| Structural highlights
Disease
[RASK_HUMAN] Defects in KRAS are a cause of acute myelogenous leukemia (AML) [MIM:601626]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development.[1] Defects in KRAS are a cause of juvenile myelomonocytic leukemia (JMML) [MIM:607785]. JMML is a pediatric myelodysplastic syndrome that constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukemia. It is characterized by leukocytosis with tissue infiltration and in vitro hypersensitivity of myeloid progenitors to granulocyte-macrophage colony stimulating factor. Defects in KRAS are the cause of Noonan syndrome type 3 (NS3) [MIM:609942]. Noonan syndrome (NS) [MIM:163950] is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. It is a genetically heterogeneous and relatively common syndrome, with an estimated incidence of 1 in 1000-2500 live births. Rarely, NS is associated with juvenile myelomonocytic leukemia (JMML). NS3 inheritance is autosomal dominant.[2] [3] [4] [5] [6] [7] Defects in KRAS are a cause of gastric cancer (GASC) [MIM:613659]; also called gastric cancer intestinal or stomach cancer. Gastric cancer is a malignant disease which starts in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach that accounts for most of all gastric malignant tumors. Two main histologic types are recognized, diffuse type and intestinal type carcinomas. Diffuse tumors are poorly differentiated infiltrating lesions, resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease.[8] [9] [10] Note=Defects in KRAS are a cause of pylocytic astrocytoma (PA). Pylocytic astrocytomas are neoplasms of the brain and spinal cord derived from glial cells which vary from histologically benign forms to highly anaplastic and malignant tumors.[11] Defects in KRAS are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM:115150]; also known as cardio-facio-cutaneous syndrome. CFC syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The inheritance of CFC syndrome is autosomal dominant. Note=KRAS mutations are involved in cancer development.
Function
[RASK_HUMAN] Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
Publication Abstract from PubMed
KRAS mutations are the most common genetic abnormalities in cancer but the distribution of specific mutations across cancers and the differential responses of patients with specific KRAS mutations in therapeutic clinical trials suggest that different KRAS mutations have unique biochemical behaviors. To further explain these high-level clinical differences and to explore potential therapeutic strategies for specific KRAS isoforms, we characterized the most common KRAS mutants biochemically for substrate binding kinetics, intrinsic and GTPase-activating protein (GAP) stimulated GTPase activities and interactions with the RAS effector, RAF kinase. Of note, KRAS G13D shows rapid nucleotide exchange kinetics compared to other mutants analyzed. This property can be explained by changes in the electrostatic charge distribution of the active site induced by the G13D mutation as shown by x-ray crystallography. High resolution x-ray structures are also provided for the GDP bound forms of KRAS G12V, G12R and Q61L and reveal additional insight. Overall, the structural data and measurements, obtained herein, indicate that measurable biochemical properties provide clues for identifying KRAS-driven tumors that preferentially signal through RAF. IMPLICATIONS: Biochemical profiling and subclassification of KRAS-driven cancers will enable the rational selection of therapies targeting specific KRAS isoforms or specific RAS effectors.
Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations.,Hunter JC, Manandhar A, Carrasco MA, Gurbani D, Gondi S, Westover KD Mol Cancer Res. 2015 Jun 2. pii: molcanres.0203.2015. PMID:26037647[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bollag G, Adler F, elMasry N, McCabe PC, Conner E Jr, Thompson P, McCormick F, Shannon K. Biochemical characterization of a novel KRAS insertion mutation from a human leukemia. J Biol Chem. 1996 Dec 20;271(51):32491-4. PMID:8955068
- ↑ Carta C, Pantaleoni F, Bocchinfuso G, Stella L, Vasta I, Sarkozy A, Digilio C, Palleschi A, Pizzuti A, Grammatico P, Zampino G, Dallapiccola B, Gelb BD, Tartaglia M. Germline missense mutations affecting KRAS Isoform B are associated with a severe Noonan syndrome phenotype. Am J Hum Genet. 2006 Jul;79(1):129-35. Epub 2006 May 1. PMID:16773572 doi:10.1086/504394
- ↑ Schubbert S, Zenker M, Rowe SL, Boll S, Klein C, Bollag G, van der Burgt I, Musante L, Kalscheuer V, Wehner LE, Nguyen H, West B, Zhang KY, Sistermans E, Rauch A, Niemeyer CM, Shannon K, Kratz CP. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006 Mar;38(3):331-6. Epub 2006 Feb 12. PMID:16474405 doi:ng1748
- ↑ Bertola DR, Pereira AC, Brasil AS, Albano LM, Kim CA, Krieger JE. Further evidence of genetic heterogeneity in Costello syndrome: involvement of the KRAS gene. J Hum Genet. 2007;52(6):521-6. Epub 2007 Apr 28. PMID:17468812 doi:10.1007/s10038-007-0146-1
- ↑ Zenker M, Lehmann K, Schulz AL, Barth H, Hansmann D, Koenig R, Korinthenberg R, Kreiss-Nachtsheim M, Meinecke P, Morlot S, Mundlos S, Quante AS, Raskin S, Schnabel D, Wehner LE, Kratz CP, Horn D, Kutsche K. Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. J Med Genet. 2007 Feb;44(2):131-5. Epub 2006 Oct 20. PMID:17056636 doi:10.1136/jmg.2006.046300
- ↑ Kratz CP, Zampino G, Kriek M, Kant SG, Leoni C, Pantaleoni F, Oudesluys-Murphy AM, Di Rocco C, Kloska SP, Tartaglia M, Zenker M. Craniosynostosis in patients with Noonan syndrome caused by germline KRAS mutations. Am J Med Genet A. 2009 May;149A(5):1036-40. doi: 10.1002/ajmg.a.32786. PMID:19396835 doi:10.1002/ajmg.a.32786
- ↑ Gremer L, Merbitz-Zahradnik T, Dvorsky R, Cirstea IC, Kratz CP, Zenker M, Wittinghofer A, Ahmadian MR. Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders. Hum Mutat. 2011 Jan;32(1):33-43. doi: 10.1002/humu.21377. Epub 2010 Dec 9. PMID:20949621 doi:10.1002/humu.21377
- ↑ Deng GR, Lu YY, Chen SM, Miao J, Lu GR, Li H, Cai H, Xu XL, E Z, Liu PN. Activated c-Ha-ras oncogene with a guanine to thymine transversion at the twelfth codon in a human stomach cancer cell line. Cancer Res. 1987 Jun 15;47(12):3195-8. PMID:3034404
- ↑ Lee KH, Lee JS, Suh C, Kim SW, Kim SB, Lee JH, Lee MS, Park MY, Sun HS, Kim SH. Clinicopathologic significance of the K-ras gene codon 12 point mutation in stomach cancer. An analysis of 140 cases. Cancer. 1995 Jun 15;75(12):2794-801. PMID:7773929
- ↑ Lee SH, Lee JW, Soung YH, Kim HS, Park WS, Kim SY, Lee JH, Park JY, Cho YG, Kim CJ, Nam SW, Kim SH, Lee JY, Yoo NJ. BRAF and KRAS mutations in stomach cancer. Oncogene. 2003 Oct 9;22(44):6942-5. PMID:14534542 doi:10.1038/sj.onc.1206749
- ↑ Motojima K, Urano T, Nagata Y, Shiku H, Tsurifune T, Kanematsu T. Detection of point mutations in the Kirsten-ras oncogene provides evidence for the multicentricity of pancreatic carcinoma. Ann Surg. 1993 Feb;217(2):138-43. PMID:8439212
- ↑ Hunter JC, Manandhar A, Carrasco MA, Gurbani D, Gondi S, Westover KD. Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations. Mol Cancer Res. 2015 Jun 2. pii: molcanres.0203.2015. PMID:26037647 doi:http://dx.doi.org/10.1158/1541-7786.MCR-15-0203
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