Protein tyrosine phosphatase non-receptor type 2 andinflammatory bowel disease

Genome wide association studies have associated single nucleotide polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2(PTPN2) with the onset of inflammatory bowel disease(IBD) and other inflammatory disorders. Expression of PTPN2 is enhanced in actively inflamed intestinal tissue featuring a marked up-regulation in intestinal epithelial cells. PTPN2 deficient mice suffer from severe intestinal and systemic inflammation and display aberrant innate and adaptive immune responses. In particular, PTPN2 is involved in the regulation of inflammatory signalling cascades, and critical for protecting intestinal epithelial barrier function, regulating innate and adaptive immune responses, and finally for maintaining intestinal homeostasis. On one hand, dysfunction of PTPN2 has drastic effects on innate host defence mechanisms, including increased secretion of pro-inflammatory cytokines, limited autophagosome formation in response to invading pathogens, and disruption of the intestinal epithelial barrier. On the other hand, PTPN2 function is crucial for controlling adaptive immune functions, by regulating T cell proliferation and differentiation as well as maintaining T cell tolerance. In this way, dysfunction of PTPN2 contributes to the manifestation of IBD. The aim of this review is to present an overview of recent findings on the role of PTPN2 in intestinal homeostasis and the impact of dysfunctional PTPN2 on intestinal inflammation.

An association study of protein tyrosine phosphatase receptor type R gene polymorphism and the resting-state functional magnetic resonance imaging in major depressive disorder

Objective To explore the influence of a polymorphism of protein tyrosine phosphatase receptor type R(PTPRR)gene rs1513105 on abnormal brain activities in resting-state patients with major depressive disorder(MDD)using the gene-imaging technology.Methods 54MDD and 43 gender-,age-,and education-matched con-

Prediction of functional phosphorylation sites by incorporating evolutionary information

Protein phosphorylation is a ubiquitous protein post-translational modification,which plays an important role in cellular signaling systems underlying various physiological and pathological processes.Current in silico methods mainly focused on the prediction of phosphorylation sites,but rare methods considered whether a phosphorylation site is functional or not.Since functional phosphorylation sites are more valuable for further experimental research and a proportion of phosphorylation sites have no direct functional effects,the prediction of functional phosphorylation sites is quite necessary for this research area.Previous studies have shown that functional phosphorylation sites are more conserved than non-functional phosphorylation sites in evolution.Thus,in our method,we developed a web server by integrating existing phosphorylation site prediction methods,as well as both absolute and relative evolutionary conservation scores to predict the most likely functional phosphorylation sites.Using our method,we predicted the most likely functional sites of the human,rat and mouse proteomes and built a database for the predicted sites.By the analysis of overall prediction results,we demonstrated that protein phosphorylation plays an important role in all the enriched KEGG pathways.By the analysis of protein-specific prediction results,we demonstrated the usefulness of our method for individual protein studies.Our method would help to characterize the most likely functional phosphorylation sites for further studies in this research area.

植物GYF结构域的进化和功能分析

根据GYF结构域蛋白质分布的广泛性及功能的多样性,更深入地研究GYF结构域蛋白,并对其进行进化分析是十分必要的。因AtEXA1是植物里研究最为透彻的GYF结构域蛋白,因此,本研究主要聚焦于与AtEXA1类似的蛋白的研究。通过分析真核生物(范围从单细胞低等真菌到高等生物)中的8053个GYF结构域蛋白,研究发现类似AtEXA1的蛋白质主要存在于植物物种中,而来自动物的GYF蛋白质与AtEXA1的相似性较低。研究还发现,类似AtEXA1的蛋白质存在于几乎所有的农作物中。本研究展示了GYF结构域蛋白的保守性,初步解构了GYF结构域蛋白进化的历程,并为后续对GYF结构域蛋白功能特征的研究提供了启示。

乙醇脱氢酶(ADH)家族生物信息学分析

本研究用生物信息学的方法分析了玉米等7个物种ADH的保守功能域、蛋白二级结构和进化关系。分析证实,植物ADH通常含有3个保守功能域,它们具有GroES结构的ADH_N结构域,Rossmann折叠NAD(P)(+)结合蛋白和锌结合位点,这3个保守结构在物种中具有相当的保守性。二级结构的分析表明,在我们研究的物种中,每个物种的两个ADH同工酶折叠情况大体相同,物种间蛋白二级结构也趋向一致。通过构建系统进化树,分析了供试物种中ADH以及ADH两个同工酶间的进化关系。初步显示,在进化上,单、双子叶植物源自不同的ADH祖先。双子叶植物ADH在物种间具有差异;而在单子叶植物不同物种其ADH同工酶出现分化。

蛋白质序列和结构的保守性与其功能的关系

以蛋白质酪氨酸磷酸酶为模型，通过序列和结构的比较，对蛋白质序列、结构的保守性与其功能和进化的关系问题进行了研究。结果显示，虽然在酪氨酸磷酸酶超家族分子的序列中，仅有３个与其催化功能密切相关的残基是高度保守的，但它们功能结构域的核心拓扑结构却明显类似，其中存在着βαβ和βαβα２个保守的结构单元；此外，它们活性位点的拓扑结构也极其相似。因此，在保持蛋白质功能方面具有重要作用的残基是高度保守的，而具维持蛋白质结构作用的残基则是相对保守的。在进化过程中，蛋白质三维拓扑结构的保守性，似乎主要是体现在保持某些共同的特有二级结构单元和共同的折叠方式上。

蛋白酪氨酸磷酸酶H型受体的生物学功能及其在肿瘤中的研究进展

蛋白酪氨酸磷酸酶H型受体(protein tyrosine phosphatase H receptor,PTPRH)基因是一种编码胃癌相关蛋白的基因,通过翻译后COOH-末端区域的酪氨酸磷酸化修饰发挥其生物学功能。PTPRH在多种肿瘤中呈异常表达,其生物学功能与肿瘤的发生、发展及预后密切相关。

杆状病毒的酪氨酸蛋白磷酸酯酶研究

酪氨酸蛋白磷酸酯酶是生命细胞内一类重要的酶 ,与细胞信号转导有关 ,对多种生理过程如生长、分化、代谢、细胞周期调节和细胞骨架等具有重要的调节功能。某些杆状病毒和痘苗病毒的基因组中具有编码酪氨酸蛋白磷酸酯酶的开读框 ,与感染性和致病性有关。病毒编码的酪氨酸蛋白磷酸酯酶具有双重底物特异性 ,即可以同时催化蛋白质酪氨酸和丝氨酸

植物冷休克结构域蛋白的生物学功能研究进展

冷休克结构域蛋白(Cold shock domain proteins,CSDPs)是一类从细菌到高等动植物中均广泛存在的具有高度进化保守性的核酸结合蛋白。综述了植物冷休克结构域蛋白的进化与结构、生物学功能及其结构与功能的关系等方面的研究进展,同时对今后植物冷休克结构域蛋白研究方向进行了探讨。

妊娠期葡萄糖筛查异常孕妇的PTP-1B与IR相关性的研究

目的探讨蛋白酪氨酸磷酸酶1B（PTP-1B）与胰岛素抵抗（IR）的关系及在妊娠期糖尿病（GDM）发病机制中的作用，以早期预防和干预GDM，减少母儿并发症。方法2011年4～10月在我院产前检查的妊娠期糖尿病孕妇（C组）、葡萄糖负荷试验（GCT）异常而葡萄糖耐量试验（OGTr）正常的孕妇（B组）及葡萄糖负荷试验正常的孕妇（A组）各30例，分别测定空腹PTP-1B、空腹血糖、空腹胰岛素水平，同时计算胰岛素抵抗指数（HOMA—IR）和胰岛B细胞功能指数（HOMA—HBCI），分析比较各组的差异与关系。结果①C组的HOMA—IR明显高于A组、B组，差异有统计学意义（P〈0．01，P〈0．05）。②C组的PTP-1B值明显高于A组、B组，差异有统计学意义（P〈0．01）。③相关性分析：血浆PTP-1B与孕前BMI、空腹血糖、空腹胰岛素、HOMA—IR呈正相关．相关系数分别为：r=0．347，P=0．001；r=0．263，P=0．012；r=0．287，P=0．006；r=0．318，P=0．002。结论GDM存在更严重的IR，PTP-1B与IR有关，可能参与GDM的发生和发展。

Identification of protein superfamily from structure-based sequence motif

The structure-based sequence motif of the distant proteins in evolution, protein tyrosine phosphatases (PTP) I and Ⅱ superfamilies, as an example, has been defined by the structural comparison, structure-based sequence alignment and analyses on substitution patterns of residues in common sequence conserved regions. And the phosphatases I and Ⅱ can be correctly identified together by the structure-based PTP sequence motif from SWISS-PROT and TrEBML databases. The results show that the correct rates of identification are over 98%. This is the first time to identify PTP I and Ⅱ together by this motif.

蛋白酪氨酸磷酸酶调控血小板功能的研究现状

血小板为血液重要组成成分,在止血及血栓形成过程中发挥关键作用。血小板行使功能涉及多种信号通路,蛋白磷酸化作用能够特异性调控血小板信号通路的激活。蛋白酪氨酸磷酸酶(PTP)参与调控血小板的蛋白磷酸化及去磷酸化过程。既往研究已发现多种血小板蛋白激酶,但对发挥负向调控作用的PTP研究较少。笔者拟从血小板生理功能及其活化、血小板内信号蛋白的磷酸化调控、PTP在血小板功能调控中的作用和靶向血小板PTP的临床应用方面,对PTP调控血小板功能的研究现状进行阐述,旨在为新靶向药物的研发提供依据。

非受体型蛋白酪氨酸磷酸酶2在肿瘤免疫中的研究进展

非受体型蛋白酪氨酸磷酸酶2 (protein tyrosine phosphatase non-receptor type 2, PTPN2)作为蛋白酪氨酸磷酸酶家族成员,通过催化去磷酸化反应,在细胞信号传递中起着重要作用。PTPN2过表达与多种癌症患者预后不良密切相关,而其缺失能有效抑制肿瘤的增长、迁移,并促进细胞凋亡。在免疫系统中,PTPN2在T细胞功能以及肿瘤微环境的调节中起着关键作用。因此,PTPN2在肿瘤发展过程和肿瘤免疫中扮演了重要角色,是一个潜在抗肿瘤新靶点。目前,有多个PTPN2抑制剂或降解剂被发现,其中两个抑制剂已进入临床I期试验阶段。该文综述了PTPN2的结构特性、在抗肿瘤免疫中的功能与应用,以及当前对其抑制剂和降解剂在肿瘤治疗中的研究进展。

Identification of PTPRR and JAG1 as key genes in castrationresistant prostate cancer by integrated bioinformatics methods

To identify novel genes in castration-resistant prostate cancer(CRPC),we downloaded three microarray datasets containing CRPC and primary prostate cancer in Gene Expression Omnibus(GEO).R packages affy and limma were performed to identify differentially expressed genes(DEGs)between primary prostate cancer and CRPC.After that,we performed functional enrichment analysis including gene ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)pathway.In addition,protein–protein interaction(PPI)analysis was used to search for hub genes.Finally,to validate the significance of these genes,we performed survival analysis.As a result,we identified 53 upregulated genes and 58 downregulated genes that changed in at least two datasets.Functional enrichment analysis showed significant changes in the positive regulation of osteoblast differentiation pathway and aldosteroneregulated sodium reabsorption pathway.PPI network identified hub genes like cortactin-binding protein 2(CTTNBP2),Rho family guanosine triphosphatase(GTPase)3(RND3),protein tyrosine phosphatase receptor-type R(PTPRR),Jagged1(JAG1),and lumican(LUM).Based on PPI network analysis and functional enrichment analysis,we identified two genes(PTPRR and JAG1)as key genes.Further survival analysis indicated a relationship between high expression of the two genes and poor prognosis of prostate cancer.In conclusion,PTPRR and JAG1 are key genes in the CRPC,which may serve as promising biomarkers of diagnosis and prognosis of CRPC.

植物蛋白酪氨酸磷酸酶的生理功能研究进展

植物蛋白酪氨酸磷酸酶与蛋白激酶共同控制可逆磷酸酶作用,在植物的生长、器官发育、激素应答、信号传递和胁迫应答过程中发挥着重要的生理功能。文章主要介绍植物蛋白酪氨酸磷酸酶的分类、蛋白酪氨酸磷酸酶在其生长发育、非生物和生物胁迫应答中的生物学功能及其参与的信号途径,以期为后续研究提供理论参考。

靶向SHP2^(E76A)突变体的小分子降解剂有效抑制野生型和突变体SHP2肿瘤细胞增殖

SHP2 (Src homology 2 domain-containing protein tyrosine phosphatase-2)是由Ptpn11基因编码的非受体型蛋白酪氨酸磷酸酶,通过RAS (rat sarcoma)-ERK (extracellular regulated protein kinases)信号通路的活化调控细胞生长、分化和凋亡,并参与PD-1 (programmed cell death protein 1)/PD-L1(programmed cell death ligand 1)通路的免疫监控,已成为有突破意义的抗癌药物新靶标.靶向SHP2变构位点的抑制剂通过稳定SHP2非活性构象而抑制磷酸酶催化功能,具有很好的成药性.但是,SHP2功能获得性突变(gainoffunction,简称GOF)导致一系列发育障碍疾病和肿瘤的发生,并对SHP2野生型变构抑制剂产生耐药性.本工作首次以靶向SHP2激活突变体的变构抑制剂为靶头,基于PROTACs(proteolysis-targeting chimeras)技术,设计合成了一系列全新SHP2小分子降解剂.其中先导化合物3f和4d保持了对突变型SHP2^(E76A)的酶抑制活性,而且对于野生型SHP2依赖的人食管鳞癌细胞KYSE-520和突变型SHP2^(N58S)人大细胞肺癌细胞NCI-H661都显示强效抗增殖活性,比相应变构抑制剂的活性提高了5~10倍,为治疗SHP2突变或活化导致的遗传性疾病或肿瘤提供了新的干预策略.