Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

LRP6 (O75581) - Overview - Molecular Target Synopsis

Protein


LRP6, Low-density lipoprotein receptor-related protein 6
UniProt O75581

Also Known as LRP6_HUMAN, LRP6

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). 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 (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. Interacts with TMEM198. Interacts with CAPRIN2; the interaction promotes LRP6 phosphorylation at Ser-1490 (PubMed:18762581, PubMed:25331957). 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 (PubMed:27821587). Interacts with LYPD6 (PubMed:23987510). Forms a ternary complex with DKK1 and KREM1 (PubMed:27524201). Interacts with KREM1 in a DKK1-dependent manner (PubMed:17804805). Interacts with MDK: this interaction is calcium dependent (By similarity).

6H16
STRUCTURE OF LRP6 P3E3P4E4 IN COMPLEX WITH VHH L-P2-D07
RCSB/PDB
Inspect Structure
See all 3D Structures for LRP6

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: LRP6 is active in the following subcellular-locations: cell membrane, endoplasmic reticulum, membrane raft.
GO terms: LRP6 is active in the following subcellular-locations: caveola, cell surface, cytoplasmic vesicle, early endosome membrane, endoplasmic reticulum, extracellular region, integral component of membrane, neuronal cell body, plasma membrane, synapse, Wnt signalosome, Wnt-Frizzled-LRP5/6 complex.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project LRP6 has gain in 7 cell-lines, loss in 5 cell-lines and no signal in 993 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: IGROV1, SW_620, NCI_H322M

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: NCI-H441, MHH-ES-1, NTERA-2

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: NHLF, HSMM, AG445

(see details)

3D Structures


For LRP6 there are:
16 structures (22 chains) solved
10 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


LRP6 has been screened with 30 compounds (45 bioactivities). (see details)