DIRAS1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Aliases | DIRAS1 , Di-Ras1, GBTS1, RIG, DIRAS family GTPase 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 607862; MGI: 2183442; HomoloGene: 64823; GeneCards: DIRAS1; OMA:DIRAS1 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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. [5] This gene is a member of the Ras superfamily and is highly expressed in heart and brain tissue. [6] 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. [7] 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 members of the Ras superfamily. [7]
DIRAS1 is linked to human glioblastoma, colorectal cancer, renal cell carcinoma, and ovarian cancer. [5] The DIRAS1 gene includes two exons with a 597 bp protein-coding region. [6] The DIRAS1 protein is a GTPase belonging to the Ras superfamily and shares 40–50% homology with Ras and Rap. [8] DIRAS1 differs from the more well-researched DIRAS3 in the length of its N-terminal extensions. [8]
While RIG is structurally similar to other GTPase proteins, its function is remarkably different from Ras. Ras is an oncogenic protein involved in cellular proliferation and signal transduction, and while the Ras superfamily generally consists of positive growth regulators, RIG is a tumor-suppressor gene. In contrast to Ras, RIG works as an inhibitor for cell growth, thus functioning as a negative growth regulator. RIG has also been shown to have less GTPase activity than most Ras proteins even though the proteins share a very similar structure. [6]
The underlying cause for these dramatic differences in function is thought to be structural variations between RIG and the Ras superfamily. The negative growth regulation exhibited by RIG is most likely due to the unique length of its N-terminus extension. This sequence is not generally found in the Ras superfamily, most of which show no inhibitory activity towards cell growth and even act as positive growth regulators. The shorter 4 Amino Acid N-terminus of DIRAS1 and DIRAS 2 lacking the leucine-rich, hydrophobic domain may account for the variation in autophagy mechanisms between DIRAS1, DIRAS2 and DIRAS3. [8]
DIRAS1 is believed to be a tumor suppressor in several human malignant tumors. [9] DIRAS1, along with DIRAS2, is associated with overall and progression-free survival. [8] Re-expression of the DIRAS1 gene induces and regulates autophagy by inhibiting the AKT1-MTOR and RAS-MAPK signaling pathway and modulating nuclear localization of the autophagy-related transcription factors FOXO3/FOXO3A and TFEB, suggesting that DIRAS1, along with DIRAS2, may behave as a surrogates in the murine genome for DIRAS3, and may function as a backup system for autophagy in humans. [8] The DIRAS3 gene has been lost from the murine genome by telomeric chromosomal rearrangement. [8]
In ovarian cancer cells, the re-expression of the DIRAS1 gene was found to inhibit cancer cell growth in vitro. [8] Additionally, short-term cell viability was also significantly decreased as determined by sulforhodamine B colorimetric staining. [8] While it was not found that DIRAS1 primarily inhibits cell growth through the mechanisms of apoptosis or cell cycle arrest, the autophagy pathway is essential for DIRAS1-induced growth inhibition. [8]
The expression of DIRAS1 in Osteosarcoma cells was analyzed using the Western blot technique and was regulated by the METTL3 and METTL14 protein coding genes. [10] While it is well known that the ERK and AKT signaling pathways are important in the tumorigenesis and metastasis of osteosarcoma, the DIRAS1 protein regulates the Akt/PKB signaling pathway in osteosarcoma cells. [10] The ERK pathway is important for the development of cells, and the overactivation of the ERK pathway results in the development and progression of cancer. [11]
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.
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 MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.
Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). A variety of unrelated structural domains have been shown to exhibit guanine nucleotide exchange activity. Some GEFs can activate multiple GTPases while others are specific to a single GTPase.
The tumor suppressor gene FLCN encodes the protein folliculin, also known as Birt–Hogg–Dubé syndrome protein, which functions as an inhibitor of Lactate Dehydrogenase-A and a regulator of the Warburg effect. Folliculin (FLCN) is also associated with Birt–Hogg–Dubé syndrome, which is an autosomal dominant inherited cancer syndrome in which affected individuals are at risk for the development of benign cutaneous tumors (folliculomas), pulmonary cysts, and kidney tumors.
Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase protein in the Rho family of GTPases that in humans is encoded by the RHOA gene. While the effects of RhoA activity are not all well known, it is primarily associated with cytoskeleton regulation, mostly actin stress fibers formation and actomyosin contractility. It acts upon several effectors. Among them, ROCK1 and DIAPH1 are the best described. RhoA, and the other Rho GTPases, are part of a larger family of related proteins known as the Ras superfamily, a family of proteins involved in the regulation and timing of cell division. RhoA is one of the oldest Rho GTPases, with homologues present in the genomes since 1.5 billion years. As a consequence, RhoA is somehow involved in many cellular processes which emerged throughout evolution. RhoA specifically is regarded as a prominent regulatory factor in other functions such as the regulation of cytoskeletal dynamics, transcription, cell cycle progression and cell transformation.
Tuberous sclerosis complex 2 (TSC2), also known as tuberin, is a protein that in humans is encoded by the TSC2 gene.
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.
RhoC is a small signaling G protein, and is a member of the Rac subfamily of the family Rho family of GTPases. It is encoded by the gene RHOC.
Ras association domain-containing protein 5 is a protein that in humans is encoded by the RASSF5 or F5 gene.
Deleted in Liver Cancer 1 also known as DLC1 and StAR-related lipid transfer protein 12 (STARD12) is a protein which in humans is encoded by the DLC1 gene.
Rho GDP-dissociation inhibitor 2 is a protein that in humans is encoded by the ARHGDIB gene. Aliases of this gene include RhoGDI2, GDID4, Rho GDI 2, and others.
Ras-related protein Ral-B (RalB) is a protein that in humans is encoded by the RALB gene on chromosome 2. This protein is one of two paralogs of the Ral protein, the other being RalA, and part of the Ras GTPase family. RalA functions as a molecular switch to activate a number of biological processes, majorly cell division and transport, via signaling pathways. Its biological role thus implicates it in many cancers.
Ras Related Glycolysis Inhibitor and Calcium Channel Regulator (RRAD) is a protein that in humans is encoded by the RRAD gene. RRAD is a Ras-related small GTPase that is regulated by p53 and plays a role in the regulation of aerobic glycolysis.
Ras-related protein M-Ras, also known as muscle RAS oncogene homolog and R-Ras3, is a protein that in humans is encoded by the MRAS gene on chromosome 3. It is ubiquitously expressed in many tissues and cell types. This protein functions as a signal transducer for a wide variety of signaling pathways, including those promoting neural and bone formation as well as tumor growth. The MRAS gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
Tuberous sclerosis proteins 1 and 2, also known as TSC1 (hamartin) and TSC2 (tuberin), form a protein-complex. The encoding two genes are TSC1 and TSC2. The complex is known as a tumor suppressor. Mutations in these genes can cause tuberous sclerosis complex. Depending on the grade of the disease, intellectual disability, epilepsy and tumors of the skin, retina, heart, kidney and the central nervous system can be symptoms.
mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.
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.
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.