Low Density Lipoprotein Receptor-related Protein 8
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Low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2), is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''LRP8''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. ApoER2 is a
cell surface receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integra ...
that is part of the low-density lipoprotein receptor family. These receptors function in signal transduction and endocytosis of specific ligands. Through interactions with one of its ligands,
reelin Reelin, encoded by the ''RELN'' gene, is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this importa ...
, ApoER2 plays an important role in embryonic neuronal migration and postnatal
long-term potentiation In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neuron ...
. Another LDL family receptor,
VLDLR The very-low-density-lipoprotein receptor (VLDLR) is a transmembrane lipoprotein receptor of the low-density-lipoprotein (LDL) receptor family. VLDLR shows considerable homology with the members of this lineage. Discovered in 1992 by Tokuo. Yama ...
, also interacts with reelin, and together these two receptors influence brain development and function. Decreased expression of ApoER2 is associated with certain neurological diseases.


Structure

ApoER2 is a protein made up of 870 amino acids. It is separated into a ligand binding domain of eight ligand binding regions, an
EGF-like domain The EGF-like domain is an evolutionary conserved protein domain, which derives its name from the epidermal growth factor where it was first described. It comprises about 30 to 40 amino-acid residues and has been found in a large number of most ...
containing three
cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...
-rich repeats, an O-linked
glycosylation Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
domain of 89 amino acids, a transmembrane domain of 24 amino acids, and a cytoplasmic domain of 115 amino acids, including an NPXY motif. Each letter in the NPXY motif represents a certain amino acid where N is
arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...
, P is
proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...
, X is any amino acid, and Y is
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...
.


Cytoplasmic tail

All LDL receptor family proteins contain a cytoplasmic tail with at least one NPXY motif. This motif is important for binding intracellular adapter proteins and
endocytosis Endocytosis is a cellular process in which Chemical substance, substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a Vesicle (biology and chem ...
. ApoER2 is distinct from most other members of the LDL family of receptors due to a unique insert on its cytoplasmic tail. In ApoER2, there is a proline-rich 59 amino acid insert encoded by the alternatively spliced exon 19. This insert allows for protein interactions that are unable to occur with other
LDL receptor The low-density lipoprotein receptor (LDL-R) is a mosaic protein of 839 amino acids (after removal of 21-amino acid signal peptide) that mediates the endocytosis of cholesterol-rich low-density lipoprotein (LDL). It is a cell-surface receptor ...
s. It binds the
PSD-95 PSD-95 (postsynaptic density protein 95) also known as SAP-90 (synapse-associated protein 90) is a protein that in humans is encoded by the ''DLG4'' (discs large homolog 4) gene. PSD-95 is a member of the membrane-associated guanylate kinase (MA ...
adapter protein, cross-linking ApoER2 and the
NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...
s during the process of
long-term potentiation In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neuron ...
, and is also bound specifically by JIP-2, an important interaction in the
JNK c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are r ...
signalling pathway. It is also speculated that this insert may diminish the function of ApoER2 in
lipoprotein A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, sur ...
endocytosis by somehow disrupting the NPXY motif.


Function


Reelin/Dab1 signalling pathway

ApoER2 plays a critical role as a receptor in the reelin signalling pathway, which is important for brain development and postnatal function of the brain. This pathway specifically affects cortical migration and long-term potentiation.


Cortical migration

In development, reelin is secreted by Cajal-Retzius cells. Reelin acts as an extracellular ligand binding to ApoER2 and VLDLR on migrating neurons. A specific lysine residue on reelin binds to the first repeat on the ligand binding domain of ApoER2. This interaction with the two receptors activates intracellular processes that begin with the phosphorylation of Dab1, a tyrosine kinase phosphorylated protein which is encoded by the
DAB1 The Disabled-1 (Dab1) gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. DAB1 functions downstream of Reln in a signaling pathway that c ...
gene. This protein associates with the NPXY motifs on the intracellular tails of ApoER2 and VLDLR. Upon reelin binding, Dab1 is phosphorylated by two
tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...
s,
Fyn Proto-oncogene tyrosine-protein kinase Fyn (p59-FYN, Slk, Syn, MGC45350, Gene ID 2534) is an enzyme that in humans is encoded by the ''FYN'' gene. Fyn is a 59-kDa member of the Src family of kinases typically associated with T-cell and neurona ...
and Src. The phosphorylated Dab1 then causes further activation of these two kinases and others, including a phosphatidylinositol-3-kinase (PI3K). PI3K activation leads to inhibitory phosphorylation of the tau kinase glycogen synthase kinase 3 beta (
GSK3B Glycogen synthase kinase-3 beta, (GSK-3 beta), is an enzyme that in humans is encoded by the ''GSK3B'' gene. In mice, the enzyme is encoded by the Gsk3b gene. Abnormal regulation and expression of GSK-3 beta is associated with an increased susce ...
), which alters the activity of tau protein, a protein involved in stabilizing microtubules. This transduction is combined with the activation of other pathways that influence the cytoskeletal rearrangement necessary for proper cortical cell migration. The result of proper neuronal migration through the
cortical plate The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of neural integration in the central nervous system, and plays a key ...
(CP) is an inside-out arrangement of neurons, where the younger neurons migrate past the older neurons to their proper locations. Studies in
reeler A reeler is a mouse mutant, so named because of its characteristic "reeling" gait. This is caused by the profound underdevelopment of the mouse's cerebellum, a segment of the brain responsible for locomotion. The mutation is autosomal and rece ...
mutant mice show that knocking out the ''reeler'' gene results in aberrant migration as well as outside-in layering, in which younger neurons are unable to travel past the older ones. Such abnormal layering is also seen in ''VLDLR''−''apoER2''− and ''dab1''- mutants, indicating the importance of this entire pathway in cortical migration of the developing embryo. There is some confusion as to the exact function of the reelin-signalling pathway in the process of cortical migration. Some studies have shown that reelin release is necessary for the initiation of cell movement to its proper location, whereas others have shown that it is part of the process of terminating migration. These conflicting results have led researchers to speculate that it plays a role in both processes through interactions with different molecules at different stages of
neuronal migration The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The field ...
.


Long-term potentiation

After development, reelin is secreted in the
cortex Cortex or cortical may refer to: Biology * Cortex (anatomy), the outermost layer of an organ ** Cerebral cortex, the outer layer of the vertebrate cerebrum, part of which is the ''forebrain'' *** Motor cortex, the regions of the cerebral cortex i ...
and
hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...
by gamma-aminobutyric acid-ergic interneurons. Through binding of ApoER2 in the hippocampus, it plays a role in the
NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...
activation that is required for long-term potentiation, a mechanism by which two neurons gain a stronger, longer-lasting transmission due to simultaneous firing. The increased
synaptic plasticity In neuroscience, synaptic plasticity is the ability of synapses to Chemical synapse#Synaptic strength, strengthen or weaken over time, in response to increases or decreases in their activity. Since memory, memories are postulated to be represent ...
associated with this process is essential in development of memory and spatial learning. Studies with mice have shown less expression of ApoER2 leads to impaired spatial learning, fear conditioned learning, and a mild disruption to the hippocampus. In the hippocampus, ApoER2 is complexed with NMDA receptors through the
PSD-95 PSD-95 (postsynaptic density protein 95) also known as SAP-90 (synapse-associated protein 90) is a protein that in humans is encoded by the ''DLG4'' (discs large homolog 4) gene. PSD-95 is a member of the membrane-associated guanylate kinase (MA ...
adapter protein. When reelin binds ApoER2, it initiates tyrosine phosphorylation of NMDA receptors. This occurs through Dab-1 activation of
Src family kinase Src kinase family is a family of non-receptor tyrosine kinases that includes nine members: Src (gene), Src, YES1, Yes, FYN, Fyn, and FGR (gene), Fgr, forming the SrcA subfamily, Lck, HCK, Hck, Tyrosine-protein kinase BLK, Blk, and Lyn (Src fam ...
s, which have been shown to play a role in regulating synaptic plasticity. VLDLR also acts as a receptor coupled to ApoER2 as it does during development, but its role is not well understood. ApoER2 plays a more important role in this process, most likely due to its ability to bind the PSD-95 adapter protein through the 59 amino acid insert on its cytoplasmic tail. Studies with mice have shown that knocking out ApoER2 or just the alternatively spliced exon 19 causes a much greater impairment of LTP than knocking out VLDLR.


Other interacting proteins


Apolipoprotein E

Apolipoprotein E Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene ''APOE''. Apo-E belongs to a family ...
(ApoE) plays an important role in phospholipid and cholesterol homeostasis. After binding ApoER2, ApoE is taken up into the cell and may remain in the intracellular space, be shipped to the cell surface, or be degraded. ApoE binding leads to the cleavage of ApoER2 into secreted proteins by the actions of the plasma membrane protein
gamma secretase Gamma secretase is a multi-subunit protease complex, an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases. The most ...
. ApoE may be the signalling ligand responsible for ApoER2's role in modulating the
JNK c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are r ...
signalling pathway.


FE65

FE65 is an intracellular protein that binds to the NPXY motif of ApoER2 and plays a role in linking other proteins, such as
amyloid precursor protein Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many biological tissue, tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of s ...
, to ApoER2. This protein aids in a cell's migrational functions.
Knockout A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, Muay Thai, mixed martial arts, karate, some forms of taekwondo and other sports involving striking, ...
studies of FE65 have shown a link to
lissencephaly Lissencephaly (, meaning 'smooth brain') is a set of rare brain disorders whereby the whole or parts of the surface of the brain are smooth. It is caused by defective neuronal migration during the 12th to 24th weeks of gestation, resulting in a ...
.


JIP1 and JIP2

JIP1 and JIP2 are involved in the JNK-signaling pathway and interact with exon 19 of ApoER2. For JIP2, interaction with exon 19 of ApoER2 is through the PID domain. This interaction has led researchers to believe that ApoER2 is involved in many interactions at the surface of cells.


Selenoprotein P

Selenoprotein P In molecular biology, the protein domain selenoprotein P (SelP) is the only known eukaryotic selenoprotein that contains multiple selenocysteine (Sec) residues. It is a secreted glycoprotein, often found in the plasma. Its precise function rema ...
transports the trace element
selenium Selenium is a chemical element; it has symbol (chemistry), symbol Se and atomic number 34. It has various physical appearances, including a brick-red powder, a vitreous black solid, and a grey metallic-looking form. It seldom occurs in this elem ...
from the liver to the testes and brain, and binds to ApoER2 in these areas. ApoER2 functions to internalize this complex to maintain normal levels of selenium in these cells. Selenium is necessary in the testes for proper spermatozoa development. Mice that have had their ApoER2 or Selenoprotein P expression knocked out show impaired spermatozoa development and decreased fertility. In the brain, deficiencies in selenium and selenium uptake mechanisms result in brain damage.


Thrombospondin and F-spondin

Thrombospondin Thrombospondins (TSPs) are a family of secreted glycoproteins with antiangiogenic functions. Due to their dynamic role within the extracellular matrix they are considered matricellular proteins. The first member of the family, thrombospondin 1 ...
is a protein found in the
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...
that competes with reelin to bind ApoER2. It is involved with cell-to-cell communication and migration of neurons, and causes the activation of Dab1. F-spondin is a secreted protein that also binds ApoER2 and leads to phosphorylation of Dab1.


Clinical significance


Alzheimer's disease

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
is the most common form of dementia, and studies have shown that manipulation of pathways involving LRP8/ApoER2 can lead to the disease. Certain
allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...
s, such as
apoe Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene ''APOE''. Apo-E belongs to a family ...
, app, ps1 and
ps2 The PlayStation 2 (PS2) is a home video game console developed and marketed by Sony Computer Entertainment. It was first released in Japan on 4 March 2000, in North America on 26 October, in Europe on 24 November, in Australia on 30 November, ...
, may lead to being genetically predisposed to the disease. A decrease in LRP8 expression is observed in patients with Alzheimer's disease. An example of a decrease in expression of LRP8 is when
gamma secretase Gamma secretase is a multi-subunit protease complex, an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases. The most ...
cleaves LRP8 as well as the ligand
amyloid precursor protein Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many biological tissue, tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of s ...
(APP). The degradation products control transcription factors, which lead to the expression of a
tau protein The tau proteins (abbreviated from tubulin associated unit) form a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintainin ...
. The cascade dysfunction caused by the altered gene expression may be implicated with Alzheimer's disease. The presence of
amyloid beta Amyloid beta (Aβ, Abeta or beta-amyloid) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor prot ...
(Aβ) protein deposits in neuronal extracellular space is one of the hallmarks of Alzheimer's disease. The role of ApoER2 in Alzheimer's disease is relevant, yet incompletely understood. New evidence suggests ApoER2 plays a major role in the regulation of amyloid-β formation in the brain. The amyloid-β peptide is derived from the cleavage of APP by gamma secretase. ApoER2 works to reduce APP trafficking by altering break down. This interaction decreases APP
endocytosis Endocytosis is a cellular process in which Chemical substance, substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a Vesicle (biology and chem ...
leading to an increase in amyloid-β production. In addition, the expression of ApoER2 within intracellular compartments leads to increased gamma secretase activity, a protease which works to cleave APP into Aβ. ApoER2 splice variants can act as a receptor for
alpha-2-macroglobulin α2-Macroglobulin (α2M) or alpha-2-macroglobulin is a large (720 KDa) plasma protein found in the blood. It is mainly produced by the liver, and also locally synthesized by macrophages, fibroblasts, and adrenocortical cells. In humans it is en ...
which can have a role in clearance of alpha-2-macroglobulin/proteinase complex.
Protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...
s may play a role in
synaptic plasticity In neuroscience, synaptic plasticity is the ability of synapses to Chemical synapse#Synaptic strength, strengthen or weaken over time, in response to increases or decreases in their activity. Since memory, memories are postulated to be represent ...
balancing proteolytic activity and inhibition, which is controlled by proteolytic inhibitors such as alpha-2-macroglobulin. Studies have shown that a high presence of alpha-2-macroglobulin is present in the neuritic plaques in many Alzheimer patients. Isolation of
cDNA In genetics, complementary DNA (cDNA) is DNA that was reverse transcribed (via reverse transcriptase) from an RNA (e.g., messenger RNA or microRNA). cDNA exists in both single-stranded and double-stranded forms and in both natural and engin ...
encoding proteins associated with Aβ was used to discover alpha-2-macroglobulin. These discoveries may link alpha-2-macroglobulin and its receptors, one of them being ApoER2, to Alzheimer's disease. ApoER2 interaction with reelin and ApoE has implications with Alzheimer's disease. Binding of reelin to ApoER2 leads to cascade of signals that modulate
NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...
functions. ApoE competes with reelin in binding to ApoER2 resulting in weakened reelin signaling. Reduced reelin signaling leads to impaired plasticity in neurons and increases in the
phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...
of tau protein, which is a
microtubule Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nanometer, nm and have an inner diameter bet ...
stabilizing protein that is abundant in the
Central Nervous System The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
(CNS), producing
neurofibrillary tangles Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary Biomarker (medicine), biomarker of Alzheimer's disease. Their presence is also found in numerous other disea ...
which are implicated in Alzheimer's disease.


Antiphospholipid syndrome

Antiphospholipid syndrome Antiphospholipid syndrome, or antiphospholipid antibody syndrome (APS or APLS), is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS can lead to blood clots (thrombosis) in both arteries and veins, pregnancy-relate ...
is an
autoimmune disease An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
characterized by
thrombosis Thrombosis () is the formation of a Thrombus, blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thrombocytes) and fib ...
and complications during pregnancy, often leading to
fetal death Perinatal mortality (PNM) is the death of a fetus or neonate and is the basis to calculate the perinatal mortality rate. ''Perinatal'' means "relating to the period starting a few weeks before birth and including the birth and a few weeks after bi ...
. It is caused by the presence of
antibodies An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...
against anionic
phospholipid Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
s and β2-glycoprotein I (β2GPI). The anti-β2GPI antibodies are most prevalent in causing the
symptom Signs and symptoms are diagnostic indications of an illness, injury, or condition. Signs are objective and externally observable; symptoms are a person's reported subjective experiences. A sign for example may be a higher or lower temperature ...
s of the disease. When bound by an antibody, β2GPI begins to interact with
monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
s,
endothelial cells The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the res ...
, and
platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...
s. ApoER2 is thought to play a key role in the process of platelet binding. β2GPI has the proper binding site for interaction with ApoER2 and other LDL family receptors, and it is speculated that the antibody/β2GPI complexes interact with ApoER2 on platelets. This causes the phosphorylation of a p38MAPkinase, resulting in the production of
thromboxane A2 Thromboxane A2 (TXA2) is a type of thromboxane that is produced by activated platelets during hemostasis and has prothrombotic properties: it stimulates activation of new platelets as well as increases platelet aggregation. This is achieved by a ...
. Thromboxane A2 functions to activate more platelets, and this leads to a greater chance for
blood clots A thrombus ( thrombi) is a solid or semisolid aggregate from constituents of the blood (platelets, fibrin, red blood cells, white blood cells) within the circulatory system during life. A blood clot is the final product of the blood coagulati ...
to form. There is also speculation that the antibody/β2GPI complexes sensitize other cell types through various LDL family receptors to lead to less common symptoms other than thrombosis.


Cancer

ApoER2 has been found to promote
ferroptosis Ferroptosis (also known as oxytosis) is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides. Ferroptosis is biochemically, genetically, and morphologically distinct from other forms of regulat ...
resistance in
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
. Loss of ApoER2 results in insufficient selenium levels, leading to failed translation of the key ferroptosis regulator and selenoprotein
GPX4 Glutathione peroxidase 4, also known as GPX4, is an enzyme that in humans is encoded by the ''GPX4'' gene. GPX4 is a phospholipid hydroperoxidase that protects cells against membrane lipid peroxidation. Discovery GPX4 was first discovered in ...
.


Major depressive disorder

Reduced expression of ApoER2 in peripheral blood lymphocytes can contribute to
major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...
(MDD) in some patients. Major depressive disorder is the most common psychiatric disorder, where people show symptoms of low self-esteem and a loss of interest in pleasure. By studying the levels of ApoER2
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
, low levels of ApoER2 were discovered. Results from experiments have shown that this could be because of transcriptional alterations in lymphocytes. However, low levels of ApoER2 do not appear to correlate with the severity or duration of the disease. It only aids as a trait marker in identification of the disease. The impact of the low levels of ApoER2 mRNA function relating to the disease remains unknown.


References


Further reading

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External links


Are You reelin in the Years? Not without Alternative Splicing
{{Good article Low-density lipoprotein receptor gene family Receptors