PDGFB的文章总结.docx

1、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。Targeting the PDGF signaling pathway(路) in tumor(肿瘤) treatmentAbstract Platelet-derived growth factor(因素) (PDGF) isoforms(同种型) and PDGF receptors(受体) have impo

2、rtant functions in the regulation of growth and survival(幸存) of certain cell types during embryonal(胚的) development and e.g. tissue(纸巾) repair in the adult. Overactivity(过于活泼) of PDGF receptor signaling, by overexpression(超表达) or mutational(突变的) events, may drive tumor(肿瘤) cell growth. In addition,

3、pericytes(周皮细胞) of the vasculature(脉管系统) and fibroblasts(纤维原细胞) and myofibroblasts of the stroma(基质) of solid tumors express PDGF receptors, and PDGF stimulation(刺激) of such cells promotes(促进) tumorigenesis(肿瘤发生). Inhibition(抑制) of PDGF receptor signaling has proven(证明) to useful for the treatment o

4、f patients with certain rare tumors. Whether treatment with PDGF/PDGF receptor antagonists(敌手) will be beneficial(有益的) for more common malignancies(恶性) is the subject for ongoing studies.Introduction Platelet-derived growth factor (PDGF) isoforms stimulate(刺激) growth, survival and motility(运动性) of m

5、esenchymal(间叶细胞的) cells and certain other cell types 1,2. They have important functions during embryonal development and in the control of tissue homeostasis(体内平衡) in the adult. Overactivity of PDGF signaling is associated(交往) with the development of certain malignant(恶性的) diseases, as well as non-m

6、alignant diseases characterized(以为特点的) by excessive(过多的) cell proliferation(增殖). The involvement(牵连) of PDGF overactivity in non-malignant diseases has been discussed in a recent review 3. The present review will focus on the role of PDGF signaling in tumor development, and on the use of PDGF antago

7、nists in tumor treatment. PDGF isoforms The PDGF family consists of disulphide-bonded homodimers of A-, B-, C- and D-polypeptide chains, and the heterodimer(异质二聚体) PDGF-AB. The PDGF isoforms are synthesized(合成的) as precursor(先驱) molecules(分子). PDGF-AA, -AB and BB are cleaved(裂开) already inside the p

8、roducer cells in secretory(分泌的) vesicles(泡). In contrast(对比), PDGF-CC and DD are secreted(分泌) as inactive(不活跃的) precursor molecules; N-terminal CUB-domains need to be cleaved off to activate(刺激) the growth factors. This cleavage(劈开) serves an important regulatory(管理的) role, and is performed by tissu

9、e-type plasminogen(血纤维蛋白溶酶原) activator(催化剂) (tPA) or plasmin(胞浆素) in the case of PDGF-CC, and by urokinase-type PA (uPA) or matriptase (MT-Sp1) in the case of PDGF-DD 4-7 (Figure 1).Binding of the five PDGF isoforms induces different homo- and heterodimeric complexes of PDGFR and PDGFR.The PDGF isof

10、orms are synthesized as precursor molecules前体分子 with signal sequences信号肽 (grey), precursor sequences前体序列 (open) and growth factor domains生长因子域 (red, blue, yellow and green). After dimerization二聚化, the isoforms亚型 are proteolytically蛋白水解的 processed (arrows) to their active forms which bind to the rece

11、ptors. The extracellular细胞外的parts of the receptors contain 5 Ig-like domains; ligand binding occurs preferentially to domains 2 and 3, and domain 4 stabilizes the dimer稳定的二聚体 by a direct receptor-receptor interaction. The intracellular parts of the receptors contain tyrosine kinase domains split int

12、o two parts by an intervening sequence. Ligand-induced dimerization induces autophosphorylation自身磷酸化 of the receptors, which activates their kinases and create docking sites for SH2-domain-containing signaling molecules, some of which are indicated in the figure. Activation of these signaling pathwa

13、ys promotes cell growth, survival, migration and actin reorganization肌动蛋白重组.Signaling via PDGFreceptors(受体)PDGF isoformsexert(运用)theircellular(细胞的)effects by binding to - and -tyrosinekinase(激酶)receptors (PDGFR and PDGFR,respectively(分别的). The two PDGF receptors arestructurally(在结构上)similar and cons

14、ist ofextracellular(细胞外的)domains with fiveimmunoglobulin(免疫球蛋白)(Ig) - like domains andintracellular(细胞内的)parts with kinase domains which containcharacteristic(特征)inserts of about 100amino(氨基的)acid(酸)residues(残渣)withouthomology(同源)to kinases.Ligand(配合基)binding occurs mainly to Ig-like domains 2 and 3

15、, and causesdimerization(二聚)of the receptors, which is furtherstabilized(稳固)by direct receptor-receptorinteractions(相互作用)involving(包含)Ig-like domain 4 8,9. The dimerization is a key event inactivation(激活)since it brings the intracellular parts of the receptors close to each otherpromoting(促进)autopho

16、sphorylation(自身磷酸化)in transbetween the receptors. The PDGFpolypeptide(多肽)chains bind to the receptors with differentaffinities(密切关系). Thus, PDGF-AA, -AB, -BB and -CC induce receptor homodimers, PDGF-BB and PDGF-DD receptor homodimers, and PDGF-AB, -BB, -CC and DD receptorheterodimers(异质二聚体)Figure1;

17、2.The autophosphorylation serves two important functions. First, it changes theconformation(构造)of the intracellular part of the receptor so that the kinase isactivated(刺激). There is no 3-dimensionalstructure(结构)yet for PDGF receptors, soprecise(精确的)information aboutmechanisms(机制)that control the kin

18、ase is not available. However, it is likely that in the resting state, the kinase is keptinactive(不活跃的)by at least three mechanisms:i) The activationloop(环)in the kinase domain is likely to be folded over thecatalytic(接触反应的)cleft(分裂的); autophosphorylation of aconserved(保存)tyrosine(酪氨酸)residue in thi

19、s region causes the loop to move away from the active site 10.ii) The juxtamembrane part of thereceptor(受体)is likely to be folded in aloop(环)which restricts the access to the active site;autophosphorylation(自身磷酸化)of two tyrosine(酪氨酸)residues(残渣)in this region changes theconformation(构造)andenhances(提

20、高)the kinase(激酶)activity 11.iii) The C-terminal tail of the receptor is most likely folded over the kinase domain; autophosphorylation of two C-terminallylocated(位于)tyrosine residuesrelieves(救济)the kinase of thisinhibition(抑制)12. Similarregulatory(管理的)mechanisms(机制)have been observed in the structur

21、ally(在结构上)relatedcolony(殖民地)stimulating(刺激)factor-1 receptor (CSF1R) and FLT3.Second, autophosphorylation createsdocking(入坞)sites for SH2-domain-containing signalingmolecules(分子). The - and -receptors contain 10 and 11 known autophosphorylated tyrosine residues,respectively(分别的)13. About 10 differen

22、t families of SH2-domain-containing molecules have been shown toselectively(有选择地)bind(绑)to differentphosphorylated(磷酸化)residues in the PDGF receptors. These include signaling molecules withintrinsic(本质的)enzymatic(酶的)activities, such as tyrosine kinases of the Src family, the SHP-2 tyrosinephosphatas

23、e(磷酸酶),phospholipase(磷脂酶)C- (PLC-) and the GTPaseactivating(刺激)protein(蛋白质的)(GAP) for Ras. Moreover, the receptors bind and activate signaltransducers(转换)andactivators(催化剂)oftranscription(抄写)(STATs), which afteractivation(激活)aretranslocated(改变的位置)to thenucleus(核)where they act as transcriptionfactor

24、s(因素). Finally, the receptors bindadaptor(适配器)molecules which lack intrinsic enzymatic activities, but can formcomplexes(复体)with other signaling molecules. Examples include the regulatorysubunit(亚组)p85 of thephosphatidylinositol(磷脂酰肌醇)3-kinase (PI3K), which forms complex with the p110catalytic(接触反应的

25、)subunit, and Grb2 which binds thenucleotide(核苷)exchange molecule SOS1, activating Ras and the Erk MAP-kinasepathway(路)(Figure1). In addition, the PDGF receptors bind other adaptors,e.g.Shc, Nck, Crk and GAB, whichmediate(间接的)interactions(相互作用)with aplethora(过多)of differentdownstream(下游地)signaling m

26、olecules. The activation of these signaling pathways leads to cellproliferation(增殖)andsurvival(幸存), as well as toactin(肌动蛋白)reorganization(改组)and cellmigration(迁移). Theextensive(广泛的)cross-talk(相声)between the different signaling pathways makes it difficult toassign(分配)individual(个人的)pathways tospecif

27、ic(特殊的)responses; in a cell-type- andcontext-dependent(上下文相关的)manner, several signaling pathwayscontribute(贡献)to each of thecellular(细胞的)responses.对SH2 domain的解释 The function of SH2 domains is tospecifically(特别地)recognize thephosphorylated(磷酸化)state oftyrosine(酪氨酸)residues(残渣), thereby allowing SH2

28、domain-containing proteins tolocalize(地方化)to tyrosine-phosphorylated sites. This processconstitutes(组成)thefundamental(基本的)event of signaltransduction(转导)through amembrane(膜), in which a signal in theextracellular(细胞外的)compartment(隔间)is sensed by areceptor(受体)and isconverted(转变)in theintracellular(细胞

29、内的)compartment to a different chemical form, i.e. that of a phosphorylated tyrosine. Tyrosinephosphorylation(磷酸化作用)leads toactivation(激活)of acascade(层叠)of protein-proteininteractions(相互作用)whereby(凭什么)SH2 domain-containing proteins arerecruited(招聘)to tyrosine-phosphorylated sites.Modulation(调制)andter

30、mination(结束)of PDGF receptor signalingSignaling via PDGF receptors is carefully controlled andmodulated(已调的). In the earlyphase(相)of signaling different mechanismsassure(保证)that the signal rapidly reachessufficient(足够的)strength. Forinstance(实例), in PDGF stimulated cellsreactive oxygenspecies活性氧are p

31、roduced in a PI3-kinase-dependent pathway, whichinhibit(抑制)tyrosine phosphatases byreacting(反应)with acysteine(半胱氨酸)residue in their active site 14,15. Anothermechanism(机制)thatamplifies(放大)the signaling is theubiquitination(泛素化)and degradation(退化)of MAP-kinasephosphatase(磷酸酶)3, whichdephosphorylates(

32、脱去磷酸)and inactivates(使不活动)Erk MAP-kinase;removal(免职)of this phosphataseenhances(提高)Erk MAP-kinaseactivation(激活)16.There are also mechanisms thatnegatively(负的)modulate(调节)PDGF signaling. One example is the docking(入坞)of Ras-GAP to theactivated(刺激)PDGFR; thiscounteracts(抵消)the activation of Ras which occurs by thesimultaneous(同时的)docking of the Grb2-SOS1complex(复杂的)17. Int