KRAS

Kirsten rat sarcoma viral oncogene homolog
Rendering of 1D8D​
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1D8D​, 1D8E​, 1KZO​, 1KZP​, 2MSC​, 2MSD​, 2MSE​, 3GFT​, 4DSN​, 4DSO​, 4EPR​, 4EPT​, 4EPV​, 4EPW​, 4EPX​, 4EPY​, 4L8G​, 4LDJ​, 4LPK​, 4LRW​, 4LUC​, 4LV6​, 4LYF​, 4LYH​, 4LYJ​, 4M1O​, 4M1S​, 4M1T​, 4M1W​, 4M1Y​, 4M21​, 4M22​, 4NMM​, 4OBE​, 4PZY​, 4PZZ​, 4Q01​, 4Q02​, 4Q03​
Identifiers
Symbols	KRAS ; C-K-RAS; CFC2; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; KI-RAS; KRAS1; KRAS2; NS; NS3; RASK2
External IDs	OMIM: 190070 MGI: 96680 HomoloGene: 37990 GeneCards: KRAS Gene
Gene ontology Molecular function • protein binding • GTP binding • GMP binding • GDP binding • LRR domain binding • protein complex binding Cellular component • cytoplasm • mitochondrion • cytosol • plasma membrane • focal adhesion • membrane • extrinsic component of cytoplasmic side of plasma membrane • membrane raft Biological process • MAPK cascade • activation of MAPKK activity • positive regulation of protein phosphorylation • stimulatory C-type lectin receptor signaling pathway • epidermal growth factor receptor signaling pathway • small GTPase mediated signal transduction • Ras protein signal transduction • axon guidance • blood coagulation • positive regulation of cell proliferation • insulin receptor signaling pathway • visual learning • fibroblast growth factor receptor signaling pathway • positive regulation of gene expression • cytokine-mediated signaling pathway • actin cytoskeleton organization • regulation of synaptic transmission, GABAergic • positive regulation of Rac protein signal transduction • social behavior • endocrine signaling • Fc-epsilon receptor signaling pathway • positive regulation of MAP kinase activity • negative regulation of neuron apoptotic process • innate immune response • negative regulation of cell differentiation • vascular endothelial growth factor receptor signaling pathway • neurotrophin TRK receptor signaling pathway • regulation of long-term neuronal synaptic plasticity • homeostasis of number of cells within a tissue • leukocyte migration • positive regulation of nitric-oxide synthase activity • positive regulation of NF-kappaB transcription factor activity • striated muscle cell differentiation • response to glucocorticoid • response to mineralocorticoid • epithelial tube branching involved in lung morphogenesis Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3845	16653
Ensembl	ENSG00000133703	ENSMUSG00000030265
UniProt	P01116	P32883
RefSeq (mRNA)	NM_004985	NM_021284
RefSeq (protein)	NP_004976	NP_067259
Location (UCSC)	Chr 12: 25.2 – 25.25 Mb	Chr 6: 145.22 – 145.25 Mb
PubMed search

GTPase KRas also known as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog and KRAS, is a protein that in humans is encoded by the KRAS gene.^[1][2]

The protein product of the normal KRAS gene performs an essential function in normal tissue signaling, and the mutation of a KRAS gene is an essential step in the development of many cancers.^[3] Like other members of the ras subfamily, the KRAS protein is a GTPase and is an early player in many signal transduction pathways. KRAS is usually tethered to cell membranes because of the presence of an isoprene group on its C-terminus. There are two protein products of the KRAS gene in mammalian cells that result from the use of alternative exon 4 (exon 4A and 4B respectively): K-Ras4A and K-Ras4B, these proteins have different structure in their C-terminal region and utilise different mechanisms to localize to cellular membranes including plasma membrane.^[4]

Function

KRAS acts as a molecular on/off switch. Once it is turned on, it recruits and activates proteins necessary for the propagation of growth factor and other receptors' signal such as c-Raf and PI 3-kinase. KRAS upregulates the GLUT1 glucose transporter, thereby contributing to the Warburg effect in cancer cells.^[5] KRAS binds to GTP in the active state and possesses an intrinsic enzymatic activity which cleaves the terminal phosphate of the nucleotide converting it to GDP. Upon conversion of GTP to GDP, KRAS 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 KRAS can bind to proteins of the Guanine Nucleotide Exchange Factor (GEF) class, for example SOS1, which forces the release of bound nucleotide (GDP). Subsequently, KRAS binds GTP present in the cytosol and the GEF is released from ras-GTP.

Other members of the Ras family include: HRAS 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

This proto-oncogene is a Kirsten ras oncogene homolog from the mammalian ras gene family. A single amino acid substitution, and in particular a single nucleotide substitution, is responsible for an activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma,^[6] mucinous adenoma, ductal carcinoma of the pancreas and colorectal carcinoma.^[7][8]

Several germline KRAS mutations have been found to be associated with Noonan syndrome^[9] and cardio-facio-cutaneous syndrome.^[10]

Somatic KRAS mutations are found at high rates in leukemias, colon cancer,^[11] pancreatic cancer^[12] and lung cancer.^[13]

Colorectal cancer

The chronological order of mutations is important in the impact of KRAS mutations in regard to colorectal cancer, with a primary KRAS mutation generally leading to a self-limiting hyperplastic or borderline lesion, but if occurring after a previous APC mutation it often progresses to cancer.^[14] KRAS mutations are more commonly observed in cecal cancers than colorectal cancers located in any other places from ascending colon to rectum.^[15][16]

KRAS mutation is predictive of a very poor response to panitumumab (Vectibix®) and cetuximab (Erbitux®) therapy in colorectal cancer.^[17] Currently, the most reliable way to predict whether a colorectal cancer patient will respond to one of the EGFR-inhibiting drugs is to test for certain “activating” mutations in the gene that encodes KRAS, which occurs in 30%-50% of colorectal cancers. Studies show patients whose tumors express the mutated version of the KRAS gene will not respond to cetuximab or panitumumab.^[18]

Although presence of the wild-type (or normal) KRAS gene does not guarantee that these drugs will work, a number of large studies^[19][20] have shown that cetuximab has significant efficacy in mCRC patients with KRAS wild-type tumors. In the Phase III CRYSTAL study, published in 2009, patients with the wild-type KRAS gene treated with Erbitux plus chemotherapy showed a response rate of up to 59% compared to those treated with chemotherapy alone. Patients with the KRAS wild-type gene also showed a 32% decreased risk of disease progression compared to patients receiving chemotherapy alone.^[20]

Emergence of KRAS mutations is a frequent driver of acquired resistance to cetuximab anti-EGFR therapy in colorectal cancers. The emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression. It suggests to perform an early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.^[21]

KRAS amplification

KRAS gene can also be amplified in colorectal cancer. KRAS amplification is mutually exclusive with KRAS mutations. Tumors or cell lines harboring this genetic lesion are not responsive to EGFR inhibitors. Although KRAS amplification is an infrequent event in colorectal cancer, it might be responsible for precluding response to anti-EGFR treatment in some patients.^[22] Amplification of wild-type Kras has also been observed in ovarian,^[23] gastric, uterine, and lung cancers.^[24]

Lung cancer

Whether a patient is positive or negative for a mutation in the epidermal growth factor receptor (EGFR) will predict how patients will respond to certain EGFR antagonists such as erlotinib (Tarceva) or gefitinib (Iressa). Patients who harbor an EGFR mutation have a 60% response rate to erlotinib. However, the mutation of KRAS and EGFR are generally mutually exclusive.^[25][26][27] Lung cancer patients who are positive for KRAS mutation (and the EGFR status would be wild type) have a low response rate to erlotinib or gefitinib estimated at 5% or less.^[25]

KRAS Testing

In July 2009, the US Food and Drug Administration (FDA) updated the labels of two anti-EGFR monoclonal antibody drugs (panitumumab (Vectibix) and cetuximab (Erbitux)) indicated for treatment of metastatic colorectal cancer to include information about KRAS mutations.^[28]

In 2012, the FDA also cleared QIAGEN’s therascreen KRAS test, which is a genetic test designed to detect the presence of seven mutations in the KRAS gene in colorectal cancer cells. This test is used to aid physicians in identifying patients with metastatic colorectal cancer for treatment with Erbitux. The presence of KRAS mutations in colorectal cancer tissue indicates that the patient may not benefit from treatment with Erbitux. If the test result indicates that the KRAS mutations are absent in the colorectal cancer cells, then the patient may be considered for treatment with Erbitux.^[29]

Interactions

KRAS has been shown to interact with:

• C-Raf,^[30][31]
• PIK3CG,^[32]
• RALGDS,^[30][33] and
• RASSF2.^[34]

References

Further reading

External links

• KRAS Standards - Learn more about KRAS Reference Controls
• GeneReviews/NCBI/NIH/UW entry on Cardiofaciocutaneous Syndrome
• GeneReviews/NCBI/NIH/UW entry on Noonan syndrome
• KRAS2 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)

PDB gallery 121p: STRUKTUR UND GUANOSINTRIPHOSPHAT-HYDROLYSEMECHANISMUS DES C-TERMINAL VERKUERZTEN MENSCHLICHEN KREBSPROTEINS P21-H-RAS  1aa9: HUMAN C-HA-RAS(1-171)(DOT)GDP, NMR, MINIMIZED AVERAGE STRUCTURE  1agp: THREE-DIMENSIONAL STRUCTURES AND PROPERTIES OF A TRANSFORMING AND A NONTRANSFORMING GLY-12 MUTANT OF P21-H-RAS  1bkd: COMPLEX OF HUMAN H-RAS WITH HUMAN SOS-1  1clu: H-RAS COMPLEXED WITH DIAMINOBENZOPHENONE-BETA,GAMMA-IMIDO-GTP  1crp: THE SOLUTION STRUCTURE AND DYNAMICS OF RAS P21. GDP DETERMINED BY HETERONUCLEAR THREE AND FOUR DIMENSIONAL NMR SPECTROSCOPY  1crq: THE SOLUTION STRUCTURE AND DYNAMICS OF RAS P21. GDP DETERMINED BY HETERONUCLEAR THREE AND FOUR DIMENSIONAL NMR SPECTROSCOPY  1crr: THE SOLUTION STRUCTURE AND DYNAMICS OF RAS P21. GDP DETERMINED BY HETERONUCLEAR THREE AND FOUR DIMENSIONAL NMR SPECTROSCOPY  1ctq: STRUCTURE OF P21RAS IN COMPLEX WITH GPPNHP AT 100 K  1gnp: X-RAY CRYSTAL STRUCTURE ANALYSIS OF THE CATALYTIC DOMAIN OF THE ONCOGENE PRODUCT P21H-RAS COMPLEXED WITH CAGED GTP AND MANT DGPPNHP  1gnq: X-RAY CRYSTAL STRUCTURE ANALYSIS OF THE CATALYTIC DOMAIN OF THE ONCOGENE PRODUCT P21H-RAS COMPLEXED WITH CAGED GTP AND MANT DGPPNHP  1gnr: X-RAY CRYSTAL STRUCTURE ANALYSIS OF THE CATALYTIC DOMAIN OF THE ONCOGENE PRODUCT P21H-RAS COMPLEXED WITH CAGED GTP AND MANT DGPPNHP  1he8: RAS G12V - PI 3-KINASE GAMMA COMPLEX  1iaq: C-H-RAS P21 PROTEIN MUTANT WITH THR 35 REPLACED BY SER (T35S) COMPLEXED WITH GUANOSINE-5'-[B,G-IMIDO] TRIPHOSPHATE  1ioz: Crystal Structure of the C-HA-RAS Protein Prepared by the Cell-Free Synthesis  1jah: H-RAS P21 PROTEIN MUTANT G12P, COMPLEXED WITH GUANOSINE-5'-[BETA,GAMMA-METHYLENE] TRIPHOSPHATE AND MAGNESIUM  1jai: H-RAS P21 PROTEIN MUTANT G12P, COMPLEXED WITH GUANOSINE-5'-[BETA,GAMMA-METHYLENE] TRIPHOSPHATE AND MANGANESE  1k8r: Crystal structure of Ras-Bry2RBD complex  1lf0: Crystal Structure of RasA59G in the GTP-bound form  1lf5: Crystal Structure of RasA59G in the GDP-bound Form  1lfd: CRYSTAL STRUCTURE OF THE ACTIVE RAS PROTEIN COMPLEXED WITH THE RAS-INTERACTING DOMAIN OF RALGDS  1nvu: Structural evidence for feedback activation by RasGTP of the Ras-specific nucleotide exchange factor SOS  1nvv: Structural evidence for feedback activation by RasGTP of the Ras-specific nucleotide exchange factor SOS  1nvw: Structural evidence for feedback activation by RasGTP of the Ras-specific nucleotide exchange factor SOS  1nvx: Structural evidence for feedback activation by RasGTP of the Ras-specific nucleotide exchange factor SOS  1p2s: H-Ras 166 in 50% 2,2,2 triflouroethanol  1p2t: H-Ras 166 in Aqueous mother liqour, RT  1p2u: H-Ras in 50% isopropanol  1p2v: H-RAS 166 in 60 % 1,6 hexanediol  1plj: CRYSTALLOGRAPHIC STUDIES ON P21H-RAS USING SYNCHROTRON LAUE METHOD: IMPROVEMENT OF CRYSTAL QUALITY AND MONITORING OF THE GTPASE REACTION AT DIFFERENT TIME POINTS  1plk: CRYSTALLOGRAPHIC STUDIES ON P21H-RAS USING SYNCHROTRON LAUE METHOD: IMPROVEMENT OF CRYSTAL QUALITY AND MONITORING OF THE GTPASE REACTION AT DIFFERENT TIME POINTS  1pll: CRYSTALLOGRAPHIC STUDIES ON P21H-RAS USING SYNCHROTRON LAUE METHOD: IMPROVEMENT OF CRYSTAL QUALITY AND MONITORING OF THE GTPASE REACTION AT DIFFERENT TIME POINTS  1q21: CRYSTAL STRUCTURES AT 2.2 ANGSTROMS RESOLUTION OF THE CATALYTIC DOMAINS OF NORMAL RAS PROTEIN AND AN ONCOGENIC MUTANT COMPLEXED WITH GSP  1qra: STRUCTURE OF P21RAS IN COMPLEX WITH GTP AT 100 K  1rvd: H-RAS COMPLEXED WITH DIAMINOBENZOPHENONE-BETA,GAMMA-IMIDO-GTP  1wq1: RAS-RASGAP COMPLEX  1xcm: Crystal structure of the GppNHp-bound H-Ras G60A mutant  1xd2: Crystal Structure of a ternary Ras:SOS:Ras*GDP complex  1xj0: Crystal Structure of the GDP-bound form of the RasG60A mutant  1zvq: Structure of the Q61G mutant of Ras in the GDP-bound form  1zw6: Crystal Structure of the GTP-bound form of RasQ61G  221p: THREE-DIMENSIONAL STRUCTURES OF H-RAS P21 MUTANTS: MOLECULAR BASIS FOR THEIR INABILITY TO FUNCTION AS SIGNAL SWITCH MOLECULES  2c5l: STRUCTURE OF PLC EPSILON RAS ASSOCIATION DOMAIN WITH HRAS  2ce2: CRYSTAL STRUCTURE ANALYSIS OF A FLUORESCENT FORM OF H-RAS P21 IN COMPLEX WITH GDP  2cl0: CRYSTAL STRUCTURE ANALYSIS OF A FLUORESCENT FORM OF H-RAS P21 IN COMPLEX WITH GPPNHP  2cl6: CRYSTAL STRUCTURE ANALYSIS OF A FLUORESCENT FORM OF H-RAS P21 IN COMPLEX WITH S-CAGED GTP  2cl7: CRYSTAL STRUCTURE ANALYSIS OF A FLUORESCENT FORM OF H-RAS P21 IN COMPLEX WITH GTP  2clc: CRYSTAL STRUCTURE ANALYSIS OF A FLUORESCENT FORM OF H-RAS P21 IN COMPLEX WITH GTP (2)  2cld: CRYSTAL STRUCTURE ANALYSIS OF A FLUORESCENT FORM OF H-RAS P21 IN COMPLEX WITH GDP (2)  2evw: Crystal structure analysis of a fluorescent form of H-Ras p21 in complex with R-caged GTP  2q21: CRYSTAL STRUCTURES AT 2.2 ANGSTROMS RESOLUTION OF THE CATALYTIC DOMAINS OF NORMAL RAS PROTEIN AND AN ONCOGENIC MUTANT COMPLEXED WITH GSP  421p: THREE-DIMENSIONAL STRUCTURES OF H-RAS P21 MUTANTS: MOLECULAR BASIS FOR THEIR INABILITY TO FUNCTION AS SIGNAL SWITCH MOLECULES  521p: THREE-DIMENSIONAL STRUCTURES OF H-RAS P21 MUTANTS: MOLECULAR BASIS FOR THEIR INABILITY TO FUNCTION AS SIGNAL SWITCH MOLECULES  5p21: REFINED CRYSTAL STRUCTURE OF THE TRIPHOSPHATE CONFORMATION OF H-RAS P21 AT 1.35 ANGSTROMS RESOLUTION: IMPLICATIONS FOR THE MECHANISM OF GTP HYDROLYSIS  621p: THREE-DIMENSIONAL STRUCTURES OF H-RAS P21 MUTANTS: MOLECULAR BASIS FOR THEIR INABILITY TO FUNCTION AS SIGNAL SWITCH MOLECULES  6q21: MOLECULAR SWITCH FOR SIGNAL TRANSDUCTION: STRUCTURAL DIFFERENCES BETWEEN ACTIVE AND INACTIVE FORMS OF PROTOONCOGENIC RAS PROTEINS  721p: THREE-DIMENSIONAL STRUCTURES OF H-RAS P21 MUTANTS: MOLECULAR BASIS FOR THEIR INABILITY TO FUNCTION AS SIGNAL SWITCH MOLECULES  821p: THREE-DIMENSIONAL STRUCTURES AND PROPERTIES OF A TRANSFORMING AND A NONTRANSFORMING GLYCINE-12 MUTANT OF P21H-RAS