
  Description: Homo sapiens low density lipoprotein receptor-related protein 6 (LRP6), mRNA.
RefSeq Summary (NM_002336): 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.[provided by RefSeq, Dec 2009]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. ##Evidence-Data-START## Transcript exon combination :: SRR1803614.74061.1, SRR1660805.173648.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support SAMEA1965299, SAMEA1966682 [ECO:0000350] ##Evidence-Data-END## ##RefSeq-Attributes-START## MANE Ensembl match :: ENST00000261349.9/ ENSP00000261349.4 RefSeq Select criteria :: based on conservation, expression, longest protein ##RefSeq-Attributes-END##
Transcript (Including UTRs)
   Position: hg19 chr12:12,268,961-12,419,811 Size: 150,851 Total Exon Count: 23 Strand: -
Coding Region
   Position: hg19 chr12:12,274,060-12,419,669 Size: 145,610 Coding Exon Count: 23 

Page IndexSequence and LinksUniProtKB CommentsGenetic AssociationsMalaCardsCTD
Gene AllelesRNA-Seq ExpressionMicroarray ExpressionRNA StructureProtein StructureOther Species
GO AnnotationsmRNA DescriptionsPathwaysOther NamesModel InformationMethods
Data last updated: 2013-06-14

-  Sequence and Links to Tools and Databases
Genomic Sequence (chr12:12,268,961-12,419,811)mRNA (may differ from genome)Protein (1613 aa)
Gene SorterGenome BrowserOther Species FASTAVisiGeneGene interactionsTable Schema
BioGPSCGAPEnsemblEntrez GeneExonPrimerGeneCards
OMIMPubMedReactomeStanford SOURCETreefamUniProtKB

-  Comments and Description Text from UniProtKB
DESCRIPTION: RecName: Full=Low-density lipoprotein receptor-related protein 6; Short=LRP-6; Flags: Precursor;
FUNCTION: Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor- ligand complexes into ribosome-sized signalsomes. Cell-surface coreceptor of Wnt/beta-catenin signaling, which plays a pivotal role in 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 signalsomes and inhibiting AXIN1/GSK3- mediated phosphorylation and destruction of beta-catenin. Required for posterior patterning of the epiblast during gastrulation (By similarity).
SUBUNIT: 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 C1orf187. 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 (By similarity). Interacts (via the phosphorylated PPPSP motifs) with AXIN1; the interaction recruits the AXIN1/GSK3B complex to cell surface LRP6 signalsomes. Interacts with GRB10; the interaction prevents AXIN1 binding, thus negatively regulating the Wnt signaling pathway (By similarity). 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 (By similarity). 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.
INTERACTION: Q9H6X2:ANTXR1; NbExp=3; IntAct=EBI-910915, EBI-905643; Q5S007:LRRK2; NbExp=3; IntAct=EBI-910915, EBI-5323863;
SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane protein. Endoplasmic reticulum. Note=On Wnt signaling, undergoes a cycle of caveolin- or clathrin-mediated endocytosis and plasma membrane location. Released from the endoplasmic reticulum on palmitoylation. Mono-ubiquitination retains it in the endoplasmic reticulum in the absence of palmitoylation. On Wnt signaling, phosphorylated, aggregates and colocalizes with AXIN1 and GSK3B at the plasma membrane in LRP6-signalsomes. Chaperoned to the plasma membrane by MESD (By similarity).
TISSUE SPECIFICITY: Widely coexpressed with LRP5 during embryogenesis and in adult tissues.
INDUCTION: Decreased levels on WNT3A stimulation.
DOMAIN: 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.
DOMAIN: The PPPSP motifs play a central role in signal transduction by being phosphorylated, leading to activate the Wnt signaling pathway.
PTM: 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.
PTM: 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.
PTM: Palmitoylation on the two sites near the transmembrane domain leads to release of LRP6 from the endoplasmic reticulum.
PTM: Mono-ubiquitinated which retains LRP6 in the endoplasmic reticulum. Ubiquitinated by ZNRF3, leading to its degradation by the proteasome.
PTM: N-glycosylation is required for cell surface location.
DISEASE: Defects in LRP6 are a cause of coronary artery disease, autosomal dominant, type 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.
SIMILARITY: Belongs to the LDLR family.
SIMILARITY: Contains 4 EGF-like domains.
SIMILARITY: Contains 3 LDL-receptor class A domains.
SIMILARITY: Contains 20 LDL-receptor class B repeats.

-  Genetic Association Studies of Complex Diseases and Disorders
  Genetic Association Database (archive): LRP6
CDC HuGE Published Literature: LRP6
Positive Disease Associations: Coronary Artery Disease|Dyslipidemias|
Related Studies:
  1. Coronary Artery Disease|Dyslipidemias|
    Maciej Tomaszewski , et al. Arteriosclerosis, thrombosis, and vascular biology 2009 29(9):1316-21, A common variant in low-density lipoprotein receptor-related protein 6 gene (LRP6) is associated with LDL-cholesterol., Arteriosclerosis, thrombosis, and vascular biology 2009 29(9):1316-21. [PubMed 19667113]
    Variant in LRP6 is associated with LDL-cholesterol

-  MalaCards Disease Associations
  MalaCards Gene Search: LRP6
Diseases sorted by gene-association score: coronary artery disease, autosomal dominant, 2* (1280), tooth agenesis, selective, 7* (1229), tooth agenesis* (783), lrp6-related coronary artery disease susceptibility* (500), artery disease (21), craniodiaphyseal dysplasia (9), descending colon cancer (9), idiopathic juvenile osteoporosis (8), coronary artery disease (6), sclerosteosis (5), osteoporosis (3), neural tube defects (2), myocardial infarction (2), colorectal cancer (1)
* = Manually curated disease association

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

+  Common Gene Haplotype Alleles
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-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 9.84 RPKM in Uterus
Total median expression: 232.99 RPKM

View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
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-  mRNA Secondary Structure of 3' and 5' UTRs
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -61.60142-0.434 Picture PostScript Text
3' UTR -1356.015099-0.266 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR011042 - 6-blade_b-propeller_TolB-like
IPR000742 - EG-like_dom
IPR023415 - LDLR_class-A_CS
IPR000033 - LDLR_classB_rpt
IPR002172 - LDrepeatLR_classA_rpt
IPR017049 - Low_density_Lipo_rcpt-rel_p5/6

Pfam Domains:
PF00057 - Low-density lipoprotein receptor domain class A
PF00058 - Low-density lipoprotein receptor repeat class B
PF14670 - Coagulation Factor Xa inhibitory site

SCOP Domains:
50952 - Soluble quinoprotein glucose dehydrogenase
63825 - YWTD domain
63829 - Calcium-dependent phosphotriesterase
69304 - Tricorn protease N-terminal domain
101898 - NHL repeat
75011 - 3-carboxy-cis,cis-mucoante lactonizing enzyme
101908 - Putative isomerase YbhE
50969 - YVTN repeat-like/Quinoprotein amine dehydrogenase
50974 - Nitrous oxide reductase, N-terminal domain
69322 - Tricorn protease domain 2
57424 - LDL receptor-like module
57196 - EGF/Laminin

Protein Data Bank (PDB) 3-D Structure
MuPIT help

- X-ray MuPIT

- X-ray MuPIT

- X-ray MuPIT
To conserve bandwidth, only the images from the first 3 structures are shown.
3S94 - X-ray MuPIT 3SOB - X-ray MuPIT 3SOQ - X-ray MuPIT
3SOV - X-ray MuPIT 4A0P - X-ray MuPIT 4DG6 - X-ray MuPIT

ModBase Predicted Comparative 3D Structure on O75581
The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.

-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
No orthologNo orthologNo orthologGenome BrowserNo orthologNo ortholog
Gene Details  Gene Details  
Gene Sorter  Gene Sorter  
   Protein Sequence  

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0005041 low-density lipoprotein receptor activity
GO:0005102 receptor binding
GO:0005109 frizzled binding
GO:0005515 protein binding
GO:0017147 Wnt-protein binding
GO:0019210 kinase inhibitor activity
GO:0019534 toxin transporter activity
GO:0034185 apolipoprotein binding
GO:0042802 identical protein binding
GO:0042803 protein homodimerization activity
GO:0042813 Wnt-activated receptor activity
GO:0071936 coreceptor activity involved in Wnt signaling pathway
GO:1904928 coreceptor activity involved in canonical Wnt signaling pathway

Biological Process:
GO:0001843 neural tube closure
GO:0001933 negative regulation of protein phosphorylation
GO:0003344 pericardium morphogenesis
GO:0006355 regulation of transcription, DNA-templated
GO:0006469 negative regulation of protein kinase activity
GO:0006897 endocytosis
GO:0007204 positive regulation of cytosolic calcium ion concentration
GO:0007268 chemical synaptic transmission
GO:0007275 multicellular organism development
GO:0009880 embryonic pattern specification
GO:0014029 neural crest formation
GO:0014033 neural crest cell differentiation
GO:0016055 Wnt signaling pathway
GO:0021587 cerebellum morphogenesis
GO:0021794 thalamus development
GO:0021987 cerebral cortex development
GO:0030917 midbrain-hindbrain boundary development
GO:0034392 negative regulation of smooth muscle cell apoptotic process
GO:0035261 external genitalia morphogenesis
GO:0042475 odontogenesis of dentin-containing tooth
GO:0043434 response to peptide hormone
GO:0044332 Wnt signaling pathway involved in dorsal/ventral axis specification
GO:0044335 canonical Wnt signaling pathway involved in neural crest cell differentiation
GO:0044340 canonical Wnt signaling pathway involved in regulation of cell proliferation
GO:0045787 positive regulation of cell cycle
GO:0045893 positive regulation of transcription, DNA-templated
GO:0045944 positive regulation of transcription from RNA polymerase II promoter
GO:0051091 positive regulation of sequence-specific DNA binding transcription factor activity
GO:0060021 palate development
GO:0060026 convergent extension
GO:0060059 embryonic retina morphogenesis in camera-type eye
GO:0060070 canonical Wnt signaling pathway
GO:0060325 face morphogenesis
GO:0060535 trachea cartilage morphogenesis
GO:0060828 regulation of canonical Wnt signaling pathway
GO:0071397 cellular response to cholesterol
GO:0071542 dopaminergic neuron differentiation
GO:0071901 negative regulation of protein serine/threonine kinase activity
GO:0072659 protein localization to plasma membrane
GO:0090009 primitive streak formation
GO:0090090 negative regulation of canonical Wnt signaling pathway
GO:0090118 receptor-mediated endocytosis involved in cholesterol transport
GO:0090244 Wnt signaling pathway involved in somitogenesis
GO:0090245 axis elongation involved in somitogenesis
GO:0090263 positive regulation of canonical Wnt signaling pathway
GO:0098609 cell-cell adhesion
GO:1901998 toxin transport
GO:1904886 beta-catenin destruction complex disassembly
GO:1904948 midbrain dopaminergic neuron differentiation
GO:1904953 Wnt signaling pathway involved in midbrain dopaminergic neuron differentiation
GO:2000055 positive regulation of Wnt signaling pathway involved in dorsal/ventral axis specification

Cellular Component:
GO:0005576 extracellular region
GO:0005783 endoplasmic reticulum
GO:0005886 plasma membrane
GO:0009986 cell surface
GO:0016020 membrane
GO:0016021 integral component of membrane
GO:0031410 cytoplasmic vesicle
GO:0031901 early endosome membrane
GO:0043025 neuronal cell body
GO:0043235 receptor complex
GO:0045121 membrane raft
GO:0045202 synapse
GO:1990851 Wnt-Frizzled-LRP5/6 complex
GO:1990909 Wnt signalosome
GO:0005769 early endosome
GO:0005794 Golgi apparatus
GO:0005901 caveola

-  Descriptions from all associated GenBank mRNAs
  AB209683 - Homo sapiens mRNA for low density lipoprotein receptor-related protein 6 variant protein.
AF074264 - Homo sapiens LDL receptor-related protein 6 (LRP6) mRNA, complete cds.
BC117136 - Homo sapiens low density lipoprotein receptor-related protein 6, mRNA (cDNA clone MGC:150745 IMAGE:40125687), complete cds.
BC126405 - Homo sapiens low density lipoprotein receptor-related protein 6, mRNA (cDNA clone MGC:161683 IMAGE:8992121), complete cds.
BC143725 - Homo sapiens low density lipoprotein receptor-related protein 6, mRNA (cDNA clone MGC:177256 IMAGE:9052239), complete cds.
AK094666 - Homo sapiens cDNA FLJ37347 fis, clone BRAMY2021523.
AK124760 - Homo sapiens cDNA FLJ42770 fis, clone BRAWH3003727.
BC029941 - Homo sapiens low density lipoprotein receptor-related protein 6, mRNA (cDNA clone IMAGE:3924200).
AK074902 - Homo sapiens cDNA FLJ90421 fis, clone NT2RP3000304, highly similar to Low-density lipoprotein receptor-related protein 6 precursor.
AK074543 - Homo sapiens cDNA FLJ90062 fis, clone HEMBA1003392, highly similar to Low-density lipoprotein receptor-related protein 6 precursor.
JD038994 - Sequence 20018 from Patent EP1572962.
JD317851 - Sequence 298875 from Patent EP1572962.
JD202689 - Sequence 183713 from Patent EP1572962.
JD309846 - Sequence 290870 from Patent EP1572962.
JD058583 - Sequence 39607 from Patent EP1572962.
JD245538 - Sequence 226562 from Patent EP1572962.
JD219325 - Sequence 200349 from Patent EP1572962.
JD436231 - Sequence 417255 from Patent EP1572962.
JD406202 - Sequence 387226 from Patent EP1572962.
JD151816 - Sequence 132840 from Patent EP1572962.

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa04310 - Wnt signaling pathway

Reactome (by CSHL, EBI, and GO)

Protein O75581 (Reactome details) participates in the following event(s):

R-NUL-1458871 mFz8CRD binds LRP6N in vitro
R-NUL-209104 Frog CKIgamma further phosphorylates Human LRP6 in the receptor complex
R-HSA-1458875 WNT binds to FZD and LRP5/6
R-HSA-3769397 SOST binds LRP5/6
R-HSA-3769401 DKK and KRM bind LRP5/6
R-HSA-1504188 FZD recruits DVL to the receptor complex
R-HSA-4641249 ZNRF3,RNF43 binds the FZD:LRP5/6 receptor complex
R-HSA-4641236 USP8 deubiquitinates FZD to potentiate WNT signaling
R-HSA-4641253 ZNRF3 ubiquitinates FZD to promote its downregulation
R-HSA-201691 Phosphorylation of LRP5/6 cytoplasmic domain by CSNKI
R-NUL-1458902 frog CK1gamma phosphorylates LRP5/6
R-HSA-201677 Phosphorylation of LRP5/6 cytoplasmic domain by membrane-associated GSK3beta
R-HSA-1504186 DVL recruits GSK3beta:AXIN1 to the receptor complex
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 RNF mutants show enhanced WNT signaling and proliferation
R-HSA-195721 Signaling by WNT
R-HSA-4791275 Signaling by WNT in cancer
R-HSA-162582 Signal Transduction
R-HSA-5663202 Diseases of signal transduction
R-HSA-1643685 Disease

-  Other Names for This Gene
  Alternate Gene Symbols: LRP6_HUMAN, NM_002336, NP_002327, O75581, Q17RZ2
UCSC ID: uc001rah.4
RefSeq Accession: NM_002336
Protein: O75581 (aka LRP6_HUMAN)
CCDS: CCDS8647.1

-  Gene Model Information
category: coding nonsense-mediated-decay: no RNA accession: NM_002336.2
exon count: 23CDS single in 3' UTR: no RNA size: 10088
ORF size: 4842CDS single in intron: no Alignment % ID: 100.00
txCdsPredict score: 8501.00frame shift in genome: no % Coverage: 99.95
has start codon: yes stop codon in genome: no # of Alignments: 1
has end codon: yes retained intron: no # AT/AC introns 0
selenocysteine: no end bleed into intron: 0# strange splices: 0
Click here for a detailed description of the fields of the table above.

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.