 | This article may be too technical for most readers to understand.(October 2013) |
| RASEF | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | RASEF , RAB45, RAS and EF-hand domain containing, TSG | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 611344 MGI: 2448565 HomoloGene: 28424 GeneCards: RASEF | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Ras and EF-hand domain-containing protein also known as Ras-related protein Rab-45 is a protein that in humans is encoded by the RASEF gene. [5]
The RASEF gene is located on chromosome 9 (9q21.32). [6]
RASEF belongs to the small GTPase family, which means that it's able to hydrolyse a molecule of GTP; known for its unusual conformation. In the small GTPase family it is classified in the RAS domain, a special group of oncogenes and oncoproteins that take part in the synthesis of molecules related to cell reproduction. [7]
A feature of RASEF is its N-terminal EF-hand motif and C-terminal Rab-homology domain, that enables it to bind calcium. [7] Lately, RASEF has been studied for its role as an oncoprotein. Investigating which mutations affect it and how we could inhibit them could allow us to fight cancers that have an elevated mortality rate, such as lung cancer. [7]
When studying cancer's molecular biology we can identify two types of genes that intervene in its development:
Oncogenes generally code for growth factors and their receptors, enzymes related to transduction signal or for DNA transcription factors. When those genes suffer some kind of mutation or translocation, they can change their conformation and cause a catalytic activity in cell reproduction that is normally inactivated, which causes abnormal cell proliferation. This could provoke a malignant tumor if combined with a separate mutation in a protein's RAS group. [8]
RASEF or Rab 45 is classified in the Ras superfamily, which includes small (20kDa) guanosine triphosphatases (GTPases). The basic members of this group of proteins are Ras oncogenes. It's divided into five major families (Ras, Rho, Arf/Sar, Ran and Rab). [9] RASEF is included in the Rab family (the largest family), which is responsible for vesicular traffic of proteins between organelles via endocytotic and secretory pathways. Their function is to make budding from the donor compartment, transport, vesicle fusion and cargo release easier. [10]
RASEF is a 740 amino acids [11] long protein which contains 3 distinct regions: 2 EF hand domains (which in turn contain 2 Calcium bindings and 3 nucleotide bindings -assumed by similarity with other proteins, without direct evidence-), a Coiled Coil region and a C-terminal Rab-homology domain. [7]
Sequence found in RASEF protein that contains 35 amino acids (36 in the second one). The two EF hand domains are consecutively located at the “beginning” of the protein. Its name “N-terminal” indicates an amino group (characteristic of this group of biomolecules, as well as the C- terminal ending). The first one goes from the 8th amino acid to the 42nd, and the other to the 42nd to the 77th. [9] “EF hand” refers to the shape of this domain (similarity with the right hand's morphology). Ca+2 ions are responsible for this structure, which by binding metals join two alpha helixes. [12]
Structural motif in proteins: from two to seven alpha helixes entwined. Each one of these helixes is a repeated 7 amino acid sequence (HPPHCPC), where H refers to hydrophobic amino acids. [13] The position of hydrophobic remains (alpha helix exterior) causes their amphipathic behaviour.[ citation needed ] The bond between different chains, produced in cytoplasm (aqueous region), is extremely tight, as Van der Waals forces appear between the hydrophobic radicals (H), surrounded by the hydrophilic amino acids (amphipathic molecule). This bond is known as the “Knobs into holes packing”. [14] Coiled coil motif, located in the intermediate region of the protein, is responsible for self-interaction. [15]
Located at the end of the protein (opposite to N-terminal domain), it's a carboxyl group (COOH). In this region, there are guanine nucleotide bonds to tri-phosphates and di-phosphates. The variability of this domain is responsible for the high appearance of elements needed in the joints between proteins and their targets in the membrane. [16] Both the C-Terminal Rab-homology domain and the intermediate region of the protein are responsible for the intracellular location of the protein (perinuclear region).[ citation needed ]
RASEF intervenes in a direct manner in biological processes such as protein transport and small GTPase mediated signal transduction. Its molecular functions include GTP binding and calcium ion binding. [17]
As mentioned previously, RASEF has 3 distinct structural regions: the C-terminus Rab domain, the N-terminus EF-hand domain and the self-interacting mid-region. Each of these has an individual function.[ citation needed ]
The guanine-nucleotide forms of the Rab domain regulate the protein's localization. RASEF is mainly found in the perinuclear region of the cell. In addition, the protein's mid-region also seems to be involved in the perinuclear localization. This could be due to its interaction with membrane compartments.[ citation needed ] The EF-hand domain's function still remains to be discovered. However, it is speculated that due to its conformational changes upon binding with Ca2+ ions, and these being responsible for interactions with target molecules; that in cooperation with the Rab-domain, the EF-hand domain's main function is regulating membrane traffic.[ citation needed ] Over 60 Rab-family GTPase proteins have key roles in membrane traffic regulation. This isn't surprising given the amount and variety of intracellular compartments, which require a high level of control to ensure a proper delivery and fusion of vesicles at the correct site. [7]
This connects the RASEF protein directly to cell-growth mechanisms, making it susceptible to having a decisive role in the apparition of cancerous cells.[ citation needed ]
Ras and Ef-hand domain containing proteins are commonly overexpressed in primary lung cancers and its intervention is crucial for the proliferation and survival of cancerous cells. Apart from binding calcium ions in the N-terminus, RASEF plays a significant role in lung cancer cell-growth. This occurs because of its interaction with ERK (extracellular signal-regulated kinase) molecules involved in the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells, whose pathway can be activated by carcinogens or viral infections. . [18]
There is ongoing research that is studying the possibility of using RASEF as a clinically promising prognostic biomarker and therapeutic target for lung cancer. Some recent studies have revealed the viability of using RASEF as a target for this disease. [18]
Also, a segregation study in families with uveal and cutaneous melanoma identified a potential locus harboring a tumor-suppressor gene (TSG). One of the genes in this area (9q21), RASEF, was then analyzed as a candidate TSG, but the lack of point mutations and copy number changes could not confirm this. Nowadays, the RASEF gene has been investigated for potential mutations and gene silencing by promoting methylation in uveal melanoma. It appears to be the mechanism targeting RASEF in uveal melanoma, and allelic imbalance at this locus supports a TSG role for the Ras and Ef-hand domain containing. [19]
Ras, from "Rat sarcoma virus", is a family of related proteins that are expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells. Ras is the prototypical member of the Ras superfamily of proteins, which are all related in three-dimensional structure and regulate diverse cell behaviours.
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.
GTPase HRas, from "Harvey Rat sarcoma virus", also known as transforming protein p21 is an enzyme that in humans is encoded by the HRAS gene. The HRAS gene is located on the short (p) arm of chromosome 11 at position 15.5, from base pair 522,241 to base pair 525,549. HRas is a small G protein in the Ras subfamily of the Ras superfamily of small GTPases. Once bound to Guanosine triphosphate, H-Ras will activate a Raf kinase like c-Raf, the next step in the MAPK/ERK pathway.
The PAX3 gene encodes a member of the paired box or PAX family of transcription factors. The PAX family consists of nine human (PAX1-PAX9) and nine mouse (Pax1-Pax9) members arranged into four subfamilies. Human PAX3 and mouse Pax3 are present in a subfamily along with the highly homologous human PAX7 and mouse Pax7 genes. The human PAX3 gene is located in the 2q36.1 chromosomal region, and contains 10 exons within a 100 kb region.
RAF proto-oncogene serine/threonine-protein kinase, also known as proto-oncogene c-RAF or simply c-Raf or even Raf-1, is an enzyme that in humans is encoded by the RAF1 gene. The c-Raf protein is part of the ERK1/2 pathway as a MAP kinase (MAP3K) that functions downstream of the Ras subfamily of membrane associated GTPases. C-Raf is a member of the Raf kinase family of serine/threonine-specific protein kinases, from the TKL (Tyrosine-kinase-like) group of kinases.
KRAS is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate). It is called KRAS because it was first identified as a viral oncogene in the KirstenRAt Sarcoma virus. The oncogene identified was derived from a cellular genome, so KRAS, when found in a cellular genome, is called a proto-oncogene.
The SKI protein is a nuclear proto-oncogene that is associated with tumors at high cellular concentrations. SKI has been shown to interfere with normal cellular functioning by both directly impeding expression of certain genes inside the nucleus of the cell as well as disrupting signaling proteins that activate genes.
Serine/threonine-protein kinase PLK1, also known as polo-like kinase 1 (PLK-1) or serine/threonine-protein kinase 13 (STPK13), is an enzyme that in humans is encoded by the PLK1 gene.
RAS p21 protein activator 1 or RasGAP, also known as RASA1, is a 120-kDa cytosolic human protein that provides two principal activities:
NRAS is an enzyme that in humans is encoded by the NRAS gene. It was discovered by a small team of researchers led by Robin Weiss at the Institute of Cancer Research in London. It was the third RAS gene to be discovered, and was named NRAS, for its initial identification in human neuroblastoma cells.
Ras-related protein Rab-7a is a protein that in humans is encoded by the RAB7A gene.
RHEB also known as Ras homolog enriched in brain (RHEB) is a GTP-binding protein that is ubiquitously expressed in humans and other mammals. The protein is largely involved in the mTOR pathway and the regulation of the cell cycle.
Ras-related protein Rab-8A is a protein that in humans is encoded by the RAB8A gene.
Methyl-CpG-binding domain protein 4 is a protein that in humans is encoded by the MBD4 gene.
CDKN2A, also known as cyclin-dependent kinase inhibitor 2A, is a gene which in humans is located at chromosome 9, band p21.3. It is ubiquitously expressed in many tissues and cell types. The gene codes for two proteins, including the INK4 family member p16 and p14arf. Both act as tumor suppressors by regulating the cell cycle. p16 inhibits cyclin dependent kinases 4 and 6 and thereby activates the retinoblastoma (Rb) family of proteins, which block traversal from G1 to S-phase. p14ARF activates the p53 tumor suppressor. Somatic mutations of CDKN2A are common in the majority of human cancers, with estimates that CDKN2A is the second most commonly inactivated gene in cancer after p53. Germline mutations of CDKN2A are associated with familial melanoma, glioblastoma and pancreatic cancer. The CDKN2A gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
BRCA1 associated protein-1 is a deubiquitinating enzyme that in humans is encoded by the BAP1 gene. BAP1 encodes an 80.4 kDa nuclear-localizing protein with a ubiquitin carboxy-terminal hydrolase (UCH) domain that gives BAP1 its deubiquitinase activity. Recent studies have shown that BAP1 and its fruit fly homolog, Calypso, are members of the polycomb-group proteins (PcG) of highly conserved transcriptional repressors required for long-term silencing of genes that regulate cell fate determination, stem cell pluripotency, and other developmental processes.
GTP-binding protein Di-Ras3 (DIRAS3) also known as aplysia ras homology member I (ARHI) is a protein that in humans is encoded by the DIRAS3 gene.
Eps15 homology domain-containing protein 3, abbreviated as EHD3 and also known as PAST3, is a protein encoded by the EHD3 gene. It has been observed in humans, mice and rats. It belongs to the EHD protein family, a group of four membrane remodeling proteins related to the Dynamin superfamily of large GTPases. Although the four of them are 70-80% amino acid identical, they all have different locations. Its main function is related to endocytic transport.
Ras-related protein Rab-2B is a protein that in humans is encoded by the RAB2B gene.
GTP-binding protein Di-Ras1 (DIRAS1) also known as Ras-related inhibitor of cell growth (RIG) is a protein that in humans is encoded by the DIRAS1 gene and is located on the chromosome band 10p13.3. This gene is a member of the Ras superfamily and is highly expressed in heart and brain tissue. DIRAS1 varies from other members of the Ras superfamily due to amino acid substitution in the RAF kinase and Ha-RAS, critical for GTP hydrolysis. Due to these substitution, DIRAS1 has a low level of GTPase activity and exists as the GTP-bound form leading to the hypothesis that DIRAS1 may regulate cell development in a different manner than other memebers of the Ras superfamily.
