Razi Journal of Medical Sciences

fa نقش های توالی EPIYA در برهم زدن مسیرهای پیام رسانی سلولی و خطر بروز سرطان The roles of EPIYA sequence to perturb the cellular signaling pathways and cancer risk بیولوژی (زیست شناسی) Biology مروري review article پروتئین&lrm;های اثرگر برخی از باکتریهای مهاجم دارای توالی EPIYA  و یا توالی مشابه ان هستند که شامل اسید امینه های گلوتامیک اسید، پرولین، ایزولوسین، تیروزین و الانین می باشد و اغلب از طریق سیستم ترشحی نوع سه و یا نوع چهار به سلول میزبان منتقل می&rlm;شوند و در اسید امینه تیروزین موجود در توالی های مذکور فسفریله می&rlm;گردند. فسفریله شدن تیروزین موجود در پروتئین&lrm;های اثرگر باکتریها، انها را قادر می&rlm;سازد که با پروتئین&lrm;های حاوی دمین SH2 سلول میزبان برهم کنش نمایند. اخیرا، نشان داده است که تعدادی از پروتئین های سلول میزبان نیز حاوی توالی&rlm;های مذکور هستند و با فسفوریله شدن تیروزین قادر به برهم کنش با پروتئین حاوی دمین  SH2داخل سلولی بطور اختصاصی می&rlm;باشند. بنابراین فرض شده است که توالی های موجود در سلول های میزبان ممکن است توسط باکتریهای مهاجم ربوده شده و با برهم کنش با تعداد زیادی پروتئین&lrm;های حاوی SH2 دومین سلول میزبانی مانند "شاه کلید" عمل &rlm;کند که باعث برهم زدن مسیرهای پیام رسانی سلول می گردد. در همین ارتباط نشان داده شده است که در برخی از باکتریها EPIYA موتیف ساختار بدون تا خوردگی و دارای خاصیت انعطاف&rlm; پذیری دارد. تا کنون ساختار پروتئین های میزبانی حاوی توالی های EPIYA شناخته نشده است. در این مقاله مروری، نقش های عملکردی توالی های EPIYA در توکسین های باکتریایی و پروتئین های میزبانی را به عنوان توالی های کلیدی در جهت برهم زدن مسیرهای پیام رسانی سلولی و خطر بروز سرطان مورد بررسی قرار می&rlm;دهیم.     It was shown that several pathogenic bacterial effector proteins including Helicobacter pylori CagA, Anaplama phagocytophilium AnkA, enteropathogenic Escherichia coli (EPEC) Tir protein, Chlamydia trachomatis Tarp, Haemophilus ducreyi LspA protein, and Bartonella henselae Bep proteins contain the Glu-Pro-Ile-Tyr-Ala (EPIYA) or a similar sequence. These bacterial EPIYA effectors are delivered into host cell via type III secretion system (or TTSS) or type IV secretion system (TFSS), where they undergo tyrosine phosphorylation at the EPIYA (or a similar sequences). The bacterial EPIYA effectors trigger interaction with huge number of host cell SH2 domain-containing proteins and thereby, they enable to manipulate host cell signaling for more effective infection. The EPIYA (or a similar sequence) of pathogenic bacterial effector proteins was discovered in H. pylori CagA. It was shown that cagA+ H. pylori strains significantly increase the risk of developing severe gastritis and gastric carcinoma. On the base of the geographic region, four distinct EPIYA-sites have been described, EPIYA-A, -B, -C, and -D, each of which is conserved. Remarkably, the EPIYA-A and EPIYA-B sequences are found in strains throughout the world, but EPIYA-C is mainly present in strains from Western countries (Australia, Europe and North America) and some Asian countries (India and Malaysia), while the EPIYA-D sequence predominates in China, Japan and Korea. Different numbers of EPIYA (or similar sequence) can appear at the C-terminal of CagA variants. CagA proteins were tyrosine phosphorylated by Src family kinases (SFKs) and then by c-Abl kinase. It was shown that EPIYA-A, -B, and -C (or –D) segments can interact with SH2 domain-containing protein tyrosine phosphatase 1 (SHP1), SH2 domain-containing protein tyrosine phosphatase 2 (SHP2), phosphatidylinositol 3-kinase (PI3K), growth factor receptor bound protein 2 (Grb2), growth factor receptor bound protein 7 (Grb7), growth factor receptor bound protein 10 (Grb10), the C-terminal Src kinase (Csk), Ras GTPase activating protein 1 (RasGap1), Crk like proto-oncogene, adaptor protein (CrkL). Moreover, it was found that H.pylori induced a characteristic morphology of host epithelial cells, which has been referred to as the hummingbird phenotype. It was revealed that the hummingbird phenotype was resulting from regulation of both the actin cytoskeleton and focal adhesion and it may be involved in carcinogenesis. Notably, it was well established that CagA injection induces the elongation morphology of host cell. Furthermore, the roles of the EPIYA (or a similar sequence) in perturbation of eukaryotic signal transduction pathways for the other pathogenic bacterial effector proteins were investigated.  A. phagocytophilum AnkA contains four different types of EPIYA segments termed EPIYA-A, -B, -C and –D. These EPIYA sequences were phosphorylated by either SFKs or c-Abl kinase and it can interact with SHP1. SHP1 phosphatase activity in infected neutrophils was deregulated after SHP1/AnkA complex formation. EPEC Tir was tyrosine phosphorylated at EPIYA similar sequences and it was able to interact with the SH2 domain-containing adaptor protein Nck and Nck/Tir complex formation promotes actin polymerization. C. terachomatis Tarp was tyrosine phosphorylated at the EPIYA similar sequences resulting the rearrangements of the cytoskeletal of host cells. The EPIYA similar sequences of H. ducreyi LspA were tyrosine phosphorylated by SFKs and it was found that tyrosine-phosphorylated LspA inhibited SFKs activity.  SFKs are responsible for tyrosine phosphorylation of B. henselae Bep at EPIYA similar sequences.  After tyrosine phosphorylation B. henselae Bep at EPIYA similar sequencse, they acquire the ability to interact with Csk and SHP2. From the other side, it was also shown that a large number of mammalian proteins contain EPIYA (or a similar sequence). Until now, functional EPIYA (or a similar sequence) was found only in two mammalian proteins (Pragmin and P140Cap). Pragmin (or SGK223), a cytoplasmic pseudokinase, contains a functional EPIYA sequences in its N-terminal region. It was found that Pragmin is tyrosine-phosphorylated at EPIYA sequence by SFKs, Csk or in response to external stimuli such as epidermal growth factor (EGF). Moreover, P140Cap (or SRC kinase signaling inhibitor 1) contains two functional EPIYA sequences (EPLYA, EGLYA) in its N-terminus and it was tyrosine-phosphorylated at EPLYA and EGLYA sequences by c-Abl kinase. Tyrosine phosphorylation at EPIYA sequences enable them to interact with Csk (a SH2-domain containing protein) specifically. Also, it was found that the overexpression of Pragmin in AGS cells induced the elongated cell morphology. In this regard, it was previously shown that SGK223/Pragmin expression were increased in pancreatic cancer cells and overexpression of SGK223/Pragmin promotes elongation of cell morphology and migration of cells in pancreatic cancer cells. It was proposed that the mammalian EPIYA motifs might have been exploited by pathogenic bacteria and they act as pathogenic “Master keys” to perturb multiple signaling pathways through promiscuous binding with SH2 domain-containing proteins. Also, it was found that EPIYA sequences in some bacterial effector proteins (such as EPEC Tir and H.pylori CagA) to be unfolded and they showed structural flexibility features. So, it would be interesting to determine whether the other bacterial EPIYA effectors (such as A. phagocytophilum AnkA, C. terachomatis Tarp, H. ducreyi LspA, and B. henselae Bep) have disordered features at EPIYA (or similar sequences). In mammals, the structure of proteins containing functional EPIYA (or similar sequences) has not investigated yet. It seems that mammalian proteins containing functional EPIYA sequences do not have disordered features at EPIYA (or similar sequences) and thereby, they unable to interact with multiple SH2-domain containing proteins. Notably, the most of mammalian proteins containing functional EPIYA (or similar sequences) are unknown and there is no information about them. By using PhosphoSite, it was explored the EPIYA (or similar sequences) in mammalian proteins and it was predicted that the most of mammalian proteins containing EPIYA (or similar sequences) showed no tyrosine phosphorylation at the EPIYA (or similar sequences). It seems that the EPIYA (or similar sequences) of mammalian proteins are not available for related kinases because of possible their restricted and inflexible structures. Up to now, the structure of mammalian host proteins containing EPIYA motifs is not revealed. In this review, we investigate the roles of functional EPIYA sequences as key sequences in several pathogenic bacterial effector proteins and mammalian proteins to perturb cell signal transduction pathways that it was associated with a large number of diseases including cancer. توالی های EPIYA , توکسین های باکتریایی, پروتئین های میزبان, پیام رسانی سلولی, سرطان EPIYA sequences, Bacterial effector proteins, Host proteins, Cell signaling, Cancer 90 102 http://rjms.iums.ac.ir/browse.php?a_code=A-10-4811-1&slc_lang=fa&sid=1 Fatemeh Safari فاطمه صفری fsafari@guilan.ac.ir 3900319475328460053917 3900319475328460053917 Yes Faculty of Science, University of Guilan, Rasht, Iran دانشکده علوم پایه، دانشگاه گیلان، گیلان، ایران Maliheh Shokohfard ملیحه شکوه فرد shokouhfard@gmail.com 3900319475328460053918 3900319475328460053918 No Biotechnology Research Center, International Campus, Shahid Sadoghi University of Medical Science, پردیس بین الملل دانشگاه علوم پزشکی شهید صدوقی یزد، یزد، ایران