• regulation of progression through cell cycle • small GTPase mediated signal transduction • sensory perception of sound • striated muscle cell differentiation
RNA expression pattern
More reference expression data
NM_004985 (mRNA) NP_004976 (protein)
NM_021284 (mRNA) NP_067259 (protein)
Chr 12: 25.25 - 25.3 Mb
Chr 6: 145.17 - 145.21 Mb
KRAS is a gene encoding the KRas proto-oncogene. Like other members of the Ras gene family, the KRAS 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.
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 binds to GTP in the active state and possesses its intrinsic enymatic activity cleves 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 Guanine nucleotide 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. Subsequently, the unbound HRAS is released from the GEF and quickly re-binds available GTP or GDP present in the cytosol. Since GTP is substantially more abundant than GDP, this usually results in HRAS activation.
Other members of the Ras family include: HRAS, RRAS and NRAS. These proteins all are regulated in the same manner and appear to differ largely in their sites of action within the cell.
Several germline KRAS mutations have been found to be associated with Noonan syndrome and cardio-facio-cutaneous syndrome.
Somatic diseases associated with KRAS
Somatic KRAS mutations are found at high rates in Leukemias, colon cancer, pancreatic cancer and lung cancer.
KRAS mutation is predictive of response to cetuximab therapy in colorectal cancer. According to this reference whatever the expression of EGFR, KRAS mutation is associated with activation of the Ras/MAPK pathway. KRAS mutations can induce non-response to anti-EGFR monoclonals (panitumumab, cetuximab), or EGFR-TK inhibitors (erlotinib, gefitinib).
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^ Niihori T, Aoki Y, Narumi Y, et al (2006). "Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome". Nat. Genet.38 (3): 294–6. doi:10.1038/ng1749. PMID 16474404.
^ Burmer GC, Loeb LA (1989). "Mutations in the KRAS2 oncogene during progressive stages of human colon carcinoma". Proc. Natl. Acad. Sci. U.S.A.86 (7): 2403–7. PMID 2648401.
^ Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M (1988). "Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes". Cell53 (4): 549–54. PMID 2453289.
^ Tam IY, Chung LP, Suen WS, et al (2006). "Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features". Clin. Cancer Res.12 (5): 1647–53. doi:10.1158/1078-0432.CCR-05-1981. PMID 16533793.
^ Lièvre A, Bachet JB, Le Corre D, et al (2006). "KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer". Cancer Res.66 (8): 3992–5. doi:10.1158/0008-5472.CAN-06-0191. PMID 16618717.
Su YH, Wang M, Aiamkitsumrit B, et al. (2007). "Detection of a K-ras mutation in urine of patients with colorectal cancer.". Cancer biomarkers : section A of Disease markers1 (2-3): 177-82. PMID 17192038.