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FLASH GENE

Symbol

LRP1

contributors: mct/pgu - updated : 14-03-2017

HGNC name	low density lipoprotein-related protein 1 (alpha-2-macroglobulin receptor)
HGNC id	6692

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	thirty one copies of the ligand binding domain, equivalent to the classical LDL receptor motif, cysteine rich, arranged in four clusters
	sixteen growth factor repeats
	one EGF-like motif
	a transmembrane segment (1TM)
	a short cytoplasmic tail, with internalization signals, common 600 RD precursor of 500 and 85kD chains
	two NPXY motifs in the intracellular domain (ICD) serve as docking sites for several cytoplasmic adaptor proteins, and interact with signaling proteins ,
	FXNPXY63 motif not only governs cellular localization of the receptor but also exerts multiple functional effects on signalling pathways involved in cell growth regulation

isoforms

Precursor

HOMOLOGY

intraspecies

homolog to low-density lipoprotein receptor 1 (LDLR)

Homologene

FAMILY

LDLR superfamily

CATEGORY

signaling , receptor

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endosome
	intracellular,cytoplasm,organelle,lysosome
	intracellular,cytoplasm,cytosolic,vesicle
	intracellular,nucleus

basic FUNCTION	macroglobulin, alpha-2-receptor (proteinase complexes receptor)
	multiligand receptor for beta lipoprotein, binding chylomicron remnants, beta VLDL, lipoprotein lipase, lactoferrin, proteinase inhibitors
	fibronectin catabolic receptor involved in the phagocytosis of apoptotic cells in mammals
	involved in the processes of cell migration and invasion, as well as in the regulation of growth factor homeostasis
	may be involved in cell migration and invasion of the retinal pigment epithelial (RPE) cells
	may facilitate the development and growth of cancer metastases
	playing an unique role in endocytosis of a coagulation protein trafficked to alpha-granules and not destined for lysosomal degradation
	controls both the surface, and biosynthetic, trafficking of PRNP in neurons
	controls signaling pathways involved in cholesterol storage and fatty acid synthesis during adipocyte differentiation
	required for lipolysis and stimulates fatty acid synthesis independently of the noradrenergic pathway, through inhibition of GSK3B and its previously unknown target acetyl-CoA carboxylase
	essential for the maintenance of vascular wall integrity, particularly in the presence of high plasma lipid levels
	integrator of adipogenic differentiation and fat storage signals
	Glucocorticoids-stimulated macrophage uptake of apoptotic cells may involve an upregulation of macrophage LRP1 expression and enhanced LRP1-mediated phagocytosis
	endocytic receptor involved in intracellular signal transduction
	regulates human hepatic stellate cells (HHSCs) proliferation and migration through modulation of ERK1,2 phosphorylation and TGFB extracellular levels
	large endocytic receptor mediating the clearance of various molecules from the extracellular matrix
	is the master regulator of extracellular levels of TIMP3, and regulates ECM catabolism
	LRP1-dependent cell signaling that includes NTRK3 activation promotes axonal growth in the CNS
	LRP1-dependent cell signaling mechanism involved in CNS plasticity and regeneration
	is a large endocytic and signaling receptor that is abundant in vascular smooth muscle cells
	likely a critical role for LRP1 in maintaining the integrity of vessels by regulating protease activity as well as matrix deposition by modulating HTRA1 and connective tissue growth factor protein levels
	assembles unique co-receptor systems to initiate cell signaling in response to tissue-type plasminogen activator and myelin-associated glycoprotein

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

cell to cell transport

PATHWAY

metabolism

signaling

signal transduction

a component

APP/APBB1/LRP1 complex is an important mediator of APP processing and affects beta-amyloid peptide production

INTERACTION

DNA

RNA

small molecule	metal binding,
	Ca2+

protein	binding lipoproteins
	cellular uptake and degradationof beta amyloid peptide (APP)
	FN1
	stimulates a canonical WNT5A signaling pathway that prevents cholesterol accumulation
	interacting with MAFB (ICD co-localizes with MAFB to the nucleus and negatively regulates its transcriptional activity, suggesting a possible role for LRP1 in brain development)
	in Schwann cells, LRP1 activates PI3K/Akt-mediated cell survival signaling pathways and counteracts endoplasmic reticulum stress
	SREBF1 play a role in transcriptional regulation of LRP1
	LRP1 and THBS2 stimulate NOTCH activity by driving trans-endocytosis of the NOTCH ectodomain into the signal-sending cell
	in addition to its role in APP trafficking--LRP1 affects APP processing by competing for cleavage by BACE1
	CTSD is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis
	is an adapter to LRP1 and mediates TGFB1 signaling in signaling-competent early endosomes
	mediates potentially the transcytosis of CTGF, which might be a crucial event that determines the distribution of CTGF in cartilage
	LRP1-mediated internalization of CD44 appeared critical to define the adhesive properties of tumor cells
	dictates physiological and pathological catabolism of aggrecan in cartilage as a key modulator of the extracellular activity of ADAMTS5
	APBB1 might have signalling properties together with APP and LRP1, whereas GULP1 only mediates LRP1 transactivation
	aggregated LDL (agLDL) prolongs the half life of LRP1 by preventing the receptor ubiquitinylation, at least in part, through CHFR targeting
	PCSK9 is capable of inducing degradation of LRP1, the latter is not an essential factor for LDLR regulation, but the LDLR effectively competes with LRP1 for PCSK9 activity
	HTRA1 is a novel LRP1 ligand
	MAG binds to LRP1 with high affinity but failed to induce phosphorylation of NTRK1 or ERK1/2
	LRP1-mediated cardiomyocyte intracellular cholesteryl ester (CE) accumulation alters the structural and physical characteristics of secreted tropoelastin (TE) through an increase in CTSS mature protein level
	mediates clearance of blood coagulation factor VIII (F8)
	F8 interacts likely with LRP1 via an extended surface of multiple lysine residues that starts at the bottom of the C1 domain and winds around the F8 molecule
	PID1 serves as a cytosolic adaptor protein of the LDL receptor-related protein 1 (LRP1)
	PID1 serves as an insulin-regulated retention adaptor protein controlling translocation of LRP1 in conjunction with SLC2A4 to the plasma membrane of adipocytes
	by acting as an insulin-dependent retention adaptor, PID1 serves as a regulator of LRP1 function controlling the disposal of postprandial lipoproteins

cell & other

REGULATION

induced by

dexamethasone induces increased macrophage expression of LRP1, which could be one mechanism behind the phagocytosis-stimulatory effect reported for glucocorticoid in terms of macrophage uptake of apoptotic cells

Other

regulated by phosphorylation

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --low   may be associated with abdominal aortic aneurysm progression

Susceptibility

putative susceptibility factor for Alzheimer disease (see AD5), not confirmed to abdominal aortic aneurysm to sporadic thoracic aortic dissection (STAD)

Variant & Polymorphism SNP	rs1466535, T allele which might disrupt a binding site for SREBF1, located within intron 1 of LRP1 significantly associated to abdominal aortic aneurysm
	SNPs in LRP1 were identified to be significantly associated with STAD

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed neurosensorial     target for therapeutic intervention in proliferative vitreoretinopathy obesity     pharmacological modulation of LRP1 activity might emerge as a novel rational approach for treating diabetes and obesity, as well as atherosclerosis diabete     pharmacological modulation of LRP1 activity might emerge as a novel rational approach for treating diabetes and obesity, as well as atherosclerosis neurology acquired   LRP1 agonists promote regeneration after spinal cord injury

ANIMAL & CELL MODELS

mice with conditional loss of LRP1 in post-mitotic neurons exhibit alterations in brain lipid metabolism, synapse loss, and neurodegeneration