AGGF1

Last updated
AGGF1
Identifiers
Aliases AGGF1 , GPATC7, GPATCH7, HSU84971, HUS84971, VG5Q, angiogenic factor with G-patch and FHA domains 1
External IDs OMIM: 608464 MGI: 1913799 HomoloGene: 41220 GeneCards: AGGF1
Orthologs
SpeciesHumanMouse
Entrez

55109

66549

Ensembl

ENSG00000164252

ENSMUSG00000021681

UniProt

Q8N302

Q7TN31

RefSeq (mRNA)

NM_018046
NM_013303
NM_138490

NM_025630

RefSeq (protein)

NP_060516

NP_079906

Location (UCSC) Chr 5: 77.03 – 77.07 Mb Chr 13: 95.49 – 95.51 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Angiogenic factor with G patch and FHA domains 1 is a protein that in humans is encoded by the AGGF1 gene. [5] [6] [7]

Contents

AGGF1 is a human gene that functions as an angiogenic factor with a G-patch and forkhead-associated domain. [8] This gene is predominantly expressed in activated, plump endothelial cells and acts to regulate angiogenesis and vascular development. [9] AGGF1 is known to interact with a wide range of proteins involved in vascular development. [10] Mutations to AGGF1 have been implicated in multiple cancers and is known to cause the rare congenital condition, Klippel-Trenaunay syndrome. [9] [11] [12]

Gene

The gene was originally named VG5Q, indicating that it was a vascular gene on chromosome 5, but the name was later changed to reflect its function, instead of just its location. [13]

The AGGF1 gene promoter does not contain a TATA box and contains 2 transcription start sites that are -367 and -364 base pairs ahead of the base translation start site. [13] The gene promoter contains over 50 CpG islands, which makes it a DNA methylation target. [13] AGGF1 is regulated by 2 repressor sites and 2 activator sites. [13] While the presence of 2 repressor and 2 activator sites is clear, the only known transcription factor that regulates AGGF1 is GATA1. [13] GATA1 binds upstream of the AGGF1 gene promoter at -295 and -300, and the binding of GATA1 will lead to increased AGGF1 expression. [9] [13] For the gene to be fully expressed, both of the activator sites must be bound by the transcription factors, GATA1 and another unknown factor. [13]

Protein

To form a protein, an mRNA transcript must be transcribed from the DNA. For AGGF1, the mRNA transcript contains 14 exons and 34 807 nucleotides. [5]

There are 714 amino acids present in this protein, and it has a molecular weight of 80997 Da. [14] It contains a coiled coil domain at positions 18-88 and an OCRE domain at the N terminus. [14] The G-patch domain is located at amino acids 619-663 while the forkhead-associated domain is located at amino acids 435-508. [14] While it is known that these domains are present in the protein, their role in protein function remains unclear.

AGGF1 was the third haploinsufficient human gene identified. [9] Haploinsufficiency means AGGF1 is "dose dependent" so any reductions in protein product can have phenotypic consequences on the vascular development of the organism.

Expression

AGGF1 is largely expressed during early embryonic vein specification, and expression is increased when endothelial cells are activated. [14] [8] While AGGF1 is predominantly functional in endothelial, vascular smooth muscle cells, and osteoblasts, it also has activity in mast cells, cardiac cells, Kupffer cells and hematopoietic stem cells. [13] [8] [15] [16] AGGF1 mRNA has been detected in the heart, kidneys and limbs which indicates that the protein likely also functions in these organs. [14] The proliferation of vascular smooth muscle cells is inhibited when AGGF1 is expressed. [17] It has been found that AGGF1 is highly expressed in some malignant tumours which has implicated AGGF1 in cancer. [17] In vitro models have shown that AGGF1 localizes to cell periphery and directly outside of the cell. [16]

Depending on the mutation type, AGGF1 mutations can be lethal in either the heterozygous or homozygous genotype due to its haploinsufficiency. [14] Mice models have shown that heterozygous mutations can cause fatality due to hemorrhaging while homozygous mutations can prevent proper stem cell differentiation. [14]

Homology

Aggf1 is not unique to humans. This gene is conserved across many species, such as chimpanzees, Rhesus monkeys, dogs, cows, mice, rats, chickens, and frogs. [7] There are 212 organisms that have genes which are orthologs to AGGF1. [7]

Within the human chromosome, there are pseudogenes related to AGGF1 are located on chromosomes 3, 4, 10 and 16 that have likely arisen due to translocation events. [7]

Function

AGGF1 functions to regulate angiogenesis and vascular development. [9] Gene ontology has also implicated AGGF1 in cell adhesion, positive regulation of angiogenesis and endothelial cell proliferation. [7] Additionally, AGGF1 has been shown to protect against inflammation and ischemic injuries. [15] During embryongenesis, AGGF1 is required for hematopoietic stem cell specification and the differentiation of hematopoietic and endothelial cell lineages. [14] Specifically, it regulates vascular endothelial cadherin (VE-cadherin) by inhibiting the phosphorylation of the cadherin and increasing its presence in the plasma membrane of endothelial cells. [9] AGGF1 is critical to the specification of veins and multipotent hemangioblasts, anti-inflammation, tumour angiogenesis, and inhibition of vascular permeability. [18] Additionally, it activates autophagy in specific cell types, such as endothelial cells, cardiac HL1 and H9C2 cells, and vascular smooth muscle cells. [9] [14] [18]

Interactions

AGGF1 directly and indirectly interacts with many proteins. There are direct interactions between AGGF1 and TNFSF12, another secreted angiogenic factor, that leads to increased angiogenesis. [16] AGGF1 acts upstream of hemangioblast genes such as scl, fil1, and etsrp. [10] AGGF1 acts similarly to VEGF - another gene implicated in vascular growth. [10] Additionally, AGGF1 is known to activate catalytic and regulatory subunits of PI3K. [9] This leads to downstream activation of AKT, GSK3b and p70S6K signalling pathway which leads to vein specification and angiogenesis. [9] [10] AGGF1 also interacts with vein specific markers such at flt4, dab2, and ephB4. [19] Ccl2 has also been shown to interact with AGGF1 in hepatocytes through blocking NF-κB/p65 from binding to Ccl2. [20] AGGF1 activity is eliminated when Elk is overexpressed. [17] AGGF1 regulates autophagy by regulating expression of JNK genes. [17] SMAD7 and Aggf1 directly interact in the liver to inhibit fibrogenesis. [15] The presence of DNMT3b will repress AGGF1 by acting on the promoter region of the gene. [15]

Clinical significance

Klippel-Trenaunay Syndrome

Heterogeneous mutations in this gene causing deregulation of expression can lead to the vascular malformations associated with Klippel-Trenaunay syndrome (KTS). [9] [13] [19] Due to the haploinsufficient nature of AGGF1, individuals who have even one mutant allele may have KTS. [9] Studies done in mouse models have shown frequent haemorrhages and increased vascular permeability has been seen in mice who are heterozygous for Aggf1. [9] A translocation between the chromosome 5 q-arm at region 13 in band 3 and the chromosome 11 p-arm at region 15 in band 1 has been implicated in KTS. [5] This translocation affects the AGGF1 promoter so there is a 3 fold increase in protein production. [5] Single nucleotide polymorphisms in intron 11 and exon 7 were associated with KTS susceptibility even though neither of these SNPs resulted in an amino acid change. [5] At one point, the E133K allele was thought to be a mutational hotspot - due to altered phosphorylation - causing KTS, but it has since been found as much as 3.3% of the population are carriers for the mutation. [16] [21]

Heart Disease

AGGF1 has also been implicated in treatment after vascular smooth muscle cell damage due to coronary artery disease and myocardial infarction. [17] By blocking vascular permeability and regulating vascular smooth muscle cell phenotypic switching, AGGF1 protein therapy is currently being investigated as a new method of treating both of these diseases. [17]

Cancer

Aberrant AGGF1 has been implicated in multiple cancers and functions in tumour initiation and progression. [12] For example, both hepatocellular carcinoma and gastric cancer survivability is related to the levels of AGGF1 expression in tumours. [11] [12] AGGF1 has been found to have higher expression in tumours than the surrounding tissues, and higher levels of AGGF1 are associated with a poor patient prognosis. [11] [12]

See also

Related Research Articles

Angiogenesis Blood vessel formation, when new vessels emerge from existing vessels

Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting. Vasculogenesis is the embryonic formation of endothelial cells from mesoderm cell precursors, and from neovascularization, although discussions are not always precise. The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.

Endothelium Layer of cells that lining inner surface of blood vessels

The endothelium 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 rest of the vessel wall. Endothelial cells form the barrier between vessels and tissue and control the flow of substances and fluid into and out of a tissue.

Vascular endothelial growth factor (VEGF), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis and angiogenesis.

Angiomotin Protein-coding gene in the species Homo sapiens

Angiomotin (AMOT) is a protein that in humans is encoded by the AMOT gene. It belongs to the motin family of angiostatin binding proteins, which includes angiomotin, angiomotin-like 1 (AMOTL1) and angiomotin-like 2 (AMOTL2) characterized by coiled-coil domains at N-terminus and consensus PDZ-binding domain at the C-terminus. Angiomotin is expressed predominantly in endothelial cells of capillaries as well as angiogenic tissues such as placenta and solid tumor.

An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through pharmaceutical drugs or diet.

Endostatin

Endostatin is a naturally occurring, 20-kDa C-terminal fragment derived from type XVIII collagen. It is reported to serve as an anti-angiogenic agent, similar to angiostatin and thrombospondin.

Angiopoietin Protein family

Angiopoietin is part of a family of vascular growth factors that play a role in embryonic and postnatal angiogenesis. Angiopoietin signaling most directly corresponds with angiogenesis, the process by which new arteries and veins form from preexisting blood vessels. Angiogenesis proceeds through sprouting, endothelial cell migration, proliferation, and vessel destabilization and stabilization. They are responsible for assembling and disassembling the endothelial lining of blood vessels. Angiopoietin cytokines are involved with controlling microvascular permeability, vasodilation, and vasoconstriction by signaling smooth muscle cells surrounding vessels. There are now four identified angiopoietins: ANGPT1, ANGPT2, ANGPTL3, ANGPT4.

Von Hippel–Lindau tumor suppressor Mammalian protein found in Homo sapiens

The Von Hippel–Lindau tumor suppressor also known as pVHL is a protein that, in humans, is encoded by the VHL gene. Mutations of the VHL gene are associated with Von Hippel–Lindau disease.

CYR61 Protein-coding gene in the species Homo sapiens

Cysteine-rich angiogenic inducer 61 (CYR61) or CCN family member 1 (CCN1), is a matricellular protein that in humans is encoded by the CYR61 gene.

XBP1 Protein-coding gene in the species Homo sapiens

X-box binding protein 1, also known as XBP1, is a protein which in humans is encoded by the XBP1 gene. The XBP1 gene is located on chromosome 22 while a closely related pseudogene has been identified and localized to chromosome 5. The XBP1 protein is a transcription factor that regulates the expression of genes important to the proper functioning of the immune system and in the cellular stress response.

EPAS1 Protein-coding gene in the species Homo sapiens

Endothelial PAS domain-containing protein 1 is a protein that is encoded by the EPAS1 gene in mammals. It is a type of hypoxia-inducible factor, a group of transcription factors involved in the physiological response to oxygen concentration. The gene is active under hypoxic conditions. It is also important in the development of the heart, and for maintaining the catecholamine balance required for protection of the heart. Mutation often leads to neuroendocrine tumors.

Vascular endothelial growth factor C Growth factor protein found in humans

Vascular endothelial growth factor C (VEGF-C) is a protein that is a member of the platelet-derived growth factor / vascular endothelial growth factor (PDGF/VEGF) family. It is encoded in humans by the VEGFC gene, which is located on chromosome 4q34.

Thymidine phosphorylase

Thymidine phosphorylase is an enzyme that is encoded by the TYMP gene and catalyzes the reaction:

PEDF

Pigment epithelium-derived factor (PEDF) also known as serpin F1 (SERPINF1), is a multifunctional secreted protein that has anti-angiogenic, anti-tumorigenic, and neurotrophic functions. Found in vertebrates, this 50 kDa protein is being researched as a therapeutic candidate for treatment of such conditions as choroidal neovascularization, heart disease, and cancer. In humans, pigment epithelium-derived factor is encoded by the SERPINF1 gene.

Placental growth factor

Placental growth factor is a protein that in humans is encoded by the PGF gene.

TNFSF12

Tumor necrosis factor ligand superfamily member 12 also known as TNF-related weak inducer of apoptosis (TWEAK) is a protein that in humans is encoded by the TNFSF12 gene.

Vascular endothelial growth factor A Protein involved in blood vessel growth

Vascular endothelial growth factor A (VEGF-A) is a protein that in humans is encoded by the VEGFA gene.

Angiogenesis is the process of forming new blood vessels from existing blood vessels. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteases (MMPs), a disintegrin and metalloprotease domain (ADAM), a disintegrin and metalloprotease domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.

Klippel–Trénaunay syndrome Medical condition

Klippel–Trénaunay syndrome, formerly Klippel–Trénaunay–Weber syndrome and sometimes angioosteohypertrophy syndrome and hemangiectatic hypertrophy, is a rare congenital medical condition in which blood vessels and/or lymph vessels fail to form properly. The three main features are nevus flammeus, venous and lymphatic malformations, and soft-tissue hypertrophy of the affected limb. It is similar to, though distinctly separate from, the less common Parkes Weber syndrome.

Parkes Weber syndrome Medical condition

Parkes Weber syndrome (PWS) is a congenital disorder of the vascular system. It is an extremely rare condition, and its exact prevalence is unknown. It is named after British dermatologist Frederick Parkes Weber, who first described the syndrome in 1907.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000164252 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000021681 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 4 5 Hu Y, Li L, Seidelmann SB, Timur AA, Shen PH, Driscoll DJ, Wang QK (September 2008). "Identification of association of common AGGF1 variants with susceptibility for Klippel-Trenaunay syndrome using the structure association program". Annals of Human Genetics. 72 (Pt 5): 636–43. doi:10.1111/j.1469-1809.2008.00458.x. PMC   2602961 . PMID   18564129.
  6. ↑ Gutierrez S, Magano L, Delicado A, Mori MA, de Torres ML, Fernández L, Palomares M, Fernández E, Tarduchy GR, Molano J, Gracia R, Pajares IL, Lapunzina P (December 2006). "The G397A (E133K) change in the AGGF1 (VG5Q) gene is a single nucleotide polymorphism in the Spanish population". American Journal of Medical Genetics. Part A. 140 (24): 2832–3. doi:10.1002/ajmg.a.31532. PMID   17103452. S2CID   19068189.
  7. 1 2 3 4 5 "Entrez Gene: AGGF1 angiogenic factor with G patch and FHA domains 1".
  8. 1 2 3 Zhan M, Hori Y, Wada N, Ikeda J, Hata Y, Osuga K, Morii E (April 2016). "Angiogenic Factor with G-patch and FHA Domain 1 (AGGF1) Expression in Human Vascular Lesions". Acta Histochemica et Cytochemica. 49 (2): 75–81. doi:10.1267/ahc.15035. PMC   4858542 . PMID   27222614.
  9. 1 2 3 4 5 6 7 8 9 10 11 12 Zhang T, Yao Y, Wang J, Li Y, He P, Pasupuleti V, Hu Z, Jia X, Song Q, Tian XL, Hu C, Chen Q, Wang QK (December 2016). "Haploinsufficiency of Klippel-Trenaunay syndrome gene Aggf1 inhibits developmental and pathological angiogenesis by inactivating PI3K and AKT and disrupts vascular integrity by activating VE-cadherin". Human Molecular Genetics. 25 (23): 5094–5110. doi:10.1093/hmg/ddw273. PMC   6078640 . PMID   27522498.
  10. 1 2 3 4 Li L, Chen D, Li J, Wang X, Wang N, Xu C, Wang QK (January 2014). "Aggf1 acts at the top of the genetic regulatory hierarchy in specification of hemangioblasts in zebrafish". Blood. 123 (4): 501–8. doi:10.1182/blood-2013-07-514612. PMC   3901065 . PMID   24277077.
  11. 1 2 3 Yao HH, Wang BJ, Wu Y, Huang Q (2017). "High Expression of Angiogenic Factor with G-Patch and FHA Domain1 (AGGF1) Predicts Poor Prognosis in Gastric Cancer". Medical Science Monitor. 23: 1286–1294. doi:10.12659/msm.903248. PMC   5362190 . PMID   28289272.
  12. 1 2 3 4 Wang W, Li GY, Zhu JY, Huang DB, Zhou HC, Zhong W, Ji CS (April 2015). "Overexpression of AGGF1 is correlated with angiogenesis and poor prognosis of hepatocellular carcinoma". Medical Oncology. 32 (4): 131. doi:10.1007/s12032-015-0574-2. PMID   25796501. S2CID   25099244.
  13. 1 2 3 4 5 6 7 8 9 Fan C, Ouyang P, Timur AA, He P, You SA, Hu Y, Ke T, Driscoll DJ, Chen Q, Wang QK (August 2009). "Novel roles of GATA1 in regulation of angiogenic factor AGGF1 and endothelial cell function". The Journal of Biological Chemistry. 284 (35): 23331–43. doi: 10.1074/jbc.M109.036079 . PMC   2749107 . PMID   19556247.
  14. 1 2 3 4 5 6 7 8 9 Liu Y, Yang H, Song L, Li N, Han QY, Tian C, Gao E, Du J, Xia YL, Li HH (August 2014). "AGGF1 protects from myocardial ischemia/reperfusion injury by regulating myocardial apoptosis and angiogenesis". Apoptosis. 19 (8): 1254–68. doi:10.1007/s10495-014-1001-4. PMID   24893993. S2CID   7164539.
  15. 1 2 3 4 Zhou B, Zeng S, Li L, Fan Z, Tian W, Li M, Xu H, Wu X, Fang M, Xu Y (June 2016). "Angiogenic factor with G patch and FHA domains 1 (Aggf1) regulates liver fibrosis by modulating TGF-β signaling". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1862 (6): 1203–13. doi: 10.1016/j.bbadis.2016.02.002 . PMID   26850475.
  16. 1 2 3 4 Tian XL, Kadaba R, You SA, Liu M, Timur AA, Yang L, Chen Q, Szafranski P, Rao S, Wu L, Housman DE, DiCorleto PE, Driscoll DJ, Borrow J, Wang Q (February 2004). "Identification of an angiogenic factor that when mutated causes susceptibility to Klippel-Trenaunay syndrome". Nature. 427 (6975): 640–5. Bibcode:2004Natur.427..640T. doi:10.1038/nature02320. PMC   1618873 . PMID   14961121.
  17. 1 2 3 4 5 6 Yao Y, Hu Z, Ye J, Hu C, Song Q, Da X, Yu Y, Li H, Xu C, Chen Q, Wang QK (June 2017). "Targeting AGGF1 (angiogenic factor with G patch and FHA domains 1) for Blocking Neointimal Formation After Vascular Injury". Journal of the American Heart Association. 6 (6): e005889. doi:10.1161/JAHA.117.005889. PMC   5669188 . PMID   28649088.
  18. 1 2 Lu Q, Yao Y, Hu Z, Hu C, Song Q, Ye J, Xu C, Wang AZ, Chen Q, Wang QK (August 2016). "Angiogenic Factor AGGF1 Activates Autophagy with an Essential Role in Therapeutic Angiogenesis for Heart Disease". PLOS Biology. 14 (8): e1002529. doi:10.1371/journal.pbio.1002529. PMC   4981375 . PMID   27513923.
  19. 1 2 Chen D, Li L, Tu X, Yin Z, Wang Q (March 2013). "Functional characterization of Klippel-Trenaunay syndrome gene AGGF1 identifies a novel angiogenic signaling pathway for specification of vein differentiation and angiogenesis during embryogenesis". Human Molecular Genetics. 22 (5): 963–76. doi: 10.1093/hmg/dds501 . PMID   23197652.
  20. ↑ Xu W, Zeng S, Li M, Fan Z, Zhou B (September 2017). "Aggf1 attenuates hepatic inflammation and activation of hepatic stellate cells by repressing Ccl2 transcription". Journal of Biomedical Research. 31 (5): 428–436. doi:10.7555/JBR.30.20160046. PMC   5706435 . PMID   28958996.
  21. ↑ Barker KT, Foulkes WD, Schwartz CE, Labadie C, Monsell F, Houlston RS, Harper J (July 2006). "Is the E133K allele of VG5Q associated with Klippel-Trenaunay and other overgrowth syndromes?". Journal of Medical Genetics. 43 (7): 613–4. doi:10.1136/jmg.2006.040790. PMC   2564558 . PMID   16443853.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.