Small GTPases最新文献_第2页

Rab3a, a small GTP-binding protein, is required for the stabilization of the murine leukaemia virus Gag protein. Rab3a是一种小的gtp结合蛋白，是稳定小鼠白血病病毒Gag蛋白所必需的。

Small GTPases Pub Date : 2022-01-01 DOI: 10.1080/21541248.2021.1939631

Mai Izumida, Katsura Kakoki, Hideki Hayashi, Toshifumi Matsuyama, Yoshinao Kubo

{"title":"Rab3a, a small GTP-binding protein, is required for the stabilization of the murine leukaemia virus Gag protein.","authors":"Mai Izumida, Katsura Kakoki, Hideki Hayashi, Toshifumi Matsuyama, Yoshinao Kubo","doi":"10.1080/21541248.2021.1939631","DOIUrl":"https://doi.org/10.1080/21541248.2021.1939631","url":null,"abstract":"We recently identified a CD63-interacting protein to understand the role of CD63 in virion production of the human immunodeficiency virus type 1, and we have found that Rab3a forms a complex with CD63. In this study, we analysed the effect of Rab3a on virion production of the murine leukaemia virus (MLV), which is another member of the retrovirus family. We found that Rab3a silencing induced lysosomal degradation of the MLV Gag protein, and recovery of the Rab3a expression restored the level of the Gag protein through a complex formation of MLV Gag and Rab3a, indicating that Rab3a is required for MLV Gag protein expression. In contrast, CD63 silencing decreased the infectivity of released virions but had no effect on virion production, indicating that CD63 facilitates the infectivity of released MLV particles. Although Rab3a induced CD63 degradation in uninfected cells, the complex of MLV Gag and Rab3a suppressed the Rab3a-mediated CD63 degradation in MLV-infected cells. Finally, we found that the MLV Gag protein interacts with Rab3a to stabilize its own protein and CD63 that facilitates the infectivity of released MLV particles. Considering the involvement of Rab3a in lysosome trafficking to the plasma membrane, it may also induce cell surface transport of the MLV Gag protein.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"13 1","pages":"162-182"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541248.2021.1939631","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10579182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

KRAS G12C fragment screening renders new binding pockets. KRAS G12C片段筛选生成新的结合袋。

Small GTPases Pub Date : 2022-01-01 Epub Date: 2021-09-24 DOI: 10.1080/21541248.2021.1979360

Magali Mathieu, Valérie Steier, Florence Fassy, Cécile Delorme, David Papin, Bruno Genet, Francis Duffieux, Thomas Bertrand, Laure Delarbre, Hélène Le-Borgne, Annick Parent, Patrick Didier, Jean-Pierre Marquette, Maryse Lowinski, Jacques Houtmann, Annabelle Lamberton, Laurent Debussche, Rak Alexey

{"title":"KRAS G12C fragment screening renders new binding pockets.","authors":"Magali Mathieu, Valérie Steier, Florence Fassy, Cécile Delorme, David Papin, Bruno Genet, Francis Duffieux, Thomas Bertrand, Laure Delarbre, Hélène Le-Borgne, Annick Parent, Patrick Didier, Jean-Pierre Marquette, Maryse Lowinski, Jacques Houtmann, Annabelle Lamberton, Laurent Debussche, Rak Alexey","doi":"10.1080/21541248.2021.1979360","DOIUrl":"https://doi.org/10.1080/21541248.2021.1979360","url":null,"abstract":"KRAS genes belong to the most frequently mutated family of oncogenes in cancer. The G12C mutation, found in a third of lung, half of colorectal and pancreatic cancer cases, is believed to be responsible for a substantial number of cancer deaths. For 30 years, KRAS has been the subject of extensive drug-targeting efforts aimed at targeting KRAS protein itself, but also its post-translational modifications, membrane localization, protein-protein interactions and downstream signalling pathways. So far, most KRAS targeting strategies have failed, and there are no KRAS-specific drugs available. However, clinical candidates targeting the KRAS G12C protein have recently been developed. MRTX849 and recently approved Sotorasib are covalent binders targeting the mutated cysteine 12, occupying Switch II pocket.Herein, we describe two fragment screening drug discovery campaigns that led to the identification of binding pockets on the KRAS G12C surface that have not previously been described. One screen focused on non-covalent binders to KRAS G12C, the other on covalent binders.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":" ","pages":"225-238"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8923024/pdf/KSGT_13_1979360.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39444572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 7

Allosteric regulation of GRB2 modulates RAS activation. GRB2的变构调控可调节RAS的激活。

Small GTPases Pub Date : 2022-01-01 DOI: 10.1080/21541248.2022.2089001

Neda S Kazemein Jasemi, Mohammad R Ahmadian

引用次数: 1

Investigating increased hematopoietic stem cell fitness in a novel mouse model. 在一种新的小鼠模型中研究增加的造血干细胞适应性。

Small GTPases Pub Date : 2022-01-01 DOI: 10.1080/21541248.2021.1882832

Laila Karra, Jeroen P Roose

{"title":"Investigating increased hematopoietic stem cell fitness in a novel mouse model.","authors":"Laila Karra, Jeroen P Roose","doi":"10.1080/21541248.2021.1882832","DOIUrl":"https://doi.org/10.1080/21541248.2021.1882832","url":null,"abstract":"T-cell acute lymphoblastic leukaemia (T-ALL) is a bone marrow (BM) malignancy affecting children and adults. Typically treated with chemotherapy, leukaemia remains a major death cause in people under 20 years old. Understanding molecularly altered pathways in T-ALL may lead to new therapeutic avenues in the future. Ras pathway dysregulation is common in T-ALL. We have shown elevated expression levels of the Ras guanine nucleotide exchange factor RasGRP1 in T-ALL patients, which results in constant production of active Ras (RasGTP). When leukaemia cell lines are exposed to cytokines, RasGTP levels further increase in a RasGRP1-dependent manner. How overexpressed RasGRP1 may impact primary BM cells has remained unknown. We recently published a new RoLoRiG mouse model that allows for pIpC-induced overexpression of RasGRP1 in haematopoietic cells, which can be traced with an ires-EGFP cassette. This novel model revealed that RasGRP1 overexpression bestows a fitness advantage to haematopoietic stem cells (HSCs) over wild-type cells. Intriguingly, this increased fitness only manifests in native Hematopoiesis, and not in BM transplantation (BMT) assays. In this commentary, we summarize key features of our RoLoRiG model, elaborate on BM niche importance, and discuss differences between native Hematopoiesis and BMT in the context of stem cell metabolism.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"13 1","pages":"7-13"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541248.2021.1882832","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9089208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting the KRAS α4-α5 allosteric interface inhibits pancreatic cancer tumorigenesis. 靶向 KRAS α4-α5 异源界面抑制胰腺癌肿瘤发生

Small GTPases Pub Date : 2022-01-01 Epub Date: 2021-05-05 DOI: 10.1080/21541248.2021.1906621

Imran Khan, Catherine Marelia-Bennet, Julia Lefler, Mariyam Zuberi, Eric Denbaum, Akiko Koide, Dean M Connor, Ann-Marie Broome, Thierry Pécot, Cynthia Timmers, Michael C Ostrowski, Shohei Koide, John P O'Bryan

{"title":"Targeting the KRAS α4-α5 allosteric interface inhibits pancreatic cancer tumorigenesis.","authors":"Imran Khan, Catherine Marelia-Bennet, Julia Lefler, Mariyam Zuberi, Eric Denbaum, Akiko Koide, Dean M Connor, Ann-Marie Broome, Thierry Pécot, Cynthia Timmers, Michael C Ostrowski, Shohei Koide, John P O'Bryan","doi":"10.1080/21541248.2021.1906621","DOIUrl":"10.1080/21541248.2021.1906621","url":null,"abstract":"RAS is the most frequently mutated oncogene in human cancer with nearly ~20% of cancer patients possessing mutations in one of three RAS genes (K, N or HRAS). However, KRAS is mutated in nearly 90% of pancreatic ductal carcinomas (PDAC). Although pharmacological inhibition of RAS has been challenging, KRAS(G12C)-specific inhibitors have recently entered the clinic. While KRAS(G12C) is frequently expressed in lung cancers, it is rare in PDAC. Thus, more broadly efficacious RAS inhibitors are needed for treating KRAS mutant-driven cancers such as PDAC. A RAS-specific tool biologic, NS1 Monobody, inhibits HRAS- and KRAS-mediated signalling and oncogenic transformation both in vitro and in vivo by targeting the α4-α5 allosteric site of RAS and blocking RAS self-association. Here, we evaluated the efficacy of targeting the α4-α5 interface of KRAS as an approach to inhibit PDAC development using an immunocompetent orthotopic mouse model. Chemically regulated NS1 expression inhibited ERK and AKT activation in KRAS(G12D) mutant KPC PDAC cells and reduced the formation and progression of pancreatic tumours. NS1-expressing tumours were characterized by increased infiltration of CD4 + T helper cells. These results suggest that targeting the #x3B1;4-#x3B1;5 allosteric site of KRAS may represent a viable therapeutic approach for inhibiting KRAS-mutant pancreatic tumours.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"13 1","pages":"114-127"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9707541/pdf/KSGT_13_1906621.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9072730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Down-regulation of miR-140-3p is a cause of the interlukin-13-induced up-regulation of RhoA protein in bronchial smooth muscle cells. miR-140-3p下调是interleukin -13诱导支气管平滑肌细胞RhoA蛋白上调的原因之一。

Small GTPases Pub Date : 2022-01-01 DOI: 10.1080/21541248.2021.1872318

Yoshihiko Chiba, Yusuke Ando, Yasuna Kato, Motohiko Hanazaki, Hiroyasu Sakai

引用次数: 7

Photodynamic treatment modulates various GTPase and cellular signalling pathways in Tauopathy. 光动力治疗可调节陶病中各种GTPase和细胞信号通路。

Small GTPases Pub Date : 2022-01-01 DOI: 10.1080/21541248.2021.1940722

Tushar Dubey, Subashchandrabose Chinnathambi

引用次数: 1

Seeing is believing: tools to study the role of Rho GTPases during cytokinesis. 眼见为实:研究Rho gtpase在细胞分裂过程中的作用的工具。

Small GTPases Pub Date : 2022-01-01 DOI: 10.1080/21541248.2021.1957384

Su Pin Koh, Nhat Phi Pham, Alisa Piekny

{"title":"Seeing is believing: tools to study the role of Rho GTPases during cytokinesis.","authors":"Su Pin Koh, Nhat Phi Pham, Alisa Piekny","doi":"10.1080/21541248.2021.1957384","DOIUrl":"https://doi.org/10.1080/21541248.2021.1957384","url":null,"abstract":"Cytokinesis is required to cleave the daughter cells at the end of mitosis and relies on the spatiotemporal control of RhoA GTPase. Cytokinesis failure can lead to changes in cell fate or aneuploidy, which can be detrimental during development and/or can lead to cancer. However, our knowledge of the pathways that regulate RhoA during cytokinesis is limited, and the role of other Rho family GTPases is not clear. This is largely because the study of Rho GTPases presents unique challenges using traditional cell biological and biochemical methods, and they have pleiotropic functions making genetic studies difficult to interpret. The recent generation of optogenetic tools and biosensors that control and detect active Rho has overcome some of these challenges and is helping to elucidate the role of RhoA in cytokinesis. However, improvements are needed to reveal the role of other Rho GTPases in cytokinesis, and to identify the molecular mechanisms that control Rho activity. This review examines some of the outstanding questions in cytokinesis, and explores tools for the imaging and control of Rho GTPases.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"13 1","pages":"211-224"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9707540/pdf/KSGT_13_1957384.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10524921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 8

GPCRs that Rhoar the Guanine nucleotide exchange factors. 含有鸟嘌呤核苷酸交换因子的gpcr。

Small GTPases Pub Date : 2022-01-01 DOI: 10.1080/21541248.2021.1896963

Aishwarya Omble, Kiran Kulkarni

引用次数: 1

Small-molecule inhibitors of P-Rex guanine-nucleotide exchange factors. P-Rex鸟嘌呤核苷酸交换因子的小分子抑制剂。

Small GTPases Pub Date : 2022-01-01 DOI: 10.1080/21541248.2022.2131313

C D Lawson, K Hornigold, D Pan, I Niewczas, S Andrews, J Clark, Hce Welch

{"title":"Small-molecule inhibitors of P-Rex guanine-nucleotide exchange factors.","authors":"C D Lawson, K Hornigold, D Pan, I Niewczas, S Andrews, J Clark, Hce Welch","doi":"10.1080/21541248.2022.2131313","DOIUrl":"https://doi.org/10.1080/21541248.2022.2131313","url":null,"abstract":"P-Rex1 and P-Rex2 are guanine-nucleotide exchange factors (GEFs) that activate Rac small GTPases in response to the stimulation of G protein-coupled receptors and phosphoinositide 3-kinase. P-Rex Rac-GEFs regulate the morphology, adhesion and migration of various cell types, as well as reactive oxygen species production and cell cycle progression. P-Rex Rac-GEFs also have pathogenic roles in the initiation, progression or metastasis of several types of cancer. With one exception, all P-Rex functions are known or assumed to be mediated through their catalytic Rac-GEF activity. Thus, inhibitors of P-Rex Rac-GEF activity would be valuable research tools. We have generated a panel of small-molecule P-Rex inhibitors that target the interface between the catalytic DH domain of P-Rex Rac-GEFs and Rac. Our best-characterized compound, P-Rex inhibitor 1 (PREX-in1), blocks the Rac-GEF activity of full-length P-Rex1 and P-Rex2, and of their isolated catalytic domains, in vitro at low-micromolar concentration, without affecting the activities of several other Rho-GEFs. PREX-in1 blocks the P-Rex1 dependent spreading of PDGF-stimulated endothelial cells and the production of reactive oxygen species in fMLP-stimulated mouse neutrophils. Structure-function analysis revealed critical structural elements of PREX-in1, allowing us to develop derivatives with increased efficacy, the best with an IC50 of 2 µM. In summary, we have developed PREX-in1 and derivative small-molecule compounds that will be useful laboratory research tools for the study of P-Rex function. These compounds may also be a good starting point for the future development of more sophisticated drug-like inhibitors aimed at targeting P-Rex Rac-GEFs in cancer.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"13 1","pages":"307-326"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9645260/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9089730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1