PDGFB的文章总结.docx

PDGFB的文章总结.docx

《PDGFB的文章总结.docx》由会员分享，可在线阅读，更多相关《PDGFB的文章总结.docx（75页珍藏版）》请在冰豆网上搜索。

PDGFB的文章总结

肝癌是世界上病死率最高的五大肿瘤之一，其发病率近年来呈不断上升趋势。

传统的外科切除和新兴的微创治疗是目前主要的治疗手段，但许多肝癌患者就诊时已是晚期，且治疗后仍有较高的复发率。

因此，揭示肝癌发生发展的分子机制，在此基础上寻找安全、有效的新的治疗方法显得十分重要。

TargetingthePDGFsignalingpathway（路）intumor（肿瘤）treatment

AbstractPlatelet-derivedgrowthfactor（因素）（PDGF）isoforms（同种型）andPDGFreceptors（受体）haveimportantfunctionsintheregulationofgrowthandsurvival（幸存）ofcertaincelltypesduringembryonal（胚的）developmentande.g.tissue（纸巾）repairintheadult.Overactivity（过于活泼）ofPDGFreceptorsignaling,byoverexpression（超表达）ormutational（突变的）events,maydrivetumor（肿瘤）cellgrowth.Inaddition,pericytes（周皮细胞）ofthevasculature（脉管系统）andfibroblasts（纤维原细胞）andmyofibroblastsofthestroma（基质）ofsolidtumorsexpressPDGFreceptors,andPDGFstimulation（刺激）ofsuchcellspromotes（促进）tumorigenesis（肿瘤发生）.Inhibition（抑制）ofPDGFreceptorsignalinghasproven（证明）tousefulforthetreatmentofpatientswithcertainraretumors.WhethertreatmentwithPDGF/PDGFreceptorantagonists（敌手）willbebeneficial（有益的）formorecommonmalignancies（恶性）isthesubjectforongoingstudies.

IntroductionPlatelet-derivedgrowthfactor（PDGF）isoformsstimulate（刺激）growth,survivalandmotility（运动性）ofmesenchymal（间叶细胞的）cellsandcertainothercelltypes[1,2].Theyhaveimportantfunctionsduringembryonaldevelopmentandinthecontroloftissuehomeostasis（体内平衡）intheadult.OveractivityofPDGFsignalingisassociated（交往）withthedevelopmentofcertainmalignant（恶性的）diseases,aswellasnon-malignantdiseasescharacterized（以…为特点的）byexcessive（过多的）cellproliferation（增殖）.Theinvolvement（牵连）ofPDGFoveractivityinnon-malignantdiseaseshasbeendiscussedinarecentreview[3].ThepresentreviewwillfocusontheroleofPDGFsignalingintumordevelopment,andontheuseofPDGFantagonistsintumortreatment.

PDGFisoformsThePDGFfamilyconsistsofdisulphide-bondedhomodimersofA-,B-,C-andD-polypeptidechains,andtheheterodimer（异质二聚体）PDGF-AB.ThePDGFisoformsaresynthesized（合成的）asprecursor（先驱）molecules（分子）.PDGF-AA,-ABand–BBarecleaved（裂开）alreadyinsidetheproducercellsinsecretory（分泌的）vesicles（泡）.Incontrast（对比）,PDGF-CCand–DDaresecreted（分泌）asinactive（不活跃的）precursormolecules;N-terminalCUB-domainsneedtobecleavedofftoactivate（刺激）thegrowthfactors.Thiscleavage（劈开）servesanimportantregulatory（管理的）role,andisperformedbytissue-typeplasminogen（血纤维蛋白溶酶原）activator（催化剂）（tPA）orplasmin（胞浆素）inthecaseofPDGF-CC,andbyurokinase-typePA（uPA）ormatriptase（MT-Sp1）inthecaseofPDGF-DD[4-7]（Figure1）.

BindingofthefivePDGFisoformsinducesdifferenthomo-andheterodimericcomplexesofPDGFRαandPDGFRβ. ThePDGFisoformsaresynthesizedasprecursormolecules前体分子withsignalsequences信号肽（grey）,precursorsequences前体序列（open）andgrowthfactordomains生长因子域（red,blue,yellowandgreen）.Afterdimerization二聚化,theisoforms亚型areproteolytically蛋白水解的processed（arrows）totheiractiveformswhichbindtothereceptors.Theextracellular细胞外的partsofthereceptorscontain5Ig-likedomains;ligandbindingoccurspreferentiallytodomains2and3,anddomain4stabilizesthedimer稳定的二聚体byadirectreceptor-receptorinteraction.Theintracellularpartsofthereceptorscontaintyrosinekinasedomainssplitintotwopartsbyaninterveningsequence.Ligand-induceddimerizationinducesautophosphorylation自身磷酸化ofthereceptors,whichactivatestheirkinasesandcreatedockingsitesforSH2-domain-containingsignalingmolecules,someofwhichareindicatedinthefigure.Activationofthesesignalingpathwayspromotescellgrowth,survival,migrationandactinreorganization肌动蛋白重组.

SignalingviaPDGF receptors（受体）

PDGFisoforms exert（运用） their cellular（细胞的） effectsbybindingtoα-andβ-tyrosine kinase（激酶） receptors（PDGFRαandPDGFRβ, respectively（分别的））.ThetwoPDGFreceptorsare structurally（在结构上） similarandconsistof extracellular（细胞外的） domainswithfive immunoglobulin（免疫球蛋白） （Ig）-likedomainsandintracellular（细胞内的） partswithkinasedomainswhichcontain characteristic（特征） insertsofabout100amino（氨基的） acid（酸） residues（残渣） without homology（同源） tokinases. Ligand（配合基） bindingoccursmainlytoIg-likedomains2and3,andcauses dimerization（二聚） ofthereceptors,whichisfurtherstabilized（稳固） bydirectreceptor-receptor interactions（相互作用） involving（包含） Ig-likedomain4[8,9].Thedimerizationisakeyeventin activation（激活） sinceitbringstheintracellularpartsofthereceptorsclosetoeachother promoting（促进） autophosphorylation（自身磷酸化） intrans betweenthereceptors.ThePDGFpolypeptide（多肽） chainsbindtothereceptorswithdifferent affinities（密切关系）.Thus,PDGF-AA,-AB,-BBand-CCinduceααreceptorhomodimers,PDGF-BBandPDGF-DDββreceptorhomodimers,andPDGF-AB,-BB,-CCand–DDαβreceptor heterodimers（异质二聚体） Figure  1;[2].

Theautophosphorylationservestwoimportantfunctions.First,itchangesthe conformation（构造） oftheintracellularpartofthereceptorsothatthekinaseis activated（刺激）.Thereisno3-dimensional structure（结构）yetforPDGFreceptors,so precise（精确的） informationabout mechanisms（机制） thatcontrolthekinaseisnotavailable.However,itislikelythatintherestingstate,thekinaseiskept inactive（不活跃的） byatleastthreemechanisms:

 i）Theactivation loop（环） inthekinasedomainislikelytobefoldedoverthe catalytic（接触反应的）cleft（分裂的）;autophosphorylationofa conserved（保存） tyrosine（酪氨酸） residueinthisregioncausesthelooptomoveawayfromtheactivesite[10]. ii）Thejuxtamembranepartofthe receptor（受体） islikelytobefoldedina loop（环） whichrestrictstheaccesstotheactivesite; autophosphorylation（自身磷酸化） oftwotyrosine（酪氨酸） residues（残渣） inthisregionchangesthe conformation（构造） and enhances（提高） thekinase（激酶） activity[11]. iii）TheC-terminaltailofthereceptorismostlikelyfoldedoverthekinasedomain;autophosphorylationoftwoC-terminally located（位于） tyrosineresidues relieves（救济） thekinaseofthisinhibition（抑制） [12].Similar regulatory（管理的） mechanisms（机制） havebeenobservedinthestructurally（在结构上） related colony（殖民地） stimulating（刺激） factor-1receptor（CSF1R）andFLT3.

Second,autophosphorylationcreates docking（入坞） sitesforSH2-domain-containingsignaling molecules（分子）.Theα-andβ-receptorscontain10and11knownautophosphorylatedtyrosineresidues, respectively（分别的）[13].About10differentfamiliesofSH2-domain-containingmoleculeshavebeenshownto selectively（有选择地）bind（绑） todifferent phosphorylated（磷酸化） residuesinthePDGFreceptors.Theseincludesignalingmoleculeswith intrinsic（本质的） enzymatic（酶的） activities,suchastyrosinekinasesoftheSrcfamily,theSHP-2tyrosinephosphatase（磷酸酶）, phospholipase（磷脂酶） C-γ（PLC-γ）andtheGTPase activating（刺激）protein（蛋白质的） （GAP）forRas.Moreover,thereceptorsbindandactivatesignal transducers（转换） andactivators（催化剂） of transcription（抄写） （STATs）,whichafter activation（激活） aretranslocated（改变…的位置） tothe nucleus（核） wheretheyactastranscription factors（因素）.Finally,thereceptorsbind adaptor（适配器） moleculeswhichlackintrinsicenzymaticactivities,butcanform complexes（复体）withothersignalingmolecules.Examplesincludetheregulatory subunit（亚组） p85ofthephosphatidylinositol（磷脂酰肌醇） 3′-kinase（PI3K）,whichformscomplexwiththep110 catalytic（接触反应的）subunit,andGrb2whichbindsthe nucleotide（核苷） exchangemoleculeSOS1,activatingRasandtheErkMAP-kinase pathway（路） （Figure  1）.Inaddition,thePDGFreceptorsbindotheradaptors, e.g. Shc,Nck,CrkandGAB,which mediate（间接的） interactions（相互作用） witha plethora（过多） ofdifferent downstream（下游地）signalingmolecules.Theactivationofthesesignalingpathwaysleadstocell proliferation（增殖） and survival（幸存）,aswellasto actin（肌动蛋白） reorganization（改组） andcell migration（迁移）.The extensive（广泛的） cross-talk（相声） betweenthedifferentsignalingpathwaysmakesitdifficultto assign（分配） individual（个人的） pathwaysto specific（特殊的） responses;inacell-type-and context-dependent（上下文相关的） manner,severalsignalingpathways contribute（贡献） toeachofthe cellular（细胞的） responses.

对SH2domain的解释

ThefunctionofSH2domainsisto specifically（特别地） recognizethe phosphorylated（磷酸化） stateof tyrosine（酪氨酸） residues（残渣）,therebyallowingSH2domain-containingproteinsto localize（地方化） totyrosine-phosphorylatedsites.Thisprocess constitutes（组成） the fundamental（基本的） eventofsignaltransduction（转导） througha membrane（膜）,inwhichasignalinthe extracellular（细胞外的） compartment（隔间） is"sensed"bya receptor（受体） andisconverted（转变） inthe intracellular（细胞内的） compartmenttoadifferentchemicalform,i.e.thatofaphosphorylatedtyrosine.Tyrosinephosphorylation（磷酸化作用） leadsto activation（激活） ofa cascade（层叠） ofprotein-protein interactions（相互作用） whereby（凭什么） SH2domain-containingproteinsare recruited（招聘） totyrosine-phosphorylatedsites.

Modulation（调制） and termination（结束） ofPDGFreceptorsignaling

SignalingviaPDGFreceptorsiscarefullycontrolledand modulated（已调的）.Intheearly phase（相） ofsignalingdifferentmechanisms assure（保证） thatthesignalrapidlyreaches sufficient（足够的） strength.For instance（实例）,inPDGFstimulatedcells reactive oxygen species活性氧 areproducedinaPI3-kinase-dependentpathway,which inhibit（抑制） tyrosinephosphatasesby reacting（反应） witha cysteine（半胱氨酸） residueintheiractivesite[14,15].Another mechanism（机制） that amplifies（放大） thesignalingisthe ubiquitination（泛素化） anddegradation（退化） ofMAP-kinase phosphatase（磷酸酶） 3,which dephosphorylates（脱去磷酸） andinactivates（使不活动） ErkMAP-kinase; removal（免职） ofthisphosphatase enhances（提高） ErkMAP-kinaseactivation（激活） [16].

Therearealsomechanismsthat negatively（负的） modulate（调节） PDGFsignaling.Oneexampleisthedocking（入坞） ofRas-GAPtothe activated（刺激） PDGFRβ;this counteracts（抵消） theactivationofRaswhichoccursbythe simultaneous（同时的） dockingoftheGrb2-SOS1 complex（复杂的） [17].Int