Urokinase receptor
Encyclopedia
The Urokinase receptor, also known as uPA
receptor or uPAR or CD87 (Cluster of Differentiation 87), is multidomain glycoprotein
tethered to the cell membrane
with a glycosylphosphotidylinositol (GPI) anchor. uPAR was originally identified as a saturable binding site for urokinase on the cell surface.
s and S2
cells from Drosophila melanogaster
. 4 out of 5 of the possible glycosylation
sites are used in vivo giving the protein
a molecular weight of 50-60 kDA. Recently the structure of uPAR was solved by X-ray crystallography
in complex with an peptide
antagonist
and with its native ligand, urokinase.
Besides the primary ligand
urokinase
, uPAR interacts with several other proteins, among others: vitronectin
, the uPAR associated protein (uPARAP
) and the integrin
family of membrane proteins.
involution and wound healing
. In order to be able to reorganize tissue it is important, that the old tissue can be degraded. An important mechanism in this degradation is the proteolysis
cascade initiated by the plasminogen activation system. uPAR binds urokinase
and thus restricts plasminogen activation to the immediate vicinity of the cell membrane
. Thus uPAR seems to be an important player in the regulation of this process.
However the components of the plasminogen activation system have been found to be highly expressed in many malignant
tumor
s, indicating that tumors are able to hijack the system, and use it in metastasis
. Thus inhibitor
s of the various components of the plasminogen activation system has been sought as possible anticancer drugs.
uPAR has been involved in various other non-proteolytical processes related to cancer, such as cell migration
, cell cycle
regulation and cell adhesion.
When uPA is bound to the receptor, there is cleavage between the GPI-anchor and the uPAR, releasing suPAR
.
with LRP1
.
Urokinase
Urokinase , also called urokinase-type plasminogen activator , is a serine protease . Urokinase was originally isolated from human urine, but is present in several physiological locations, such as blood stream and the extracellular matrix...
receptor or uPAR or CD87 (Cluster of Differentiation 87), is multidomain glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
tethered to the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
with a glycosylphosphotidylinositol (GPI) anchor. uPAR was originally identified as a saturable binding site for urokinase on the cell surface.
Molecular characteristics
uPAR consists of three different domains of the Ly-6/uPAR/alpha-neurotoxin family. All three domains are necessary for high affinity binding of the primary ligand, urokinase. It has been possible to express uPAR recombinantly in CHO-cellChinese Hamster Ovary cell
Chinese hamster ovary cells are a cell line derived from the ovary of the Chinese hamster. They are often used in biological and medical research and commercially in the production of therapeutic proteins. They were introduced in the 1960s and grow as a cultured monolayer...
s and S2
S2
-In the military:*S-2 , a military intelligence officer* Soviet submarine S-2, a Soviet World War II submarine* Grumman S-2 Tracker, a US Navy aircraft* Finnish torpedo boat S2, which sank in 1925* USS S-2 , a US Navy submarine...
cells from Drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
. 4 out of 5 of the possible glycosylation
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
sites are used in vivo giving the protein
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...
a molecular weight of 50-60 kDA. Recently the structure of uPAR was solved by X-ray crystallography
X-ray crystallography
X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread into many specific directions. From the angles and intensities of these diffracted beams, a crystallographer can produce a...
in complex with an peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
and with its native ligand, urokinase.
Besides the primary ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
urokinase
Urokinase
Urokinase , also called urokinase-type plasminogen activator , is a serine protease . Urokinase was originally isolated from human urine, but is present in several physiological locations, such as blood stream and the extracellular matrix...
, uPAR interacts with several other proteins, among others: vitronectin
Vitronectin
Vitronectin also known as VTN is a protein that in humans is encoded by the VTN gene.The protein encoded by this gene is a member of the pexin family...
, the uPAR associated protein (uPARAP
UPARAP
uPARAP, also known as Endo180, is a membrane protein involved in turnover of extracellular matrix. The name is an acronym for urokinase-type Plasminogen Activator Receptor Associated Protein...
) and the integrin
Integrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
family of membrane proteins.
Physiological significance
uPAR is a part of the plasminogen activation system, which in the healthy body is involved in tissue reorganization events such as mammary glandMammary gland
A mammary gland is an organ in mammals that produces milk to feed young offspring. Mammals get their name from the word "mammary". In ruminants such as cows, goats, and deer, the mammary glands are contained in their udders...
involution and wound healing
Wound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
. In order to be able to reorganize tissue it is important, that the old tissue can be degraded. An important mechanism in this degradation is the proteolysis
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
cascade initiated by the plasminogen activation system. uPAR binds urokinase
Urokinase
Urokinase , also called urokinase-type plasminogen activator , is a serine protease . Urokinase was originally isolated from human urine, but is present in several physiological locations, such as blood stream and the extracellular matrix...
and thus restricts plasminogen activation to the immediate vicinity of the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
. Thus uPAR seems to be an important player in the regulation of this process.
However the components of the plasminogen activation system have been found to be highly expressed in many malignant
Malignant
Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...
tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
s, indicating that tumors are able to hijack the system, and use it in metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
. Thus inhibitor
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
s of the various components of the plasminogen activation system has been sought as possible anticancer drugs.
uPAR has been involved in various other non-proteolytical processes related to cancer, such as cell migration
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
, cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
regulation and cell adhesion.
When uPA is bound to the receptor, there is cleavage between the GPI-anchor and the uPAR, releasing suPAR
SuPAR
suPAR, soluble urokinase-type plasminogen activator receptor, is the soluble form of uPAR. uPAR is a membrane bound receptor for uPA, otherwise known as urokinase. suPAR results from the cleavage and release of membrane-bound uPAR...
.
Interactions
Urokinase receptor 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 LRP1
LRP1
Low density lipoprotein receptor-related protein 1 , also known as alpha-2-macroglobulin receptor , apolipoprotein E receptor or cluster of differentiation 91 , is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis...
.
See also
- CancerCancerCancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
- Cluster of differentiationCluster of differentiationThe cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on white blood cells, providing targets for immunophenotyping of cells...
- MetastasisMetastasisMetastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
- PlasminPlasminPlasmin is an important enzyme present in blood that degrades many blood plasma proteins, most notably, fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein is encoded by the PLG gene.- Function :...
- Plasminogen activation system
- UrokinaseUrokinaseUrokinase , also called urokinase-type plasminogen activator , is a serine protease . Urokinase was originally isolated from human urine, but is present in several physiological locations, such as blood stream and the extracellular matrix...
- suPARSuPARsuPAR, soluble urokinase-type plasminogen activator receptor, is the soluble form of uPAR. uPAR is a membrane bound receptor for uPA, otherwise known as urokinase. suPAR results from the cleavage and release of membrane-bound uPAR...