Small GTPases最新文献

Small GTPase Rac promotes hyphal formation and microconidiogenesis in Trichophyton rubrum. 小GTPase Rac促进红毛霉菌丝形成和微孢子发生。

Small GTPases Pub Date : 2024-12-01 Epub Date: 2025-05-04 DOI: 10.1080/21541248.2025.2498174

Masaki Ishii, Shinya Ohata

{"title":"Small GTPase Rac promotes hyphal formation and microconidiogenesis in Trichophyton rubrum.","authors":"Masaki Ishii, Shinya Ohata","doi":"10.1080/21541248.2025.2498174","DOIUrl":"https://doi.org/10.1080/21541248.2025.2498174","url":null,"abstract":"Morphogenesis plays a pivotal role in the infection process of Trichophyton rubrum, a primary aetiological agent of dermatophytosis that inhabits superficial human tissues. T. rubrum proliferates by extending filamentous structures, or hyphae, which are composed of highly polarized cells. In response to environmental stimuli, T. rubrum also produces asexual spores called microconidia, consisting of individual cells. Although these dynamic morphological changes are critical for T. rubrum proliferation and environmental adaptation, the molecular mechanisms underlying these processes remain poorly understood. In previous research, we demonstrated that repressing Cdc24, a guanine nucleotide exchange factor (GEF) for the small GTPases Rac and Cdc42, disrupts fungal cell polarity and impairs hyphal formation in T. rubrum. In this study, we show that Rac deficiency in the Δrac strain minimally affects hyphal formation, as indicated by the cell polarity index (the ratio of a cell's long to short diameter in hyphae). However, simultaneous Rac deficiency and Cdc42 repression in the Δrac/Pctr4 cdc42 strain significantly disrupted cell polarity, suggesting that Rac and Cdc42 perform overlapping functions in hyphal morphogenesis. Interestingly, Rac deficiency inhibited microconidia formation, whereas cdc42 repression had no detectable impact. Furthermore, adding cysteine, a radical scavenger abundant in keratins, to the growth medium reduced microconidia production in the wild-type strain but not in the Δrac strain. These findings suggest that cysteine in host tissues inhibits Rac-mediated microconidia formation. Overall, this study identifies Rac as a key regulator of T. rubrum morphogenesis, with specific roles in both hyphal development and microconidia formation.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"15 1","pages":"1-8"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015257","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 structure of KRAS^G12C bound to divarasib highlights features of potent switch-II pocket engagement. 与divarasib结合的KRASG12C的结构突出了强有力的开关- ii口袋接合的特征。

Small GTPases Pub Date : 2024-12-01 Epub Date: 2025-05-20 DOI: 10.1080/21541248.2025.2505441

Micah C Fernando, Gregory B Craven, Kevan M Shokat

{"title":"The structure of KRASG12C bound to divarasib highlights features of potent switch-II pocket engagement.","authors":"Micah C Fernando, Gregory B Craven, Kevan M Shokat","doi":"10.1080/21541248.2025.2505441","DOIUrl":"10.1080/21541248.2025.2505441","url":null,"abstract":"KRAS is the most frequently mutated oncogene in human cancer. In multiple types of cancer, a missense mutation at codon 12 substitutes a glycine for a cysteine, causing hyperactivation of the GTPase and enhanced MAPK signalling. Recent drug discovery efforts culminating from work during the past decade have resulted in two FDA-approved inhibitors, sotorasib and adagrasib, which target the KRASG12C mutant allele. Ongoing medicinal chemistry efforts across academia and industry have continued developing more potent and efficacious KRASG12C inhibitors. One agent in late-stage clinical trials, divarasib, has demonstrated robust overall response rates, in some cases greater than currently approved agents. Divarasib also exhibits enhanced covalent target engagement in vitro and significant specificity for KRASG12C, yet the structural details of its binding have not been published. Here we report a high-resolution crystal structure of cysteine-light KRAS-4BG12C in complex with divarasib. Though it binds in the same allosteric pocket as sotorasib and adagrasib, the switch-II loop in each crystal structure takes on a distinct conformation differing as much as 5.6 Å between the Cα atom of residue 65 with sotorasib. Additionally, we highlight structural features of the drug complex that may guide future medicinal chemistry efforts targeting various KRAS alleles.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"15 1","pages":"1-7"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12101598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144102744","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 role of RAC1 in resistance to targeted therapies in cancer. RAC1在癌症靶向治疗耐药中的作用。

Small GTPases Pub Date : 2024-12-01 Epub Date: 2025-05-21 DOI: 10.1080/21541248.2025.2505977

Cristina Uribe-Alvarez, Jonathan Chernoff

{"title":"The role of RAC1 in resistance to targeted therapies in cancer.","authors":"Cristina Uribe-Alvarez, Jonathan Chernoff","doi":"10.1080/21541248.2025.2505977","DOIUrl":"10.1080/21541248.2025.2505977","url":null,"abstract":"RAC1 is a small 21 kDa RHO GTPase that plays a pivotal role in regulating actin cytoskeletal dynamics and cell growth. Alterations in the activity of RAC1 are implicated in a range of diseases, including cancer. Increased RAC1 activity, due to overexpression and/or activating mutations, drives transcriptional upregulation, reactive oxygen species production, mesenchymal-to-epithelial transition, membrane ruffling, and uncontrolled cell proliferation, which are hallmarks of an oncogenic phenotype. While RAC1-activating mutations alone do not appear sufficient to transform cells, their combination with other common mutations, such as BRAF, NRAS, or NF1, have been linked to drug resistance and significantly worsen patient prognosis and hinder treatment responses. The precise mechanisms underlying drug resistance, and the regulation of RAC1 splicing remain poorly understood. RAC1 is a challenging therapeutic target due to its ubiquitous presence and essential cellular functions. To date, there are no established standard treatments for cancers that harbour an additional RAC1 mutation or for RAC1-mediated drug resistance. Current experimental strategies aim to target RAC1 localization, its activators (e.g. guanine nucleotide exchange factors) and downstream effectors. Regulating RAC1 expression by targeting epigenetic regulators, and direct targeting of RAC1 itself, may also be possible in the near future.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"15 1","pages":"1-14"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12101591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111909","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

To stay in shape and keep moving: MLL emerges as a new transcriptional regulator of Rho GTPases. 保持形状并保持运动：MLL作为Rho GTP酶的新转录调节因子出现。

Small GTPases Pub Date : 2023-12-01 DOI: 10.1080/21541248.2023.2254437

Akash Chinchole, Shreyta Gupta, Shweta Tyagi

引用次数: 0

An ultra-sensitive method to detect mutations in human RAS templates 一种检测人类RAS模板突变的超灵敏方法

Small GTPases Pub Date : 2022-06-06 DOI: 10.1080/21541248.2022.2083895

Siqi Li, C. Counter

{"title":"An ultra-sensitive method to detect mutations in human RAS templates","authors":"Siqi Li, C. Counter","doi":"10.1080/21541248.2022.2083895","DOIUrl":"https://doi.org/10.1080/21541248.2022.2083895","url":null,"abstract":"ABSTRACT The RAS family of small GTPases is mutated in roughly a fifth of human cancers. Hotspot point mutations at codons G12, G13, and Q61 account for 95% of all these mutations, which are well established to render the encoded proteins oncogenic. In humans, this family comprises three genes: HRAS, NRAS, and KRAS. Accumulating evidence argues that oncogenic RAS point mutations may be initiating, as they are often truncal in human tumours and capable of inducing tumorigenesis in mice. As such, there is great interest in detecting oncogenic mutation in the RAS genes to understand the origins of cancer, as well as for early detection purposes. To this end, we previously adapted the microbial ultra-sensitive M aximum D epth S equencing (MDS) assay for the murine Kras gene, which was capable of detecting oncogenic mutations in the tissues of mice days after carcinogen exposure, essentially capturing the very first step in tumour initiation. Given this, we report here the adaption and details of this assay to detect mutations in a human KRAS sequence at an analytic sensitivity of one mutation in a million independently barcoded templates. This humanized version of MDS can thus be exploited to detect oncogenic mutations in KRAS at an incredible sensitivity and modified for the same purpose for the other RAS genes.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"13 1","pages":"287 - 295"},"PeriodicalIF":0.0,"publicationDate":"2022-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42208867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A New Crosslinking Assay to Study Guanine Nucleotide Binding in the Gtr Heterodimer of S. cerevisiae. 一种新的研究酿酒葡萄球菌Gtr异源二聚体鸟嘌呤核苷酸结合的交联试验。

Small GTPases Pub Date : 2022-01-01 DOI: 10.1080/21541248.2022.2141019

Dylan D Doxsey, Kristen Veinotte, Kuang Shen

引用次数: 1

The progress in C9orf72 research: ALS/FTD pathogenesis, functions and structure. C9orf72的研究进展:ALS/FTD的发病机制、功能和结构。

Small GTPases Pub Date : 2022-01-01 DOI: 10.1080/21541248.2021.1892443

Lan Jiang, Tizhong Zhang, Kefeng Lu, Shiqian Qi

引用次数: 5

Phylogenetic reconstruction and evolution of the Rab GTPase gene family in Amoebozoa. 变形虫Rab GTPase基因家族的系统发育重建与进化。

Small GTPases Pub Date : 2022-01-01 DOI: 10.1080/21541248.2021.1903794

Alfredo L Porfírio-Sousa, Alexander K Tice, Matthew W Brown, Daniel J G Lahr

{"title":"Phylogenetic reconstruction and evolution of the Rab GTPase gene family in Amoebozoa.","authors":"Alfredo L Porfírio-Sousa, Alexander K Tice, Matthew W Brown, Daniel J G Lahr","doi":"10.1080/21541248.2021.1903794","DOIUrl":"https://doi.org/10.1080/21541248.2021.1903794","url":null,"abstract":"Rab GTPase is a paralog-rich gene family that controls the maintenance of the eukaryotic cell compartmentalization system. Diverse eukaryotes have varying numbers of Rab paralogs. Currently, little is known about the evolutionary pattern of Rab GTPase in most major eukaryotic 'supergroups'. Here, we present a comprehensive phylogenetic reconstruction of the Rab GTPase gene family in the eukaryotic 'supergroup' Amoebozoa, a diverse lineage represented by unicellular and multicellular organisms. We demonstrate that Amoebozoa conserved 20 of the 23 ancestral Rab GTPases predicted to be present in the last eukaryotic common ancestor and massively expanded several 'novel' in-paralogs. Due to these 'novel' in-paralogs, the Rab family composition dramatically varies between the members of Amoebozoa; as a consequence, 'supergroup'-based studies may significantly change our current understanding of the evolution and diversity of this gene family. The high diversity of the Rab GTPase gene family in Amoebozoa makes this 'supergroup' a key lineage to study and advance our knowledge of the evolution of Rab in Eukaryotes.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"13 1","pages":"100-113"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541248.2021.1903794","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9072723","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

Biallelic ELMO3 mutations and loss of function for DOCK-mediated RAC1 activation result in intellectual disability. 双等位基因ELMO3突变和dock介导的RAC1激活功能丧失导致智力残疾。

Small GTPases Pub Date : 2022-01-01 DOI: 10.1080/21541248.2021.1888557

Viviane Tran, Marie-Anne Goyette, Mónica Martínez-García, Ana Jiménez de Domingo, Daniel Martín Fernández-Mayoralas, Ana Laura Fernández-Perrone, Pilar Tirado, Beatriz Calleja-Pérez, Sara Álvarez, Jean-François Côté, Alberto Fernández-Jaén

{"title":"Biallelic ELMO3 mutations and loss of function for DOCK-mediated RAC1 activation result in intellectual disability.","authors":"Viviane Tran, Marie-Anne Goyette, Mónica Martínez-García, Ana Jiménez de Domingo, Daniel Martín Fernández-Mayoralas, Ana Laura Fernández-Perrone, Pilar Tirado, Beatriz Calleja-Pérez, Sara Álvarez, Jean-François Côté, Alberto Fernández-Jaén","doi":"10.1080/21541248.2021.1888557","DOIUrl":"https://doi.org/10.1080/21541248.2021.1888557","url":null,"abstract":"The engulfment and cell motility 3 (ELMO3) protein belongs to the ELMO-family of proteins. ELMO proteins form a tight complex with the DOCK1-5 guanine nucleotide exchange factors that regulate RAC1 spatiotemporal activation and signalling. DOCK proteins and RAC1 are known to have fundamental roles in central nervous system development. Here, we searched for homozygous or compound heterozygous mutations in the ELMO3 gene in 390 whole exomes sequenced in trio in individuals with neurodevelopmental disorders compatible with a genetic origin. We found a compound heterozygous mutation in ELMO3 (c.1153A>T, p.Ser385Cys and c.1009 G > A, p.Val337Ile) in a 5 year old male child with autism spectrum disorder (ASD) and developmental delay. These mutations did not interfere with the formation of an ELMO3/DOCK1 complex, but markedly impaired the ability of the complex to promote RAC1-GTP-loading. Consequently, cells expressing DOCK1 and either of the ELMO3 mutants displayed impaired migration and invasion. Collectively, our results suggest that biallelic loss-of-function mutations in ELMO3 may cause a developmental delay and provide new insight into the role of ELMO3 in neurodevelopmental as well as the pathological consequences of ELMO3 mutations.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"13 1","pages":"48-55"},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541248.2021.1888557","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9089210","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: 3

Regulation of Leukaemia Associated Rho GEF (LARG/ARHGEF12). 白血病相关Rho-GEF（LARG/ARGGEF12）的调节。

Small GTPases Pub Date : 2022-01-01 DOI: 10.1080/21541248.2021.1951590

Neda Z Ghanem, Michelle L Matter, Joe W Ramos

引用次数: 7