BackgroundInformation | RasproteinsfunctionasGDP/GTP-regulatedbinaryswitchesinsignaltransductioncascadesthatcanleadtocellgrowth,proliferation,differentiation,orsurvival.ThisRassuperfamilyhasatleastfivemajorbranchesthatincludeRas,Rho,Ran,Arf/Sar,Rab.Rasitselfhas3primaryisoforms(H-Ras,N-Ras,andK-Ras)thatdifferintheirapproximately20C-terminalaminoacids.TheyarecollectivelyreferredtoasRas.Initsactiveform,RasisboundtoGTP.Thiscausesaconformationalchangethatallowittointeractandbindtoseveraleffectormolecules,mostnotablythemembersoftheRaffamily,theRalGDSfamily,andPhosphoinositide3-kinases(PI3Kinase).RasthencleavesGTPtoGDPresultinginitsinactivation.Initsoncogenic,mutatedstate,RasisunabletohydrolyzeGTPtoGDP,thusstayinginanactivestateandactivatingnumerouspathways. Duetoitsroleasakeyregulatorofcellularfunctionsanditsimplicationsinvariouscancers,Rashasbeenapopulartargetforcancerresearchandanti-cancertherapeuticsforthepasttwodecadesforbothacademicandpharmaceuticalresearch.Itwasalsothefirsthumanoncogeneidentified.MutationsincellularRashavebeenfoundtobepresentinalargepercentageofallhumancancers.Morespecifically,K-Rasmutationsoccurfrequentlyinlung,pancreatic,andcoloncancers,whereasH-Rasmutationsareprevalentinbladder,kidney,andthyroidcancers,andN-Rasmutationsareassociatedwithmelanoma,hepatocellularcarcinoma,andleukemia(3).Inrecentstudies,RasactivityhasalsobeenimplicatedinanumberofhumandevelopmentdefectssuchasCostellosyndromeandNoonansyndrome(4). OnepaththatthepharmaceuticalindustryhastakentocontrolRasanditsactivityisbyattackingwhatsomeconsideritsAchilles’heel.Foritsactivation,Rasmustlocalizetotheplasmamembrane,butinterestingly,itlacksatransmembranedomain.Toachievethis,Rasmustfirstundergoapost-translationalmodificationknownasprenylationorgeranylationatitsC-terminalCAAXmotif.ThesedrugshaveyettopassclinicaltrialsthoughandthereisdoubtthattheywilleverbesuccessfulintreatingtumorsassociatedwithRasactivation.
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