HRAS
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GTPase HRas, from "Harvey Rat sarcoma virus", also known as transforming protein p21 is an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that in humans is encoded by the
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. The ''HRAS'' gene is located on the short (p) arm of
chromosome 11 Chromosome 11 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome. Chromosome 11 spans about 135 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tot ...
at position 15.5, from
base pair A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...
522,241 to base pair 525,549. HRas is a
small G protein Small GTPases (), also known as small G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotr ...
in the
Ras subfamily 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 ...
of the
Ras superfamily The Ras superfamily, derived from "Rat sarcoma virus", is a protein superfamily of small GTPases. Members of the superfamily are divided into families and subfamilies based on their structure, sequence and function. The five main families are Ras ...
of
small GTPase Small GTPases (), also known as small G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotri ...
s. Once bound to
Guanosine triphosphate Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanosine nucleoside, the only diffe ...
, H-Ras will activate a Raf kinase like
c-Raf 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 ( ...
, the next step in the
MAPK/ERK pathway The MAPK/ERK pathway (also known as the Ras-Raf-MEK-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. The signal starts when a signaling ...
.


Function

GTPase HRas is involved in regulating cell division in response to
growth factor A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...
stimulation.
Growth factors A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...
act by binding cell surface
receptors Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
that span the cell's plasma membrane. Once activated, receptors stimulate signal transduction events in the
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
, 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 GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a pro ...
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 The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
. 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 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 ( ...
and PI 3-kinase. HRAS binds to GTP in the active state and possesses an intrinsic enzymatic activity that cleaves the terminal phosphate of this nucleotide converting it to
GDP Gross domestic product (GDP) is a monetary measure of the market value of all the final goods and services produced and sold (not resold) in a specific time period by countries. Due to its complex and subjective nature this measure is ofte ...
. 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 RAS p21 protein activator 1 or RasGAP (Ras GTPase activating protein), also known as RASA1, is a 120- kDa cytosolic human protein that provides two principal activities: * Inactivation of Ras from its active GTP-bound form to its inactive GDP-bo ...
. In turn HRAS can bind to proteins of the Guanine Nucleotide Exchange Factor (GEF) class, for example
SOS1 Son of sevenless homolog 1 is a protein that in humans is encoded by the ''SOS1'' gene. Function SOS1 is a guanine nucleotide exchange factor (GEF) which interacts with RAS proteins to phosphorylate GDP into GTP, or from an inactive state to an ...
, which forces the release of bound nucleotide. Subsequently, GTP present in the
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
binds and HRAS-GTP dissociates from the GEF, resulting in HRAS activation. HRAS is in the
Ras Ras or RAS may refer to: Arts and media * RAS Records Real Authentic Sound, a reggae record label * Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service * Rás 1, an Icelandic radio station * Rás 2, an Icelandic radio stati ...
family, which also includes two other proto-oncogenes:
KRAS ''KRAS'' (Kirsten rat sarcoma virus) 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 ...
and 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


Costello syndrome

At least five inherited
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s in the ''HRAS'' gene have been identified in people with
Costello syndrome Costello syndrome, also called faciocutaneoskeletal syndrome or FCS syndrome, is a rare genetic disorder that affects many parts of the body. It is characterized by delayed development and intellectual disabilities, distinctive facial features, unu ...
. Each of these mutations changes an amino acid in a critical region of the HRAS protein. The most common mutation replaces the
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
with the amino acid
serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...
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 An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
. When mutated, proto-oncogenes have the potential to cause normal cells to become
cancerous Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Poss ...
. Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes are called
somatic mutation A somatic mutation is a change in the DNA sequence of a somatic cell of a multicellular organism with dedicated reproductive cells; that is, any mutation that occurs in a cell other than a gamete, germ cell, or gametocyte. Unlike germline mutatio ...
s and are not inherited. Somatic mutations in the ''HRAS'' gene in bladder cells have been associated with
bladder cancer Bladder cancer is any of several types of cancer arising from the tissues of the urinary bladder. Symptoms include blood in the urine, pain with urination, and low back pain. It is caused when epithelial cells that line the bladder become mali ...
. 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 Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
with the amino acid
valine Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotonat ...
at position 12 (written as Gly12Val, G12V, or H-RasV12). 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, epithelial-myoepithelial carcinoma, 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 Astrocytomas are a type of brain tumor. They originate in a particular kind of glial cells, star-shaped brain cells in the cerebrum called astrocytes. This type of tumor does not usually spread outside the brain and spinal cord and it does not usu ...
patient's outcome. The HRAS protein also may be produced at higher levels (overexpressed) in other types of cancer cells.


References


Further reading

* * * * *


External links


GeneReviews/NCBI/NIH/UW entry on Costello syndrome
* {{Intracellular signaling peptides and proteins Oncogenes