View source for HRAS

{{Short description|Protein-coding gene in humans}}
{{about|the gene and protein it encodes|the singular of HRAs|HRA (disambiguation)}}
{{Infobox_gene}}
'''GTPase HRas''', from "Harvey Rat sarcoma virus", also known as '''transforming protein p21''' is an [[enzyme]] that in humans is encoded by the {{gene|HRAS}} [[gene]].<ref name="pmid6264598">{{cite journal | vauthors = Wong-Staal F, Dalla-Favera R, Franchini G, Gelmann EP, Gallo RC | title = Three distinct genes in human DNA related to the transforming genes of mammalian sarcoma retroviruses | journal = Science | volume = 213 | issue = 4504 | pages = 226–8 | date = Jul 1981 | pmid = 6264598 | doi = 10.1126/science.6264598 | bibcode = 1981Sci...213..226W }}</ref><ref name="pmid8661149">{{cite journal | vauthors = Russell MW, Munroe DJ, Bric E, Housman DE, Dietz-Band J, Riethman HC, Collins FS, Brody LC | title = A 500-kb physical map and contig from the Harvey ras-1 gene to the 11p telomere | journal = Genomics | volume = 35 | issue = 2 | pages = 353–60 | date = Jul 1996 | pmid = 8661149 | doi = 10.1006/geno.1996.0367 | url = https://zenodo.org/record/1229685 }}</ref> The ''HRAS'' gene is located on the short (p) arm of [[chromosome 11 (human)|chromosome 11]] at position 15.5, from [[base pair]] 522,241 to base pair 525,549.<ref name="entrez">{{cite web | title = Entrez Gene: v-Ha-ras Harvey rat sarcoma viral oncogene homolog| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3265}}</ref> HRas is a [[small G protein]] in the [[Ras subfamily]] of the [[Ras superfamily]] of [[small GTPase]]s. Once bound to [[Guanosine triphosphate]], H-Ras will activate a [[Raf kinase]] like [[c-Raf]], the next step in the [[MAPK/ERK pathway]].

== Function ==
GTPase HRas is involved in regulating cell division in response to [[growth factor]] stimulation. [[Growth factors]] act by binding cell surface [[Receptor (biochemistry)|receptors]] that span the cell's plasma membrane.  Once activated, receptors stimulate signal transduction events in the [[cytoplasm]], a process by which proteins and second messengers relay signals from outside the cell to the cell nucleus and instructs the cell to grow or divide. The HRAS protein is a [[GTPase]] and is an early player in many signal transduction pathways and is usually associated with [[cell membranes]] due to the presence of an [[isoprenyl]] group on its [[C-terminus]].  HRAS acts as a molecular on/off switch, once it is turned on it recruits and activates proteins necessary for the propagation of the receptor's signal, such as [[c-Raf]] and [[PI 3-kinase]].  HRAS binds to [[Guanosine triphosphate|GTP]] in the active state and possesses an intrinsic enzymatic activity that cleaves the terminal phosphate of this nucleotide converting it to [[Guanosine diphosphate|GDP]]. Upon conversion of GTP to GDP, HRAS is turned off.  The rate of conversion is usually slow but can be sped up dramatically by an accessory protein of the GTPase activating protein (GAP) class, for example [[RasGAP]].  In turn HRAS can bind to proteins of the Guanine Nucleotide Exchange Factor (GEF) class, for example [[SOS1]], which forces the release of bound nucleotide.  Subsequently, GTP  present in the [[cytosol]] binds and HRAS-GTP dissociates from the GEF, resulting in HRAS activation.  HRAS is in the [[Ras (protein)|Ras]] family, which also includes two other proto-oncogenes: [[KRAS]] and [[Neuroblastoma RAS viral oncogene homolog|NRAS]].  These proteins all are regulated in the same manner and appear to differ largely in their sites of action within the cell.

== Clinical significance ==
{{See also|List of genes mutated in pigmented cutaneous lesions}}

=== Costello syndrome ===

At least five inherited [[mutation]]s in the ''HRAS'' gene have been identified in people with [[Costello syndrome]]. Each of these mutations changes an amino acid in a critical region of the HRAS protein. The most common mutation replaces the [[amino acid]] [[glycine]] with the amino acid [[serine]] at position 12 (written as Gly12Ser or G12S).  The mutations responsible for Costello syndrome lead to the production of an HRAS protein that is permanently active. Instead of triggering cell growth in response to particular signals from outside the cell, the overactive protein directs cells to grow and divide constantly. This uncontrolled cell division can result in the formation of noncancerous and cancerous tumors. Researchers are uncertain how mutations in the ''HRAS'' gene cause the other features of Costello syndrome (such as mental retardation, distinctive facial features, and heart problems), but many of the signs and symptoms probably result from cell overgrowth and abnormal cell

=== Bladder cancer ===
HRAS has been shown to be a [[proto-oncogene]]. When mutated, proto-oncogenes have the potential to cause normal cells to become [[cancerous]].  Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes are called [[somatic mutation]]s and are not inherited. Somatic mutations in the ''HRAS'' gene in bladder cells have been associated with [[bladder cancer]]. One specific mutation has been identified in a significant percentage of bladder tumors; this mutation substitutes one protein building block (amino acid) for another amino acid in the HRAS protein. Specifically, the mutation replaces the amino acid [[glycine]] with the amino acid [[valine]] at position 12 (written as Gly12Val, G12V, or H-RasV<sup>12</sup>). The altered HRAS protein is permanently activated within the cell. This overactive protein directs the cell to grow and divide in the absence of outside signals, leading to uncontrolled cell division and the formation of a tumor. Mutations in the ''HRAS'' gene also have been associated with the progression of bladder cancer and an increased risk of tumor recurrence after treatment.

=== Other cancers ===
Somatic mutations in the ''HRAS'' gene are probably involved in the development of several other types of cancer. These mutations lead to an HRAS protein that is always active and can direct cells to grow and divide without control. Recent studies suggest that ''HRAS'' mutations are common in thyroid, salivary duct carcinoma,<ref>{{cite journal | vauthors = Chiosea SI, Williams L, Griffith CC, Thompson LD, Weinreb I, Bauman JE, Luvison A, Roy S, Seethala RR, Nikiforova MN | title = Molecular characterization of apocrine salivary duct carcinoma | journal = The American Journal of Surgical Pathology | volume = 39 | issue = 6 | pages = 744–52 | date = Jun 2015 | pmid = 25723113 | doi = 10.1097/PAS.0000000000000410 | s2cid = 34106002 }}</ref> epithelial-myoepithelial carcinoma,<ref>{{cite journal | vauthors = Chiosea SI, Miller M, Seethala RR | title = HRAS mutations in epithelial-myoepithelial carcinoma | journal = Head and Neck Pathology | volume = 8 | issue = 2 | pages = 146–50 | date = Jun 2014 | pmid = 24277618 | doi = 10.1007/s12105-013-0506-4 | pmc=4022927}}</ref> and kidney cancers. 
DNA copy-number gain of a segment containing ''HRAS'' is included in a genome-wide pattern, which was found to be correlated with an [[astrocytoma]] patient's outcome.<ref>{{Cite journal
 | author1 = K. A. Aiello | author2 = O. Alter | title = Platform-Independent Genome-Wide Pattern of DNA Copy-Number Alterations Predicting Astrocytoma Survival and Response to Treatment Revealed by the GSVD Formulated as a Comparative Spectral Decomposition
 | journal = PLOS ONE
 | volume = 11
 | issue = 10
 | pages = e0164546
 | date = October 2016
 | doi =  10.1371/journal.pone.0164546
 | pmid = 27798635 | pmc = 5087864 | bibcode = 2016PLoSO..1164546A | doi-access = free }}</ref>
<ref>{{Cite journal
 | author1 = K. M. Reily | author2 = D. A. Loisel | author3 = R. T. Bronson | author4 = M. E. McLaughlin | author5 = T. Jacks | title = ''Nf1;Trp53'' mutant mice develop glioblastoma with evidence of strain-specific effects
 | journal = Nature Genetics
 | volume = 26
 | issue = 1
 | pages = 109–113
 | date = September 2000
 | doi =  10.1038/79075
| pmid = 10973261 | s2cid = 23076620 }}</ref>
The HRAS protein also may be produced at higher levels (overexpressed) in other types of cancer cells.

== References ==
{{Reflist}}

== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = McCormick F | title = Ras-related proteins in signal transduction and growth control | journal = Molecular Reproduction and Development | volume = 42 | issue = 4 | pages = 500–6 | date = Dec 1995 | pmid = 8607982 | doi = 10.1002/mrd.1080420419 | s2cid = 6507743 }}
* {{cite journal | vauthors = Ayllón V, Rebollo A | title = Ras-induced cellular events (review) | journal = Molecular Membrane Biology | volume = 17 | issue = 2 | pages = 65–73 | year = 2001 | pmid = 10989457 | doi = 10.1080/09687680050117093 | s2cid = 84294021 }}
* {{cite journal | vauthors = Tennant RW, Stasiewicz S, Eastin WC, Mennear JH, Spalding JW | title = The Tg.AC (v-Ha-ras) transgenic mouse: nature of the model | journal = Toxicologic Pathology | volume = 29 Suppl | issue =  5| pages = 51–9 | year = 2002 | pmid = 11695562 | doi = 10.1080/019262301753178474 | s2cid = 20211777 }}
* {{cite journal | vauthors = Mascaux C, Iannino N, Martin B, Paesmans M, Berghmans T, Dusart M, Haller A, Lothaire P, Meert AP, Noel S, Lafitte JJ, Sculier JP | title = The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis | journal = British Journal of Cancer | volume = 92 | issue = 1 | pages = 131–9 | date = Jan 2005 | pmid = 15597105 | pmc = 2361730 | doi = 10.1038/sj.bjc.6602258 }}
* {{cite journal | vauthors = Harms KL, Chen X | title = p19ras brings a new twist to the regulation of p73 by Mdm2 | journal = Science's STKE | volume = 2006 | issue = 337 | pages = pe24 | date = May 2006 | pmid = 16738062 | doi = 10.1126/stke.3372006pe24 | s2cid = 22706614 }}
{{refend}}

== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK1507/  GeneReviews/NCBI/NIH/UW entry on Costello syndrome]
* {{MeshName|HRAS+protein,+human}}

{{PDB Gallery|geneid=3265}}
{{Oncogenes}}
{{Acid anhydride hydrolases}}
{{Intracellular signaling peptides and proteins}}

[[Category:Oncogenes]]