GTPase HRas is involved in regulating cell division in response to growth factor stimulation. Growth factors act by binding cell surface 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 GTP in the active state and possesses an intrinsic enzymatic activity that cleaves the terminal phosphate of this nucleotide converting it to 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 family, which also includes two other proto-oncogenes: KRAS and NRAS. These proteins all are regulated in the same manner and appear to differ largely in their sites of action within the cell.
At least five inherited mutations 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 acidglycine 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 division.
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 mutations 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-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,[4] epithelial-myoepithelial carcinoma,[5] 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.[6][7]
The HRAS protein also may be produced at higher levels (overexpressed) in other types of cancer cells.
References
↑Wong-Staal F, Dalla-Favera R, Franchini G, Gelmann EP, Gallo RC (Jul 1981). "Three distinct genes in human DNA related to the transforming genes of mammalian sarcoma retroviruses". Science. 213 (4504): 226–8. doi:10.1126/science.6264598. PMID6264598.
↑Russell MW, Munroe DJ, Bric E, Housman DE, Dietz-Band J, Riethman HC, Collins FS, Brody LC (Jul 1996). "A 500-kb physical map and contig from the Harvey ras-1 gene to the 11p telomere". Genomics. 35 (2): 353–60. doi:10.1006/geno.1996.0367. PMID8661149.
↑Chiosea SI, Williams L, Griffith CC, Thompson LD, Weinreb I, Bauman JE, Luvison A, Roy S, Seethala RR, Nikiforova MN (Jun 2015). "Molecular characterization of apocrine salivary duct carcinoma". The American Journal of Surgical Pathology. 39 (6): 744–52. doi:10.1097/PAS.0000000000000410. PMID25723113.
↑K. M. Reily; D. A. Loisel; R. T. Bronson; M. E. McLaughlin; T. Jacks (September 2000). "Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects". Nature Genetics. 26 (1): 109–113. doi:10.1038/79075.
Further reading
McCormick F (Dec 1995). "Ras-related proteins in signal transduction and growth control". Molecular Reproduction and Development. 42 (4): 500–6. doi:10.1002/mrd.1080420419. PMID8607982.
Harms KL, Chen X (May 2006). "p19ras brings a new twist to the regulation of p73 by Mdm2". Science's STKE. 2006 (337): pe24. doi:10.1126/stke.3372006pe24. PMID16738062.
121p: STRUKTUR UND GUANOSINTRIPHOSPHAT-HYDROLYSEMECHANISMUS DES C-TERMINAL VERKUERZTEN MENSCHLICHEN KREBSPROTEINS P21-H-RAS
PDB 1aa9 EBI.jpg
1aa9: HUMAN C-HA-RAS(1-171)(DOT)GDP, NMR, MINIMIZED AVERAGE STRUCTURE
PDB 1agp EBI.jpg
1agp: THREE-DIMENSIONAL STRUCTURES AND PROPERTIES OF A TRANSFORMING AND A NONTRANSFORMING GLY-12 MUTANT OF P21-H-RAS
PDB 1bkd EBI.jpg
1bkd: COMPLEX OF HUMAN H-RAS WITH HUMAN SOS-1
PDB 1clu EBI.jpg
1clu: H-RAS COMPLEXED WITH DIAMINOBENZOPHENONE-BETA,GAMMA-IMIDO-GTP
PDB 1crp EBI.jpg
1crp: THE SOLUTION STRUCTURE AND DYNAMICS OF RAS P21. GDP DETERMINED BY HETERONUCLEAR THREE AND FOUR DIMENSIONAL NMR SPECTROSCOPY
PDB 1crq EBI.jpg
1crq: THE SOLUTION STRUCTURE AND DYNAMICS OF RAS P21. GDP DETERMINED BY HETERONUCLEAR THREE AND FOUR DIMENSIONAL NMR SPECTROSCOPY
PDB 1crr EBI.jpg
1crr: THE SOLUTION STRUCTURE AND DYNAMICS OF RAS P21. GDP DETERMINED BY HETERONUCLEAR THREE AND FOUR DIMENSIONAL NMR SPECTROSCOPY
PDB 1ctq EBI.jpg
1ctq: STRUCTURE OF P21RAS IN COMPLEX WITH GPPNHP AT 100 K
PDB 1gnp EBI.jpg
1gnp: X-RAY CRYSTAL STRUCTURE ANALYSIS OF THE CATALYTIC DOMAIN OF THE ONCOGENE PRODUCT P21H-RAS COMPLEXED WITH CAGED GTP AND MANT DGPPNHP
PDB 1gnq EBI.jpg
1gnq: X-RAY CRYSTAL STRUCTURE ANALYSIS OF THE CATALYTIC DOMAIN OF THE ONCOGENE PRODUCT P21H-RAS COMPLEXED WITH CAGED GTP AND MANT DGPPNHP
PDB 1gnr EBI.jpg
1gnr: X-RAY CRYSTAL STRUCTURE ANALYSIS OF THE CATALYTIC DOMAIN OF THE ONCOGENE PRODUCT P21H-RAS COMPLEXED WITH CAGED GTP AND MANT DGPPNHP
PDB 1he8 EBI.jpg
1he8: RAS G12V - PI 3-KINASE GAMMA COMPLEX
PDB 1iaq EBI.jpg
1iaq: C-H-RAS P21 PROTEIN MUTANT WITH THR 35 REPLACED BY SER (T35S) COMPLEXED WITH GUANOSINE-5'-[B,G-IMIDO] TRIPHOSPHATE
PDB 1ioz EBI.jpg
1ioz: Crystal Structure of the C-HA-RAS Protein Prepared by the Cell-Free Synthesis
PDB 1jah EBI.jpg
1jah: H-RAS P21 PROTEIN MUTANT G12P, COMPLEXED WITH GUANOSINE-5'-[BETA,GAMMA-METHYLENE] TRIPHOSPHATE AND MAGNESIUM
PDB 1jai EBI.jpg
1jai: H-RAS P21 PROTEIN MUTANT G12P, COMPLEXED WITH GUANOSINE-5'-[BETA,GAMMA-METHYLENE] TRIPHOSPHATE AND MANGANESE
PDB 1k8r EBI.jpg
1k8r: Crystal structure of Ras-Bry2RBD complex
PDB 1lf0 EBI.jpg
1lf0: Crystal Structure of RasA59G in the GTP-bound form
PDB 1lf5 EBI.jpg
1lf5: Crystal Structure of RasA59G in the GDP-bound Form
PDB 1lfd EBI.jpg
1lfd: CRYSTAL STRUCTURE OF THE ACTIVE RAS PROTEIN COMPLEXED WITH THE RAS-INTERACTING DOMAIN OF RALGDS
PDB 1nvu EBI.jpg
1nvu: Structural evidence for feedback activation by RasGTP of the Ras-specific nucleotide exchange factor SOS
PDB 1nvv EBI.jpg
1nvv: Structural evidence for feedback activation by RasGTP of the Ras-specific nucleotide exchange factor SOS
PDB 1nvw EBI.jpg
1nvw: Structural evidence for feedback activation by RasGTP of the Ras-specific nucleotide exchange factor SOS
PDB 1nvx EBI.jpg
1nvx: Structural evidence for feedback activation by RasGTP of the Ras-specific nucleotide exchange factor SOS
PDB 1p2s EBI.jpg
1p2s: H-Ras 166 in 50% 2,2,2 triflouroethanol
PDB 1p2t EBI.jpg
1p2t: H-Ras 166 in Aqueous mother liquor, RT
PDB 1p2u EBI.jpg
1p2u: H-Ras in 50% isopropanol
PDB 1p2v EBI.jpg
1p2v: H-RAS 166 in 60 % 1,6 hexanediol
PDB 1plj EBI.jpg
1plj: CRYSTALLOGRAPHIC STUDIES ON P21H-RAS USING SYNCHROTRON LAUE METHOD: IMPROVEMENT OF CRYSTAL QUALITY AND MONITORING OF THE GTPASE REACTION AT DIFFERENT TIME POINTS
PDB 1plk EBI.jpg
1plk: CRYSTALLOGRAPHIC STUDIES ON P21H-RAS USING SYNCHROTRON LAUE METHOD: IMPROVEMENT OF CRYSTAL QUALITY AND MONITORING OF THE GTPASE REACTION AT DIFFERENT TIME POINTS
PDB 1pll EBI.jpg
1pll: CRYSTALLOGRAPHIC STUDIES ON P21H-RAS USING SYNCHROTRON LAUE METHOD: IMPROVEMENT OF CRYSTAL QUALITY AND MONITORING OF THE GTPASE REACTION AT DIFFERENT TIME POINTS
PDB 1q21 EBI.jpg
1q21: CRYSTAL STRUCTURES AT 2.2 ANGSTROMS RESOLUTION OF THE CATALYTIC DOMAINS OF NORMAL RAS PROTEIN AND AN ONCOGENIC MUTANT COMPLEXED WITH GSP
PDB 1qra EBI.jpg
1qra: STRUCTURE OF P21RAS IN COMPLEX WITH GTP AT 100 K
PDB 1rvd EBI.jpg
1rvd: H-RAS COMPLEXED WITH DIAMINOBENZOPHENONE-BETA,GAMMA-IMIDO-GTP
PDB 1wq1 EBI.jpg
1wq1: RAS-RASGAP COMPLEX
PDB 1xcm EBI.jpg
1xcm: Crystal structure of the GppNHp-bound H-Ras G60A mutant
PDB 1xd2 EBI.jpg
1xd2: Crystal Structure of a ternary Ras:SOS:Ras*GDP complex
PDB 1xj0 EBI.jpg
1xj0: Crystal Structure of the GDP-bound form of the RasG60A mutant
PDB 1zvq EBI.jpg
1zvq: Structure of the Q61G mutant of Ras in the GDP-bound form
PDB 1zw6 EBI.jpg
1zw6: Crystal Structure of the GTP-bound form of RasQ61G
PDB 221p EBI.jpg
221p: THREE-DIMENSIONAL STRUCTURES OF H-RAS P21 MUTANTS: MOLECULAR BASIS FOR THEIR INABILITY TO FUNCTION AS SIGNAL SWITCH MOLECULES
PDB 2c5l EBI.jpg
2c5l: STRUCTURE OF PLC EPSILON RAS ASSOCIATION DOMAIN WITH HRAS
PDB 2ce2 EBI.png
2ce2: CRYSTAL STRUCTURE ANALYSIS OF A FLUORESCENT FORM OF H-RAS P21 IN COMPLEX WITH GDP
PDB 2cl0 EBI.png
2cl0: CRYSTAL STRUCTURE ANALYSIS OF A FLUORESCENT FORM OF H-RAS P21 IN COMPLEX WITH GPPNHP
PDB 2cl6 EBI.png
2cl6: CRYSTAL STRUCTURE ANALYSIS OF A FLUORESCENT FORM OF H-RAS P21 IN COMPLEX WITH S-CAGED GTP
PDB 2cl7 EBI.png
2cl7: CRYSTAL STRUCTURE ANALYSIS OF A FLUORESCENT FORM OF H-RAS P21 IN COMPLEX WITH GTP
PDB 2clc EBI.png
2clc: CRYSTAL STRUCTURE ANALYSIS OF A FLUORESCENT FORM OF H-RAS P21 IN COMPLEX WITH GTP (2)
PDB 2cld EBI.png
2cld: CRYSTAL STRUCTURE ANALYSIS OF A FLUORESCENT FORM OF H-RAS P21 IN COMPLEX WITH GDP (2)
PDB 2evw EBI.png
2evw: Crystal structure analysis of a fluorescent form of H-Ras p21 in complex with R-caged GTP
PDB 2q21 EBI.jpg
2q21: CRYSTAL STRUCTURES AT 2.2 ANGSTROMS RESOLUTION OF THE CATALYTIC DOMAINS OF NORMAL RAS PROTEIN AND AN ONCOGENIC MUTANT COMPLEXED WITH GSP
PDB 421p EBI.jpg
421p: THREE-DIMENSIONAL STRUCTURES OF H-RAS P21 MUTANTS: MOLECULAR BASIS FOR THEIR INABILITY TO FUNCTION AS SIGNAL SWITCH MOLECULES
PDB 4q21 EBI.jpg
4q21: MOLECULAR SWITCH FOR SIGNAL TRANSDUCTION: STRUCTURAL DIFFERENCES BETWEEN ACTIVE AND INACTIVE FORMS OF PROTOONCOGENIC RAS PROTEINS
PDB 521p EBI.jpg
521p: THREE-DIMENSIONAL STRUCTURES OF H-RAS P21 MUTANTS: MOLECULAR BASIS FOR THEIR INABILITY TO FUNCTION AS SIGNAL SWITCH MOLECULES
PDB 5p21 EBI.jpg
5p21: REFINED CRYSTAL STRUCTURE OF THE TRIPHOSPHATE CONFORMATION OF H-RAS P21 AT 1.35 ANGSTROMS RESOLUTION: IMPLICATIONS FOR THE MECHANISM OF GTP HYDROLYSIS
PDB 621p EBI.jpg
621p: THREE-DIMENSIONAL STRUCTURES OF H-RAS P21 MUTANTS: MOLECULAR BASIS FOR THEIR INABILITY TO FUNCTION AS SIGNAL SWITCH MOLECULES
PDB 6q21 EBI.jpg
6q21: MOLECULAR SWITCH FOR SIGNAL TRANSDUCTION: STRUCTURAL DIFFERENCES BETWEEN ACTIVE AND INACTIVE FORMS OF PROTOONCOGENIC RAS PROTEINS
PDB 721p EBI.jpg
721p: THREE-DIMENSIONAL STRUCTURES OF H-RAS P21 MUTANTS: MOLECULAR BASIS FOR THEIR INABILITY TO FUNCTION AS SIGNAL SWITCH MOLECULES
PDB 821p EBI.jpg
821p: THREE-DIMENSIONAL STRUCTURES AND PROPERTIES OF A TRANSFORMING AND A NONTRANSFORMING GLYCINE-12 MUTANT OF P21H-RAS