Small GTPases最新文献_第7页

The ins and outs of the Arf4-based ciliary membrane-targeting complex. 基于 Arf4 的睫状膜靶向复合体的来龙去脉。

Small GTPases Pub Date : 2021-01-01 Epub Date: 2019-05-17 DOI: 10.1080/21541248.2019.1616355

Dusanka Deretic, Esben Lorentzen, Theresa Fresquez

{"title":"The ins and outs of the Arf4-based ciliary membrane-targeting complex.","authors":"Dusanka Deretic, Esben Lorentzen, Theresa Fresquez","doi":"10.1080/21541248.2019.1616355","DOIUrl":"10.1080/21541248.2019.1616355","url":null,"abstract":"The small GTPase Arf4-based ciliary membrane-targeting complex recognizes specific targeting signals within sensory receptors and regulates their directed movement to primary cilia. Activated Arf4 directly binds the VxPx ciliary-targeting signal (CTS) of the light-sensing receptor rhodopsin. Recent findings revealed that at the trans-Golgi, marked by the small GTPase Rab6, activated Arf4 forms a functional complex with rhodopsin and the Arf guanine nucleotide exchange factor (GEF) GBF1, providing positive feedback that drives further Arf4 activation in ciliary trafficking. Arf4 function is conserved across diverse cell types; however, it appears that not all its aspects are conserved across species, as mouse Arf4 is a natural mutant in the conserved α3 helix, which is essential for its interaction with rhodopsin. Generally, activated Arf4 regulates the assembly of the targeting nexus containing the Arf GAP ASAP1 and the Rab11a-FIP3-Rabin8 dual effector complex, which controls the assembly of the highly conserved Rab11a-Rabin8-Rab8 ciliary-targeting module. It was recently found that this module interacts with the R-SNARE VAMP7, likely in its activated, c-Src-phosphorylated form. Rab11 and Rab8 bind VAMP7 regulatory longin domain (LD), whereas Rabin8 interacts with the SNARE domain, capturing VAMP7 for delivery to the ciliary base and subsequent pairing with the cognate SNAREs syntaxin 3 and SNAP-25. This review will focus on the implications of these novel findings that further illuminate the role of well-ordered Arf and Rab interaction networks in targeting of sensory receptors to primary cilia. Abbreviations: CTS: Ciliary-Targeting Signal; GAP: GTPase Activating Protein; GEF: Guanine Nucleotide Exchange Factor; RTC(s), Rhodopsin Transport Carrier(s); SNARE: Soluble N-ethylmaleimide-sensitive Factor Attachment Protein Receptor; TGN: Trans-Golgi Network.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"12 1","pages":"1-12"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781591/pdf/KSGT_12_1616355.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37222435","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 UIG-1/CDC-42 guanine nucleotide exchange factor acts in parallel to CED-10/Rac1 during axon outgrowth in Caenorhabditis elegans. 在秀丽隐杆线虫的轴突生长过程中，UIG-1/CDC-42鸟嘌呤核苷酸交换因子与CED-10/Rac1并行作用。

Small GTPases Pub Date : 2021-01-01 Epub Date: 2019-05-01 DOI: 10.1080/21541248.2019.1610302

Wei Cao, Shuer Deng, Roger Pocock

{"title":"The UIG-1/CDC-42 guanine nucleotide exchange factor acts in parallel to CED-10/Rac1 during axon outgrowth in Caenorhabditis elegans.","authors":"Wei Cao, Shuer Deng, Roger Pocock","doi":"10.1080/21541248.2019.1610302","DOIUrl":"10.1080/21541248.2019.1610302","url":null,"abstract":"During development of the brain, neuronal circuits are formed through the projection of axons and dendrites in response to guidance signals. Rho GTPases (Rac1/RhoA/Cdc42) are major regulators of axo-dendritic outgrowth and guidance due to their role in controlling actin cytoskeletal dynamics, cell adhesion and motility. Functional redundancy of Rho GTPase-regulated pathways in neuronal development can mask the roles of specific GTPases. To examine potential Rho GTPase redundancy, we utilized a recently isolated hypomorphic mutation in a Caenorhabditis elegans Rac1 protein - CED-10(G30E) - which reduces the GTP binding and inhibits axon outgrowth of the PVQ interneurons. Here, we show that the CDC-42-specific guanine nucleotide exchange factor UIG-1 acts in parallel to CED-10/Rac1 to control PVQ axon outgrowth. UIG-1 performs this function in a cell-autonomous manner. Further, we found that transgenic expression of CDC-42 can compensate for aberrant CED-10(G30E)-regulated signalling during PVQ axon outgrowth. Together, our study reveals a previously unappreciated function for CDC-42 in PVQ axon outgrowth in C. elegans.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"12 1","pages":"60-66"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781583/pdf/KSGT_12_1610302.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37364164","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

Regulation of RhoA activation and cell motility by c-Jun N-terminal kinases and Net1. c-Jun n端激酶和Net1对RhoA活化和细胞运动的调控。

Small GTPases Pub Date : 2020-11-01 Epub Date: 2018-10-17 DOI: 10.1080/21541248.2018.1536638

Arzu Ulu, Jeffrey A Frost

{"title":"Regulation of RhoA activation and cell motility by c-Jun N-terminal kinases and Net1.","authors":"Arzu Ulu, Jeffrey A Frost","doi":"10.1080/21541248.2018.1536638","DOIUrl":"https://doi.org/10.1080/21541248.2018.1536638","url":null,"abstract":"Jnks are mitogen activated protein kinases that are best known for regulating transcription and apoptotic signaling. However, they also play important roles in controlling cell motility and invasion by phosphorylating many actin and microtubule regulatory proteins. These mechanisms have important implications for normal cell motility as well as cancer metastasis. Jnks are activated by growth factors and cytokines that stimulate cell motility, and this often requires upstream activation of Rho GTPases. Our recent work indicates that Jnks may also regulate Rho GTPase activation. Specifically, we found that Jnk-dependent phosphorylation of the RhoA guanine nucleotide exchange factor (RhoGEF) Net1A promotes its cytosolic accumulation to drive RhoA activation and actin cytoskeletal reorganization. Net1A is unusual among RhoGEFs in that it is sequestered in the nucleus to prevent aberrant RhoA activation. Importantly, Jnk-stimulated cytosolic localization of Net1A is sufficient to stimulate cell motility and extracellular matrix invasion in non-invasive breast cancer cells. Since Net1A expression is critical for cancer cell motility and invasion in vitro, and breast cancer metastasis in vivo, these data uncover a previously unappreciated regulatory mechanism that may contribute to metastasis in multiple types of cancer.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"11 6","pages":"385-391"},"PeriodicalIF":0.0,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541248.2018.1536638","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36583829","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

"Examining RAS pathway rewiring with a chemically inducible activator of RAS". “用化学诱导的RAS激活剂检测RAS通路重新布线”。

Small GTPases Pub Date : 2020-11-01 Epub Date: 2018-04-10 DOI: 10.1080/21541248.2018.1446697

John C Rose, Emily M Dieter, Daniel Cunningham-Bryant, Dustin J Maly

引用次数: 4

The CDC42 effector protein MRCKβ autophosphorylates on Threonine 1108. CDC42 效应蛋白 MRCKβ 在苏氨酸 1108 上发生自身磷酸化。

Small GTPases Pub Date : 2020-11-01 Epub Date: 2019-01-22 DOI: 10.1080/21541248.2018.1564472

Mathieu Unbekandt, Sergio Lilla, Sara Zanivan, Michael F Olson

{"title":"The CDC42 effector protein MRCKβ autophosphorylates on Threonine 1108.","authors":"Mathieu Unbekandt, Sergio Lilla, Sara Zanivan, Michael F Olson","doi":"10.1080/21541248.2018.1564472","DOIUrl":"10.1080/21541248.2018.1564472","url":null,"abstract":"The CDC42 small GTPase is a major influence on actin-myosin cytoskeleton organization and dynamics, signalling via effector proteins including the Myotonic dystrophy related CDC42-binding protein kinases (MRCK) α and β. We previously identified Serine 1003 of MRCKα as a site of autophosphorylation, and showed that a phosphorylation-sensitive antibody raised against this site could be used as a surrogate indicator of kinase activity. In this study, a kinase-dead version of MRCKβ was established by mutation of the conserved Lysine 105 to Methionine (K105M), which was then used for mass spectrometry analysis to identify phosphorylation events that occurred in catalytically-competent MRCKβ but not in the kinase-dead form. A total of ten phosphorylations were identified on wild-type MRCKβ, of which the previously undescribed Threonine 1108 (Thr1108) was not found on kinase-dead MRCKβ K105M, consistent with this being due to autophosphorylation. Mutation of Thr1108 to non-phosphorylatable Alanine (T1108A) or phosphomimetic Glutamate (T1108E) did not affect the ability of MRCKβ to phosphorylate recombinant myosin light chain in vitro, or observably alter the subcellular localization of green fluorescent protein (GFP)-tagged MRCKβ expressed in MDA MB 231 human breast cancer cells. Although phosphorylation of Thr1108 did not appear to contribute to MRCKβ function or regulation, the identification of this phosphorylation does make it possible to characterize whether this site could be used as a surrogate biomarker of kinase activity and inhibitor efficacy as we previously demonstrated for Ser 1003 in MRCKα.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"11 6","pages":"451-460"},"PeriodicalIF":0.0,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36873849","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

Increasing spatial resolution of photoregulated GTPases through immobilized peripheral membrane proteins. 通过固定外周膜蛋白增加光调节gtpase的空间分辨率。

Small GTPases Pub Date : 2020-11-01 Epub Date: 2018-09-05 DOI: 10.1080/21541248.2018.1507411

Orry Van Geel, Roland Hartsuiker, Theodorus W J Gadella

{"title":"Increasing spatial resolution of photoregulated GTPases through immobilized peripheral membrane proteins.","authors":"Orry Van Geel, Roland Hartsuiker, Theodorus W J Gadella","doi":"10.1080/21541248.2018.1507411","DOIUrl":"https://doi.org/10.1080/21541248.2018.1507411","url":null,"abstract":"Light-induced dimerizing systems, e.g. iLID, are an increasingly utilized optogenetics tool to perturb cellular signaling. The major benefit of this technique is that it allows external spatiotemporal control over protein localization with sub-cellular specificity. However, when it comes to local recruitment of signaling components to the plasmamembrane, this precision in localization is easily lost due to rapid diffusion of the membrane anchor. In this study, we explore different approaches of countering the diffusion of peripheral membrane anchors, to the point where we detect immobilized fractions with iFRAP on a timescale of several minutes. One method involves simultaneous binding of the membrane anchor to a secondary structure, the microtubules. The other strategy utilizes clustering of the anchor into large immobile structures, which can also be interlinked by employing tandem recruitable domains. For both approaches, the anchors are peripheral membrane constructs, which also makes them suitable for in vitro use. Upon combining these slower diffusing anchors with recruitable guanine exchange factors (GEFs), we show that we can elicit much more localized morphological responses from Rac1 and Cdc42 as compared to a regular CAAX-box based membrane anchor in living cells. Thanks to these new slow diffusing anchors, more precisely defined membrane recruitment experiments are now possible.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"11 6","pages":"441-450"},"PeriodicalIF":0.0,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541248.2018.1507411","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36462637","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: 10

The Rap2c GTPase facilitates B cell receptor-induced reorientation of the microtubule-organizing center. Rap2c GTPase促进B细胞受体诱导的微管组织中心的重定向。

Small GTPases Pub Date : 2020-11-01 Epub Date: 2018-03-08 DOI: 10.1080/21541248.2018.1441626

Jia C Wang, Jeff Y-J Lee, May Dang-Lawson, Caitlin Pritchard, Michael R Gold

引用次数: 7

The Rab7 subfamily across Paramecium aurelia species; evidence of high conservation in sequence and function. 草履虫种间Rab7亚科的研究序列和功能高度保守的证据。

Small GTPases Pub Date : 2020-11-01 Epub Date: 2018-08-29 DOI: 10.1080/21541248.2018.1502056

Lydia J Bright, Michael Lynch

{"title":"The Rab7 subfamily across Paramecium aurelia species; evidence of high conservation in sequence and function.","authors":"Lydia J Bright, Michael Lynch","doi":"10.1080/21541248.2018.1502056","DOIUrl":"https://doi.org/10.1080/21541248.2018.1502056","url":null,"abstract":"We examined sequence conservation and signatures of selection in Rab7 proteins across 11 Paramecium aurelia species, and determined the localization patterns of two P. tetraurelia Rab7 paralogs when expressed as GFP fusions in live cells. We found that, while there is a variable number of Rab7 paralogs per genome, Rab7 genes are highly conserved in sequence and appear to be under strong purifying selection across aurelias. Additionally, and surprisingly based on earlier studies, we found that two P. tetraurelia Rab7 proteins have virtually identical localization patterns. Consistent with this, when we examined the gene family of a highly conserved Rab binding partner across aurelias (Rab-Interacting Lysosomal Protein, or RILP), we found that residues in key binding sites in RILPs were absolutely conserved in 13 of 21 proteins, representing genes from 9 of the 11 species examined. Of note, RILP gene number appears to be even more constrained than Rab7 gene number per genome. Abbreviation: WGD: Whole genome duplication.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"11 6","pages":"421-429"},"PeriodicalIF":0.0,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541248.2018.1502056","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36440964","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

Targeting Cdc42 with the anticancer compound MBQ-167 inhibits cell polarity and growth in the budding yeast S. cerevisiae. 用抗癌化合物MBQ-167靶向Cdc42抑制萌发酵母的细胞极性和生长。

Small GTPases Pub Date : 2020-11-01 Epub Date: 2018-07-29 DOI: 10.1080/21541248.2018.1495008

Michael John Rivera-Robles, Julia Medina-Velázquez, Gabriela M Asencio-Torres, Sahily González-Crespo, Brian C Rymond, José Rodríguez-Medina, Suranganie Dharmawardhane

{"title":"Targeting Cdc42 with the anticancer compound MBQ-167 inhibits cell polarity and growth in the budding yeast S. cerevisiae.","authors":"Michael John Rivera-Robles, Julia Medina-Velázquez, Gabriela M Asencio-Torres, Sahily González-Crespo, Brian C Rymond, José Rodríguez-Medina, Suranganie Dharmawardhane","doi":"10.1080/21541248.2018.1495008","DOIUrl":"10.1080/21541248.2018.1495008","url":null,"abstract":"The Rho GTPase Cdc42 is highly conserved in structure and function. Mechanical or chemical cues in the microenvironment stimulate the localized activation of Cdc42 to rearrange the actin cytoskeleton and establish cell polarity. A role for Cdc42 in cell polarization was first discovered in the budding yeast Saccharomyces cerevisiae, and subsequently shown to also regulate directional motility in animal cells. Accordingly, in cancer Cdc42 promotes migration, invasion, and spread of tumor cells. Therefore, we targeted Cdc42 as a therapeutic strategy to treat metastatic breast cancer and designed the small molecule MBQ-167 as a potent inhibitor against Cdc42 and the homolog Rac. MBQ-167 inhibited cancer cell proliferation and migration in-vitro, and tumor growth and spread in-vivo in a mouse xenograft model of metastatic breast cancer. Since haploid budding yeast express a single Cdc42 gene, and do not express Rac, we used this well characterized model of polarization to define the contribution of Cdc42 inhibition to the effects of MBQ-167 in eukaryotic cells. Growth, budding pattern, and Cdc42 activity was determined in wildtype yeast or cells expressing a conditional knockdown of Cdc42 in response to vehicle or MBQ-167 treatment. As expected, growth and budding polarity were reduced by knocking-down Cdc42, with a parallel effect observed with MBQ-167. Cdc42 activity assays confirmed that MBQ-167 inhibits Cdc42 activation in yeast, and thus, bud polarity. Hence, we have validated MBQ-167 as a Cdc42 inhibitor in another biological context and present a method to screen Cdc42 inhibitors with potential as anti-metastatic cancer drugs.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"11 6","pages":"430-440"},"PeriodicalIF":0.0,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21541248.2018.1495008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36280629","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: 6

ARF6 and Rab11 as intrinsic regulators of axon regeneration. ARF6和Rab11作为轴突再生的内在调节因子。

Small GTPases Pub Date : 2020-11-01 Epub Date: 2018-05-17 DOI: 10.1080/21541248.2018.1457914

Bart Nieuwenhuis, Richard Eva

引用次数: 0