SERPINF1
Encyclopedia
Pigment epithelium-derived factor (PEDF) also known as serpin F1 (SERPINF1), is a multifunctional secreted 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...

 that has anti-angiogenic
Angiogenesis inhibitor
An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels . Some angiogenesis inhibitors are a normal part of the body's control, some are administered as drugs, and some come from diet....

, anti-tumorigenic
Carcinogenesis
Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...

, and neurotrophic functions. Found in vertebrates, this 50 kDa protein holds promise in the treatment of such conditions as choroidal neovascularization
Choroidal neovascularization
Choroidal neovascularization is the creation of new blood vessels in the choroid layer of the eye. This is a common symptom of the degenerative maculopathy wet AMD .-Causes:...

, heart disease
Heart disease
Heart disease, cardiac disease or cardiopathy is an umbrella term for a variety of diseases affecting the heart. , it is the leading cause of death in the United States, England, Canada and Wales, accounting for 25.4% of the total deaths in the United States.-Types:-Coronary heart disease:Coronary...

, and cancer
Cancer
Cancer , 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...

. In humans, pigment epithelium-derived factor is encoded by the SERPINF1 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...

.

Discovery

Pigment epithelium-derived factor (PEDF) was originally discovered by Joyce Tombran-Tink and Lincoln Johnson in the late 1980s. This group was studying human retinal cell
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...

 development by identifying secreted factors produced by the retinal pigmented epithelium (RPE), a layer of cells that supports the retina. Upon noticing RPE produced a factor that promoted the differentiation of primitive retinal cells into cells of a neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

al phenotype, they set out to determine the identity of the factor. They isolated proteins unique to RPE cells and tested the individual proteins for neurotrophic function, meaning promoting a neuronal phenotype. A neurotrophic protein around 50 kilodaltons (kDa) was identified and temporarily named RPE-54 before being officially termed pigment epithelium-derived factor.

Soon thereafter, the same laboratory sequenced the PEDF protein and compared it to a human fetal eye library
Library (biology)
In molecular biology, a library is a collection of DNA fragments that is stored and propagated in a population of micro-organisms through the process of molecular cloning...

. They found that PEDF was a previously uncharacterized protein and a member of the serpin
Serpin
Serpins are a group of proteins with similar structures that were first identified as a set of proteins able to inhibit proteases. The acronym serpin was originally coined because many serpins inhibit chymotrypsin-like serine proteases .The first members of the serpin superfamily to be extensively...

 (serine protease inhibitor) family.

Gene

The 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...

 encoding human PEDF was localized to the 17th chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...

 at position 17p13.1. The human PEDF gene is around 15.6kb, and the mRNA transcript is around 1.5kb. Immediately upstream of the PEDF gene lies a 200bp promoter region with putative binding sites for the transcription factors HNF4
Hnf4
HNF4 is a nuclear receptor protein mostly expressed in the liver, gut, kidney, and pancreatic beta cells that is critical for liver development...

, CHOP
CEBPE
CCAAT/enhancer binding protein , epsilon, also known as CEBPE and CHOP, is a type of ccaat-enhancer-binding protein. CEBPE is its human gene. It is pro-apoptotic....

, and USF
USF1
Upstream stimulatory factor 1 is a protein that in humans is encoded by the USF1 gene.-Interactions:USF1 has been shown to interact with USF2, FOSL1 and GTF2I.-External links:...

. The PEDF gene consists of 8 exons and 7 introns.

The PEDF gene is present in vertebrates from human to fish, but not present in sea squirts, worms, or fruit flies. Sea squirts express several serpin genes, suggesting that the PEDF gene may have arose from another serpin family member after the evolution of vertebral animals. The gene most homologous to PEDF is its adjacent neighbor on chromosome 17, SerpinF2.

Protein

The PEDF protein is a secreted protein of roughly 50kDa size and 418 amino acids in length. The N-terminus contains a leader sequence responsible for protein secretion out of the cell at residues
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

 1-19. A 34-mer fragment of PEDF (residues 24-57) was shown to have antiangiogenic properties
Angiogenesis inhibitor
An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels . Some angiogenesis inhibitors are a normal part of the body's control, some are administered as drugs, and some come from diet....

, and a 44-mer (residues 58-101) was shown to have neurotrophic properties. A BLAST
BLAST
In bioinformatics, Basic Local Alignment Search Tool, or BLAST, is an algorithm for comparing primary biological sequence information, such as the amino-acid sequences of different proteins or the nucleotides of DNA sequences...

 search reveals a putative receptor binding site exists between residues 75-124. A nuclear localization sequence (NLS) exists about 150 amino acids into the protein. The additional molecular weight is partly due to a single 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...

 site at residue 285. Near the C-terminus at residues 365-390 lies the reactive center loop (RCL) which is normally involved in serine protease inhibitor activity; however, in PEDF this region does not retain the inhibitory function.

In 2001, the crystal structure
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...

 of PEDF was successfully generated. The PEDF structure includes 3 beta sheets and 10 alpha helices. This discovery demonstrated that PEDF has an asymmetrical charge distribution across the whole protein. One side of the protein is heavily basic and the other side is heavily acidic, leading to a polar 3-D structure. They proposed that the basic side of the protein contains a heparin binding site.

Signaling

PEDF expression is upregulated by plasminogen kringle domain
Kringle domain
Kringle Domains are autonomous protein domains that fold into large loops stabilized by 3 disulfide linkages. These are important in protein-protein interactions with blood coagulation factors...

s 1-4 (also known as angiostatin
Angiostatin
Angiostatin is a naturally occurring protein found in several animal species, including humans. It is an endogenous angiogenesis inhibitor , and it is currently undergoing clinical trials for its use in anticancer therapy.-Structure:Angiostatin is a 38 kDa fragment of a larger protein, plasmin ...

) and the kringle 5 (K5) domain. Hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...

, or low oxygen conditions, leads to the downregulation of PEDF. This effect is due to the fact that hypoxic conditions cause matrix metalloproteinase
Matrix metalloproteinase
Matrix metalloproteinases are zinc-dependent endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs belong to a larger family of proteases known as the metzincin superfamily....

s (MMPs) to proteolytically degrade PEDF. In addition, amyloid beta
Amyloid beta
Amyloid beta is a peptide of 36–43 amino acids that is processed from the Amyloid precursor protein. While it is most commonly known in association with Alzheimer's disease, it does not exist specifically to cause disease...

 has been shown to decrease PEDF mRNA levels.

Secreted PEDF binds a receptor on the cell surface termed PEDF-R
PNPLA2
Patatin-like phospholipase domain-containing protein 2 is an enzyme that in humans is encoded by the PNPLA2 gene.-Further reading:...

. PEDF-R has phospholipase A2
Phospholipase A2
Phospholipases A2 are enzymes that release fatty acids from the second carbon group of glycerol. This particular phospholipase specifically recognizes the sn-2 acyl bond of phospholipids and catalytically hydrolyzes the bond releasing arachidonic acid and lysophospholipids...

 activity which liberates fatty acids from glycerol. PEDF enhances gamma-secretase
Gamma secretase
Gamma secretase is a multi-subunit protease complex, itself 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...

 activity, leading to the cleavage of the VEGF receptor 1 (VEGFR-1) transmembrane domain. This action interferes with VEGF signaling thereby inhibiting angiogenesis. Laminin receptor is also a target for PEDF, and the interaction occurs between residues 24-57 of PEDF, a region known to regulate antiangiogenic function.

PEDF induces PPAR-gamma
Peroxisome proliferator-activated receptor gamma
Peroxisome proliferator-activated receptor gamma , also known as the glitazone receptor, or NR1C3 is a type II nuclear receptor that in humans is encoded by the PPARG gene.Two isoforms of PPARG are detected in the human and in the mouse: PPAR-γ1 and...

 expression which in turn induces p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...

, a tumor suppressor gene involved in 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 apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

. Thrombospondin
Thrombospondin
Thrombospondins are secreted proteins with antiangiogenic abilities. TSP was discovered by Nancy L. Baenziger.-Types:The thrombospondins are a family of multifunctional proteins...

, an antiangiogenic protein, is upregulated by PEDF. PEDF stimulates several other well known signaling cascades such as the Ras pathway, the NF-κB pathway, and extrinsic apoptosis cascades.

Function

PEDF has a variety of functions including antiangiogenic, antitumorigenic, and neurotrophic properties. Endothelial 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...

 is inhibited by PEDF. PEDF suppresses retinal neovascularization
Neovascularization
Neovascularization is the formation of functional microvascular networks with red blood cell perfusion. Neovascularization differs from angiogenesis in that angiogenesis is mainly characterized by the protrusion and outgrowth of capillary buds and sprouts from pre-existing blood vessels.In...

 and endothelial cell proliferation
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...

. The antiangiogenic residues 24-57 were shown to be sufficient at inhibiting angiogenesis.
PEDF is also responsible for apoptosis of endothelial cells either through the p38 MAPK pathway or through the FAS/FASL
Fas receptor
The FAS receptor also known as apoptosis antigen 1 , cluster of differentiation 95 or tumor necrosis factor receptor superfamily member 6 is a protein that in humans is encoded by the TNFRSF6 gene....

 pathway Antiangiogenic function is also conferred by PEDF through inhibition of both VEGFR-1
FLT1
Vascular endothelial growth factor receptor 1 is a protein that in humans is encoded by the FLT1 gene.-Interactions:FLT1 has been shown to interact with PLCG1 and Vascular endothelial growth factor B.-Further reading:...

 and VEGFR-2
Kinase insert domain receptor
Kinase insert domain receptor also known as vascular endothelial growth factor receptor 2 is a VEGF receptor. KDR is the human gene encoding it. KDR has also been designated as CD309...

.

The antitumorigenic effects of PEDF are not only due to inhibition of supporting vasculature, but also due to effects on the cancer cells themselves. PEDF was shown to inhibit cancer cell proliferation and increase apoptosis via the FAS/FASL pathway. VEGF expression by cancer cells is inhibited by PEDF.

PEDF also displays neurotrophic functions. Retinoblastoma cells differentiate into neurons due to the presence of PEDF. Expression of PEDF in the human retina is found at 7.4 weeks of gestation, suggesting it may play a role in retinal neuron differentiation.

Clinical Significance

PEDF, a protein with many functions, has been suggested to play a clinical role in choroidal neovascularization, cardiovascular disease, diabetes, diabetic macular edema, osteogenesis imperfecta and cancer. As an antiangiogenic protein, PEDF may help suppress unwanted neovascularization of the eye. Molecules that shift the balance towards PEDF and away from VEGF may prove useful tools in both choroidal neovascularization and preventing cancer 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...

 formation.

External links

  • The MEROPS
    Merops
    Merops may refer to:* Merops , a genus of bee-eaters.* MEROPS, an on-line database for peptidases.It may also refer to several figures from Greek mythology:* King of Ethiopia, husband of Clymene, who lay with Helios and bore Phaethon...

    online database for peptidases and their inhibitors: I04.979
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