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FLASH GENE

Symbol

LRP6

contributors: mct - updated : 02-06-2017

HGNC name	low density lipoprotein receptor-related protein 6
HGNC id	6698

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	150.85 kb     23 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
text structure	GN box in the promoter of LRP6

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_002336 23 - 10088 NP_002327 180 1613 - 2010 20053636

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular vessel       highly Homo sapiens Endocrine parathyroid       highly Hearing/Equilibrium ear inner cochlea   highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular smooth vessel   predominantly Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo

Text	coexpressed with LRP5 during embryogenesis and in adult tissues

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a putative peptide signal
	four epidermal growth factor (EGF) repeats with associated spacer domains
	three LDL-receptor (LDLR) repeats consisting of YWTD repeats (LY domain)
	a single transmembrane spanning domain
	a cytoplasmic domain containing motifs
	five PPPSP motifs in the cytosplasmic tail phosphorylated by GSK3 and casein kinase I and subsequent recruitment of the scaffold protein Axin, contributing in a combinatorial fashion to activate the canonical Wnt-beta catenin pathway
	a large extracellular domain (ECD) to which Wnt-proteins are known to bind

secondary structure

modular structure of four beta-propeller domains interconnected by an EGF-like domain followed by three LDLR type A ligand-binding domains

mono polymer

complex

HOMOLOGY

interspecies	homolog to murine Lrp6 (97.89 pc)
	homolog to rattus Lrp6 (98.51 pc)

intraspecies

homolog to low density lipoprotein receptor 6 (LDLR)

Homologene

FAMILY

LDL receptor-related family

CATEGORY

protooncogene , receptor membrane

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm
text	single pass type I membrane protein
	LRP6 and LDLR colocalized both on the cell surface and within the cytoplasm

basic FUNCTION	required for canonical Wntsignaling
	probably acting as a coreceptor
	involved in endocytosis of receptors
	upon phosphorylation by CSNK1G1, recruiting Axin
	interacting with DKK1 and blocking LRP6-mediated Wnt/beta catenin signaling via LRP6 removal via Kremen proteins-mediated endocytosis
	enabling anthrax toxin internalization by interacting at the cell surface with protective antigen receptors TEM8/ATR and/or CMG2
	can stabilize CTNNB1 by stimulating degradation of Axin, a scaffold protein required for CTNNB1 degradation, and also independently of Axin degradation by directly inhibiting GSK3 phosphorylation of CTNNB1
	play a role in cell-cycle activity in response to Wnt stimulation
	single-span transmembrane coreceptor that is essential for transmission of canonical Wnt signaling
	critical modulator of PDGF-dependent regulation of cell cycle in smooth muscle and loss of this function contributes to development of early atherosclerosis
	negatively regulates cellular proliferation in response to PDGF signaling
	critical modulator of receptor-mediated LDL endocytosis and variation in LRP6 may contribute to high serum LDL level
	functions as a critical scaffolding protein that promotes formation of a complex between LDLR and endocytic machinery and triggers their endocytosis
	LRP6-mediated LDL uptake is a clathrin but not a caveolin-dependent process
	may regulate multiple signaling pathways in mesenchyme-derived cells that play critical roles in bone mineralization, arterial wall functions, and microvascular wall functions
	coreceptor for multiple fibrogenic signaling pathways in pericytes and myofibroblasts that are inhibited by DKK1
	LRP6 in osteoblasts is essential for osteoblastic differentiation during bone remodeling and the anabolic effects of PTH
	functions as a co-receptor in the canonical Wnt/CTNNB1 signaling cascade

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

immunity/defense

PATHWAY

metabolism

signaling

signal transduction

Wnt signaling of a ternary complex with KREMEN1/2 and DKK1

a component	essential component of the Wnt7 receptor complex (LRP6/FZD5)
	component of cell-surface receptors for Wnt proteins
	LRP6 forms a complex with PDGFRB and promotes its degradation
	interacting with FAM123B (fusion of FAM123B to the cytoplasmic domain of LRP6 induces LRP6 phosphorylation and stimulates robust Wnt/beta catenin signalling)
	instead of inducing FZD4 dimerization, NDP induces the formation of a ternary complex with FZD4 and LRP5/6 by binding to their respective extracellular domains

INTERACTION

DNA

RNA

small molecule

protein	high specificity receptor for DKK1, DKK2
	receptor for DKK3, DKK4
	interacting with FZD5
	interacting with DKK1 (antagonizes LRP6 function)
	IGFBP4 physically interacted with FZD8, and a Wnt co-receptor, LRP6, and inhibited the binding of WNT3A to FZD8 and LRP6
	interacting with GRK5, GRK6 (GRK5/6 are novel kinases for the single transmembrane receptor LRP6 during Wnt signaling)
	CAPRIN2-binding protein
	MESD is a specialized chaperone for low-density lipoprotein receptor-related protein 5 (LRP5) and LRP6
	interacting with MEST (MEST inhibited maturation of LRP6 by controlling the glycosylation of LRP6)
	LGR5 interacts and forms a supercomplex with the Wnt coreceptors LRP6 and FZD5 which is rapidly internalized and then degraded
	is indispensable for proper LDLR internalization
	DAB2 selectively recruits LRP6 to the clathrin-dependent endocytic route, thereby sequestering it from caveolin-mediated endocytosis
	LRRK2 can interact with the intracellular domain of LRP6 in cells and that this binding is likely to be direct, via the LRRK2-RocCOR domain
	interacts closely with PDGFRB and TGFBR1 at the cell membrane, suggesting that it may have roles in pathways other than WNT/CTNNB
	LRP6 is required for parathyroid hormone (PTH)-stimulated signaling pathways in osteoblasts
	TGM2 binds directly to the extracellular domain of LRP6, which is also able to act as a substrate for TGM2-mediated protein cross-linking
	PTK7 and LRP6 proteins physically interact, suggesting that PTK7 stabilization of LRP6 protein reciprocally regulates both canonical and noncanonical Wnt activities in the embryo
	DKK4 interaction with LRP6 modulates WNT function during Meibomian gland (MG) development, with a novel limitation of DKK4 action by proteolytic cleavage
	LRP6 promotes TNBC cell migration and invasion by regulating the expression and func)tion of S100A4 via the WNT/CTNNB1 signaling pathway
	LRP6 is an essential WNT co-receptor of the WNT/CTNNB1 signaling pathway
	NDN binds to the GN box in the promoter of LRP6 to attenuate LRP6 transcription and inhibit the Wnt signaling pathway in colorectal cancer
	PUM1 regulates the growth and mobility of extravillous trophoblast cells (EVTs) by modulating LRP6 expression

cell & other

REGULATION

induced by	phosphorylation
		an intracellular conformational switch (from an inactive dimer to an active monomer)
		WNT3A (WNT3A acts in parallel to induce the caveolin-dependent internalization of low-density-lipoprotein receptor-related protein 6 (LRP6), as well as the phosphorylation of LRP6 and the recruitment of Axin to LRP6 on the cell surface membrane)

repressed by	a novel feedback mechanism by which Wnt, acting through beta-catenin, negatively regulates LRP6 at the mRNA level
		DKK1 (DKK1 induces the internalization of LRP6 to suppress its phosphorylation in the lipid raft and allows subsequent recycling of LRP6 so that it can be reused for signaling)

Other	modulated by MESDC2
	phosphorylation of LRP6 regulated by WNT3A-mediated formation of PIP5K1A, PIP5K1B, PIP5K1C

ASSOCIATED DISORDERS

corresponding disease(s)

CADO , OLD3

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --low   in leukemia, by hypermethylation tumoral     --low   sufficient to inhibit breast cancer tumorigenesis constitutional     --over   colocalizes with PDGFRB and is expressed abundantly in atherosclerotic lesions ( constitutional       loss of function in hyperlipidemia

Susceptibility

to premature coronary artery disease

Variant & Polymorphism other	LRP6R611C mutation with a dominant-negative effects on the inhibition of PDGFRB, linked to a form of premature coronary artery disease

Candidate gene	plausible candidate genes for SHFM
Marker
Therapy target
	System Type Disorder Pubmed cancer reproductive breast potential therapeutic target in breast cancer, and introduce Mesd (LRP6 antagonist) as a promising antitumor agent for treating breast cancer subtypes with Wnt activation at the cell surface metabolism lipid   potential target for development of novel therapeutics in hyperlipidemia

ANIMAL & CELL MODELS

in Lrp6 mutant mice, the mechanism of birth defect prevention by Folic acid supplementation (reduction of neural tube defects occurrence by amelioration versus increased embryonic loss) can vary not only with the genes associated with increased risk, but also with the type of mutation within those genes (i.e. loss or gain of function )