LRP5
Encyclopedia
Low-density lipoprotein receptor-related protein 5 is a protein
that in humans is encoded by the LRP5 gene
.
receptor
that binds and internalizes ligands in the process of receptor-mediated endocytosis
. This protein also acts as a co-receptor with Frizzled
protein family members for transducing signals by Wnt
proteins and was originally cloned on the basis of its association with diabetes mellitus type 1
in humans. This protein plays a key role in skeletal homeostasis.
and SP1. In addition, 5' region region of the LRP5 gene contains four RUNX2
binding sites. Conversely, LRP5 has been claimed to inhibit expression of TPH1
, the rate-limiting biosynthetic enzyme for serotonin
in enterochromaffin cells of the duodenum
and that excess plasma serotonin leads to inhibition in bone. This view is contested by other research indicating a direct effect of LRP5 on bone.
with AXIN1
.
Canonical WNT signals
are transduced through Frizzled
receptor and LRP5/LRP6
coreceptor to downregulate GSK3beta (GSK3B
) activity not depending on Ser-9 phosphorylation
. Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin
degradation.
LRP5 may be essential for the development of retinal vasculature, and may play a role in capillary maturation.
A glial-derived extracellular ligand, Norrin, acts on a transmembrane receptor, Frizzled4
, a coreceptor, Lrp5, and an auxiliary membrane protein, TSPAN12
, on the surface of developing endothelial cells to control a transcriptional program that regulates endothelial growth and maturation.
LRP5 knockout in mice led to increased plasma cholesterol levels on a high-fat diet because of the decreased hepatic clearance of chylomicron
remnants. When fed a normal diet, LRP5-deficient mice showed a markedly impaired glucose tolerance with marked reduction in intracellular ATP
and Ca2+
in response to glucose, and impairment in glucose-induced insulin secretion. IP3 production in response to glucose was also reduced in LRP5-- islets possibly caused by a marked reduction of various transcripts for genes involved in glucose sensing in LRP5-- islets. LRP5-deficient islets lacked the Wnt-3a
-stimulated insulin secretion. These data suggest that WntLRP5 signaling contributes to the glucose-induced insulin secretion in the islets.
In osteoarthritic
chondrocyte
s the Wnt/beta-catenin pathway is activated with a significant up-regulation of beta-catenin mRNA expression. LRP5 mRNA and protein expression are also significantly up-regulated in osteoarthritic cartilage compared to normal cartilage, and LRP5 mRNA expression was further increased by vitamin D
. Blocking LRP5 expression using siRNA
against LRP5 resulted in a significant decrease in MMP13
mRNA and protein expressions. The catabolic
role of LRP5 appears to be mediated by the Wnt/beta-catenin pathway in human osteoarthritis.
The polyphenol curcumin increases the mRNA expression of LRP5.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the LRP5 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Function
LRP5 is a transmembrane low-density lipoproteinLipoprotein
A lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
that binds and internalizes ligands in the process of receptor-mediated endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
. This protein also acts as a co-receptor with Frizzled
Frizzled
Frizzled is a family of G protein-coupled receptor proteins that serve as receptors in the Wnt signaling pathway and other signaling pathways. When activated, Frizzled leads to activation of Dishevelled in the cytosol.-Species distribution:...
protein family members for transducing signals by Wnt
Wnt signaling pathway
The Wnt signaling pathway is a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.-Discovery:...
proteins and was originally cloned on the basis of its association with diabetes mellitus type 1
Diabetes mellitus type 1
Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...
in humans. This protein plays a key role in skeletal homeostasis.
Transcription
The LRP5 promoter contains binding sites for KLF15KLF15
Krüppel-like factor 15 is a protein that in humans is encoded by the KLF15 gene in the Krüppel-like factor family. Its former designation KKLF stands for kidney-enriched Krüppel-like factor.- Expression :...
and SP1. In addition, 5' region region of the LRP5 gene contains four RUNX2
Runx2
Runt-related transcription factor 2 also known as core-binding factor subunit alpha-1 is a protein that in humans is encoded by the RUNX2 gene RUNX2 is a key transcription factor associated with osteoblast differentiation....
binding sites. Conversely, LRP5 has been claimed to inhibit expression of TPH1
TPH1
Tryptophan hydroxylase 1 , also known as TPH1, is an enzyme which in humans is encoded by the TPH1 gene.Until 2003 it was thought that there only was a single TPH gene, but then...
, the rate-limiting biosynthetic enzyme for serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
in enterochromaffin cells of the duodenum
Duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...
and that excess plasma serotonin leads to inhibition in bone. This view is contested by other research indicating a direct effect of LRP5 on bone.
Interactions
LRP5 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with AXIN1
AXIN1
Axin-1 is a protein that in humans is encoded by the AXIN1 gene.-Interactions:AXIN1 has been shown to interact with Beta-catenin, GSK3B, TSC2, APC, LRP5, DVL1, MAP3K1, CSNK1E, Casein kinase 1, alpha 1 and PPP2R5A.-Further reading:...
.
Canonical WNT signals
Wnt signaling pathway
The Wnt signaling pathway is a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.-Discovery:...
are transduced through Frizzled
Frizzled
Frizzled is a family of G protein-coupled receptor proteins that serve as receptors in the Wnt signaling pathway and other signaling pathways. When activated, Frizzled leads to activation of Dishevelled in the cytosol.-Species distribution:...
receptor and LRP5/LRP6
LRP6
Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene....
coreceptor to downregulate GSK3beta (GSK3B
GSK3B
Glycogen synthase kinase 3 beta, also known as GSK3B, is an enzyme that in humans is encoded by the GSK3B gene.- Function :Glycogen synthase kinase-3 is a proline-directed serine-threonine kinase that was initially identified as a phosphorylating and inactivating glycogen synthase. Two isoforms,...
) activity not depending on Ser-9 phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
. Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin
Catenin
Catenins are proteins found in complexes with cadherin cell adhesion molecules of animal cells. The first two catenins that were identified became known as alpha-catenin and beta-catenin. Alpha-catenin can bind to beta-catenin and can also bind actin. Beta-catenin binds the cytoplasmic domain of...
degradation.
Clinical Significance
Many bone density related diseases are caused by mutations in the LRP5 gene. Mutations in this gene also cause familial exudative vitreoretinopathy.LRP5 may be essential for the development of retinal vasculature, and may play a role in capillary maturation.
A glial-derived extracellular ligand, Norrin, acts on a transmembrane receptor, Frizzled4
FZD4
Frizzled-4 is a protein that in humans is encoded by the FZD4 gene. FZD4 has also been designated as CD344 .-External links:]*...
, a coreceptor, Lrp5, and an auxiliary membrane protein, TSPAN12
TSPAN12
TSPAN12, also known as NET-2 or TM4SF12 is a tetraspanin protein that is found in the membrane of a variety of cells. It has an unusually long C-terminal intracellular tail of approximately 60 amino acids.-Function:...
, on the surface of developing endothelial cells to control a transcriptional program that regulates endothelial growth and maturation.
LRP5 knockout in mice led to increased plasma cholesterol levels on a high-fat diet because of the decreased hepatic clearance of chylomicron
Chylomicron
Chylomicrons are lipoprotein particles that consist of triglycerides , phospholipids , cholesterol and proteins .They transport dietary lipids from the intestines to other locations in the body...
remnants. When fed a normal diet, LRP5-deficient mice showed a markedly impaired glucose tolerance with marked reduction in intracellular ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
and Ca2+
Calcium in biology
Calcium plays a pivotal role in the physiology and biochemistry of organisms and the cell. It plays an important role in signal transduction pathways, where it acts as a second messenger, in neurotransmitter release from neurons, contraction of all muscle cell types, and fertilization...
in response to glucose, and impairment in glucose-induced insulin secretion. IP3 production in response to glucose was also reduced in LRP5-- islets possibly caused by a marked reduction of various transcripts for genes involved in glucose sensing in LRP5-- islets. LRP5-deficient islets lacked the Wnt-3a
WNT3A
Protein Wnt-3a is a protein that in humans is encoded by the WNT3A gene.-Further reading:...
-stimulated insulin secretion. These data suggest that WntLRP5 signaling contributes to the glucose-induced insulin secretion in the islets.
In osteoarthritic
Osteoarthritis
Osteoarthritis also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion...
chondrocyte
Chondrocyte
Chondrocytes are the only cells found in cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans...
s the Wnt/beta-catenin pathway is activated with a significant up-regulation of beta-catenin mRNA expression. LRP5 mRNA and protein expression are also significantly up-regulated in osteoarthritic cartilage compared to normal cartilage, and LRP5 mRNA expression was further increased by vitamin D
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
. Blocking LRP5 expression using siRNA
Small interfering RNA
Small interfering RNA , sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA molecules, 20-25 nucleotides in length, that play a variety of roles in biology. The most notable role of siRNA is its involvement in the RNA interference pathway, where it...
against LRP5 resulted in a significant decrease in MMP13
Matrix metallopeptidase 13
Collagenase 3 is an enzyme that in humans is encoded by the MMP13 gene. It is a member of the matrix metalloproteinase family. Like most MMPs it secreated as an inactive pro-form. It is activated once the pro-domain is cleaved, leaving an active enzyme composed of the catalytic domain and the...
mRNA and protein expressions. The catabolic
Catabolism
Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, lipids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides, and amino...
role of LRP5 appears to be mediated by the Wnt/beta-catenin pathway in human osteoarthritis.
The polyphenol curcumin increases the mRNA expression of LRP5.