Small GTPases最新文献_第2页

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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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

Rho GTPases in kidney physiology and diseases. 肾脏生理和疾病中的 Rho GTPases。

Small GTPases Pub Date : 2022-01-01 Epub Date: 2021-06-17 DOI: 10.1080/21541248.2021.1932402

Clara Steichen, Claude Hervé, Thierry Hauet, Nicolas Bourmeyster

{"title":"Rho GTPases in kidney physiology and diseases.","authors":"Clara Steichen, Claude Hervé, Thierry Hauet, Nicolas Bourmeyster","doi":"10.1080/21541248.2021.1932402","DOIUrl":"10.1080/21541248.2021.1932402","url":null,"abstract":"Rho family GTPases are molecular switches best known for their pivotal role in dynamic regulation of the actin cytoskeleton, but also of cellular morphology, motility, adhesion and proliferation. The prototypic members of this family (RhoA, Rac1 and Cdc42) also contribute to the normal kidney function and play important roles in the structure and function of various kidney cells including tubular epithelial cells, mesangial cells and podocytes. The kidney's vital filtration function depends on the structural integrity of the glomerulus, the proximal portion of the nephron. Within the glomerulus, the architecturally actin-based cytoskeleton podocyte forms the final cellular barrier to filtration. The glomerulus appears as a highly dynamic signalling hub that is capable of integrating intracellular cues from its individual structural components. Dynamic regulation of the podocyte cytoskeleton is required for efficient barrier function of the kidney. As master regulators of actin cytoskeletal dynamics, Rho GTPases are therefore of critical importance for sustained kidney barrier function. Dysregulated activities of the Rho GTPases and of their effectors are implicated in the pathogenesis of both hereditary and idiopathic forms of kidney diseases. Diabetic nephropathy is a progressive kidney disease that is caused by injury to kidney glomeruli. High glucose activates RhoA/Rho-kinase in mesangial cells, leading to excessive extracellular matrix production (glomerulosclerosis). This RhoA/Rho-kinase pathway also seems involved in the post-transplant hypertension frequently observed during treatment with calcineurin inhibitors, whereas Rac1 activation was observed in post-transplant ischaemic acute kidney injury.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9707548/pdf/KSGT_13_1932402.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10579184","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

The N-terminal Leu-Pro-Gln sequence of Rab34 is required for ciliogenesis in hTERT-RPE1 cells. Rab34的n端Leu-Pro-Gln序列是hTERT-RPE1细胞纤毛发生所必需的。

Small GTPases Pub Date : 2022-01-01 Epub Date: 2021-04-16 DOI: 10.1080/21541248.2021.1894910

Mai E Oguchi, Yuta Homma, Mitsunori Fukuda

{"title":"The N-terminal Leu-Pro-Gln sequence of Rab34 is required for ciliogenesis in hTERT-RPE1 cells.","authors":"Mai E Oguchi, Yuta Homma, Mitsunori Fukuda","doi":"10.1080/21541248.2021.1894910","DOIUrl":"https://doi.org/10.1080/21541248.2021.1894910","url":null,"abstract":"We have previously shown that Rab34 is an important regulator of ciliogenesis and that its unique long N-terminal region (amino acids 1-49) is essential for ciliogenesis in certain cultured mammalian cells. In the present study, we performed an in-depth deletion analysis of the N-terminal region of Rab34 together with Ala-based site-directed mutagenesis to identify the essential amino acids that are required for serum-starvation-induced ciliogenesis in hTERT-RPE1 cells. The results showed that a Rab34 mutant lacking an N-terminal 18 amino acids and a Rab34 mutant carrying an LPQ-to-AAA mutation (amino acids 16-18) failed to rescue a Rab34-KO phenotype (i.e., defect in ciliogenesis). Our findings suggest that the LPQ sequence of Rab34 is crucial for ciliogenesis in hTERT-RPE1 cells.Abbreviations: AA, amino acid(s); ac-Tub, acetylated tubulin; bsr, blasticidin S-resistant gene; HRP, horseradish peroxidase; hTERT-RPE1, human telomerase reverse transcriptase retinal pigment epithelium 1; KO, knockout; NS, not significant; PBS, phosphate-buffered saline; puro, puromycin-resistant gene.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541248.2021.1894910","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38799118","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

Quantitation of RhoA activation: differential binding to downstream effectors. RhoA活化的定量:与下游效应器的差异结合。

Small GTPases Pub Date : 2022-01-01 DOI: 10.1080/21541248.2022.2111945

Yu-Wen Zhang, Holly M Torsilieri, James E Casanova

{"title":"Quantitation of RhoA activation: differential binding to downstream effectors.","authors":"Yu-Wen Zhang, Holly M Torsilieri, James E Casanova","doi":"10.1080/21541248.2022.2111945","DOIUrl":"https://doi.org/10.1080/21541248.2022.2111945","url":null,"abstract":"The small GTPase RhoA controls many important cellular processes through its ability to activate multiple downstream effector pathways. Most RhoA effectors contain a Rho-binding domain (RBD), and interaction between active RhoA and the RBD typically induces a conformational change in effectors that stimulates their recruitment or activity. Isolated GTPase binding domains fused to GST have been widely used in so-called pulldown assays to measure the activation state of other GTPases in cell lysates. Similarly, GST fusions containing the RBD of the RhoA effector Rhotekin have been widely adopted as a standardized tool for the measurement of RhoA activation. RBDs have also been used to generate fluorescent reporter constructs to localize sites of GTPase activation in intact cells. In this report, we demonstrate that not all forms of active RhoA are capable of interacting with the Rhotekin RBD. A constitutively active RhoA-G14V mutant, which interacted with the RBDs of ROCK2 and mDIA1, was unable to bind the Rhotekin RBD as evidenced by both conventional GST pulldown assay and our newly established BRET assay. Furthermore, active RhoA induced by different stimuli in cells also displayed binding preference for its diverse effectors. Our data demonstrate that RhoA may undergo effector-specific activation for differential regulation of its downstream pathways, and that RhoA activation should not be defined solely by its interaction with Rhotekin.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9377269/pdf/KSGT_13_2111945.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9978261","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