| Structural highlights
Disease
RASH_HUMAN Defects in HRAS are the cause of faciocutaneoskeletal syndrome (FCSS) [MIM:218040. A rare condition characterized by prenatally increased growth, postnatal growth deficiency, mental retardation, distinctive facial appearance, cardiovascular abnormalities (typically pulmonic stenosis, hypertrophic cardiomyopathy and/or atrial tachycardia), tumor predisposition, skin and musculoskeletal abnormalities.[1] [2] [3] [4] [5] [6] [7] Defects in HRAS are the cause of congenital myopathy with excess of muscle spindles (CMEMS) [MIM:218040. CMEMS is a variant of Costello syndrome.[8] Defects in HRAS may be a cause of susceptibility to Hurthle cell thyroid carcinoma (HCTC) [MIM:607464. Hurthle cell thyroid carcinoma accounts for approximately 3% of all thyroid cancers. Although they are classified as variants of follicular neoplasms, they are more often multifocal and somewhat more aggressive and are less likely to take up iodine than are other follicular neoplasms. Note=Mutations which change positions 12, 13 or 61 activate the potential of HRAS to transform cultured cells and are implicated in a variety of human tumors. Defects in HRAS are a cause of susceptibility to bladder cancer (BLC) [MIM:109800. A malignancy originating in tissues of the urinary bladder. It often presents with multiple tumors appearing at different times and at different sites in the bladder. Most bladder cancers are transitional cell carcinomas. They begin in cells that normally make up the inner lining of the bladder. Other types of bladder cancer include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Bladder cancer is a complex disorder with both genetic and environmental influences. Note=Defects in HRAS are the cause of oral squamous cell carcinoma (OSCC).[9] Defects in HRAS are the cause of Schimmelpenning-Feuerstein-Mims syndrome (SFM) [MIM:163200. A disease characterized by sebaceous nevi, often on the face, associated with variable ipsilateral abnormalities of the central nervous system, ocular anomalies, and skeletal defects. Many oral manifestations have been reported, not only including hypoplastic and malformed teeth, and mucosal papillomatosis, but also ankyloglossia, hemihyperplastic tongue, intraoral nevus, giant cell granuloma, ameloblastoma, bone cysts, follicular cysts, oligodontia, and odontodysplasia. Sebaceous nevi follow the lines of Blaschko and these can continue as linear intraoral lesions, as in mucosal papillomatosis.[10]
Function
RASH_HUMAN Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.[11] [12] [13]
Publication Abstract from PubMed
Activating mutants of RAS are commonly found in human cancers, but to date selective targeting of RAS in the clinic has been limited to KRAS(G12C) through covalent inhibitors. Here, we report a monobody, termed 12VC1, that recognizes the active state of both KRAS(G12V) and KRAS(G12C) up to 400-times more tightly than wild-type KRAS. The crystal structures reveal that 12VC1 recognizes the mutations through a shallow pocket, and 12VC1 competes against RAS-effector interaction. When expressed intracellularly, 12VC1 potently inhibits ERK activation and the proliferation of RAS-driven cancer cell lines in vitro and in mouse xenograft models. 12VC1 fused to VHL selectively degrades the KRAS mutants and provides more extended suppression of mutant RAS activity than inhibition by 12VC1 alone. These results demonstrate the feasibility of selective targeting and degradation of KRAS mutants in the active state with noncovalent reagents and provide a starting point for designing noncovalent therapeutics against oncogenic RAS mutants.
Selective and noncovalent targeting of RAS mutants for inhibition and degradation.,Teng KW, Tsai ST, Hattori T, Fedele C, Koide A, Yang C, Hou X, Zhang Y, Neel BG, O'Bryan JP, Koide S Nat Commun. 2021 May 11;12(1):2656. doi: 10.1038/s41467-021-22969-5. PMID:33976200[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Aoki Y, Niihori T, Kawame H, Kurosawa K, Ohashi H, Tanaka Y, Filocamo M, Kato K, Suzuki Y, Kure S, Matsubara Y. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005 Oct;37(10):1038-40. Epub 2005 Sep 18. PMID:16170316 doi:ng1641
- ↑ Gripp KW, Lin AE, Stabley DL, Nicholson L, Scott CI Jr, Doyle D, Aoki Y, Matsubara Y, Zackai EH, Lapunzina P, Gonzalez-Meneses A, Holbrook J, Agresta CA, Gonzalez IL, Sol-Church K. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am J Med Genet A. 2006 Jan 1;140(1):1-7. PMID:16329078 doi:10.1002/ajmg.a.31047
- ↑ Kerr B, Delrue MA, Sigaudy S, Perveen R, Marche M, Burgelin I, Stef M, Tang B, Eden OB, O'Sullivan J, De Sandre-Giovannoli A, Reardon W, Brewer C, Bennett C, Quarell O, M'Cann E, Donnai D, Stewart F, Hennekam R, Cave H, Verloes A, Philip N, Lacombe D, Levy N, Arveiler B, Black G. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006 May;43(5):401-5. Epub 2006 Jan 27. PMID:16443854 doi:jmg.2005.040352
- ↑ Zampino G, Pantaleoni F, Carta C, Cobellis G, Vasta I, Neri C, Pogna EA, De Feo E, Delogu A, Sarkozy A, Atzeri F, Selicorni A, Rauen KA, Cytrynbaum CS, Weksberg R, Dallapiccola B, Ballabio A, Gelb BD, Neri G, Tartaglia M. Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Hum Mutat. 2007 Mar;28(3):265-72. PMID:17054105 doi:10.1002/humu.20431
- ↑ Gripp KW, Innes AM, Axelrad ME, Gillan TL, Parboosingh JS, Davies C, Leonard NJ, Lapointe M, Doyle D, Catalano S, Nicholson L, Stabley DL, Sol-Church K. Costello syndrome associated with novel germline HRAS mutations: an attenuated phenotype? Am J Med Genet A. 2008 Mar 15;146A(6):683-90. PMID:18247425 doi:10.1002/ajmg.a.32227
- ↑ Lo IF, Brewer C, Shannon N, Shorto J, Tang B, Black G, Soo MT, Ng DK, Lam ST, Kerr B. Severe neonatal manifestations of Costello syndrome. J Med Genet. 2008 Mar;45(3):167-71. Epub 2007 Nov 26. PMID:18039947 doi:10.1136/jmg.2007.054411
- ↑ Gremer L, De Luca A, Merbitz-Zahradnik T, Dallapiccola B, Morlot S, Tartaglia M, Kutsche K, Ahmadian MR, Rosenberger G. Duplication of Glu37 in the switch I region of HRAS impairs effector/GAP binding and underlies Costello syndrome by promoting enhanced growth factor-dependent MAPK and AKT activation. Hum Mol Genet. 2010 Mar 1;19(5):790-802. doi: 10.1093/hmg/ddp548. Epub 2009 Dec, 8. PMID:19995790 doi:10.1093/hmg/ddp548
- ↑ van der Burgt I, Kupsky W, Stassou S, Nadroo A, Barroso C, Diem A, Kratz CP, Dvorsky R, Ahmadian MR, Zenker M. Myopathy caused by HRAS germline mutations: implications for disturbed myogenic differentiation in the presence of constitutive HRas activation. J Med Genet. 2007 Jul;44(7):459-62. Epub 2007 Apr 5. PMID:17412879 doi:jmg.2007.049270
- ↑ Sakai E, Rikimaru K, Ueda M, Matsumoto Y, Ishii N, Enomoto S, Yamamoto H, Tsuchida N. The p53 tumor-suppressor gene and ras oncogene mutations in oral squamous-cell carcinoma. Int J Cancer. 1992 Dec 2;52(6):867-72. PMID:1459726
- ↑ Groesser L, Herschberger E, Ruetten A, Ruivenkamp C, Lopriore E, Zutt M, Langmann T, Singer S, Klingseisen L, Schneider-Brachert W, Toll A, Real FX, Landthaler M, Hafner C. Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nat Genet. 2012 Jun 10;44(7):783-7. doi: 10.1038/ng.2316. PMID:22683711 doi:10.1038/ng.2316
- ↑ Guil S, de La Iglesia N, Fernandez-Larrea J, Cifuentes D, Ferrer JC, Guinovart JJ, Bach-Elias M. Alternative splicing of the human proto-oncogene c-H-ras renders a new Ras family protein that trafficks to cytoplasm and nucleus. Cancer Res. 2003 Sep 1;63(17):5178-87. PMID:14500341
- ↑ Lander HM, Hajjar DP, Hempstead BL, Mirza UA, Chait BT, Campbell S, Quilliam LA. A molecular redox switch on p21(ras). Structural basis for the nitric oxide-p21(ras) interaction. J Biol Chem. 1997 Feb 14;272(7):4323-6. PMID:9020151
- ↑ Williams JG, Pappu K, Campbell SL. Structural and biochemical studies of p21Ras S-nitrosylation and nitric oxide-mediated guanine nucleotide exchange. Proc Natl Acad Sci U S A. 2003 May 27;100(11):6376-81. Epub 2003 May 9. PMID:12740440 doi:10.1073/pnas.1037299100
- ↑ Teng KW, Tsai ST, Hattori T, Fedele C, Koide A, Yang C, Hou X, Zhang Y, Neel BG, O'Bryan JP, Koide S. Selective and noncovalent targeting of RAS mutants for inhibition and degradation. Nat Commun. 2021 May 11;12(1):2656. PMID:33976200 doi:10.1038/s41467-021-22969-5
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