Small GTPases最新文献_第6页

LRRK2 binds to the Rab32 subfamily in a GTP-dependent manner via its armadillo domain. LRRK2 通过其犰狳结构域以 GTP 依赖性方式与 Rab32 亚家族结合。

Small GTPases Pub Date : 2021-03-01 Epub Date: 2019-09-25 DOI: 10.1080/21541248.2019.1666623

Emma McGrath, Dieter Waschbüsch, Brian M Baker, Amir R Khan

{"title":"LRRK2 binds to the Rab32 subfamily in a GTP-dependent manner via its armadillo domain.","authors":"Emma McGrath, Dieter Waschbüsch, Brian M Baker, Amir R Khan","doi":"10.1080/21541248.2019.1666623","DOIUrl":"10.1080/21541248.2019.1666623","url":null,"abstract":"LRRK2 is a multi-domain Ser/Thr kinase that is associated with inherited and sporadic cases of Parkinson's disease. Many mutations linked to disease are associated within a central ROC-COR regulatory region and the subsequent kinase domain, leading to enhanced catalytic activity. The N-terminus of human LRRK2 consists of armadillo repeat motifs (ARMs) followed by ankyrin repeats (ANKs). Recently, Rab GTPases have emerged as key players in LRRK2 function, both as substrates of the kinase, and as regulators of the catalytic activity. Rabs recruit effector proteins via their GTP-dependent switch 1 and 2 regions to distinct sub-cellular compartments to regulate membrane trafficking. LRRK2 phosphorylates Rab8, Rab10 and Rab12 in switch 2, and this activity is regulated via interactions with Rab29. Furthermore, the related Rab32-subfamily GTPases, Rab32 and Rab38, have also been shown to interact with LRRK2. Here, we have mapped the interactions of the Rab32-subfamily to the ARM domain of LRRK2. The complexes are dependent on the GTP state of the Rabs in vitro, implying that LRRK2 may be an effector of the Rab32-subfamily of small GTPases. X-ray crystal structures of the Rab32-family GTPases and subsequent mutational studies reveal that a positively charged residue in switch 1 is critical for binding of Rab32/38 to LRRK2. Homology modelling and mutational analyses of the ARM domain point to a patch of negatively charged residues that contribute to complex formation. These structural and biochemical studies provide a framework for understanding the molecular basis for Rab regulation of LRRK2 and its role in Parkinson's disease.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"12 2","pages":"133-146"},"PeriodicalIF":0.0,"publicationDate":"2021-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849779/pdf/KSGT_12_1666623.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9620118","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

Aberrant Rac pathway signalling in glioblastoma. 胶质母细胞瘤的 Rac 通路信号异常。

Small GTPases Pub Date : 2021-03-01 Epub Date: 2019-05-06 DOI: 10.1080/21541248.2019.1612694

Ian Aj Lorimer

{"title":"Aberrant Rac pathway signalling in glioblastoma.","authors":"Ian Aj Lorimer","doi":"10.1080/21541248.2019.1612694","DOIUrl":"10.1080/21541248.2019.1612694","url":null,"abstract":"Glioblastoma is an aggressive and incurable form of brain cancer. Both mutation analysis in human glioblastoma and mouse modelling studies have shown that aberrant activation of the PI 3-kinase pathway is a central driver of glioblastoma malignancy. The small GTPase Rac is activated downstream of this pathway, mediating a subset of the effects of aberrant PI 3-kinase pathway activation. Here I discuss the current state of our knowledge on Rac activation mechanisms in glioblastoma. Current knowledge on roles for specific PI 3-kinase pathway responsive Rac guanine nucleotide exchange factors in glioblastoma is reviewed. Rac is best known for its role in promoting cell motility and invasion, but there is also evidence for roles in multiple other cellular processes with cancer relevance, including proliferation, differentiation, apoptosis, DNA damage responses, metabolism, angiogenesis and immunosuppression. I review what is known about the role of Rac in these processes in glioblastoma. Finally, I assess possible strategies to inhibit this pathway in glioblastoma through either direct inhibition of Rac or inhibition of upstream activators or downstream mediators of Rac signalling.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":" ","pages":"81-95"},"PeriodicalIF":0.0,"publicationDate":"2021-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849730/pdf/KSGT_12_1612694.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37356034","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

RhoG and Cdc42 can contribute to Rac-dependent lamellipodia formation through WAVE regulatory complex-binding. RhoG和Cdc42可以通过WAVE调节复合物结合促进rac依赖性板足的形成

Small GTPases Pub Date : 2021-03-01 Epub Date: 2019-08-26 DOI: 10.1080/21541248.2019.1657755

Matthias Schaks, Hermann Döring, Frieda Kage, Anika Steffen, Thomas Klünemann, Wulf Blankenfeldt, Theresia Stradal, Klemens Rottner

引用次数: 0

Approaches to inhibiting oncogenic K-Ras. 抑制致癌K-Ras的方法

Small GTPases Pub Date : 2021-03-01 Epub Date: 2019-08-22 DOI: 10.1080/21541248.2019.1655883

Alemayehu A Gorfe, Kwang-Jin Cho

引用次数: 0

Fgd5 is a Rac1-specific Rho GEF that is selectively inhibited by aurintricarboxylic acid. Fgd5是一种具有rac1特异性的Rho GEF，可被金三羧酸选择性抑制

Small GTPases Pub Date : 2021-03-01 Epub Date: 2019-10-10 DOI: 10.1080/21541248.2019.1674765

Sally Park, Yitian Guo, Judeah Negre, Jordane Preto, Cameron C Smithers, Abul Kalam Azad, Michael Overduin, Allan G Murray, Gary Eitzen

{"title":"Fgd5 is a Rac1-specific Rho GEF that is selectively inhibited by aurintricarboxylic acid.","authors":"Sally Park, Yitian Guo, Judeah Negre, Jordane Preto, Cameron C Smithers, Abul Kalam Azad, Michael Overduin, Allan G Murray, Gary Eitzen","doi":"10.1080/21541248.2019.1674765","DOIUrl":"10.1080/21541248.2019.1674765","url":null,"abstract":"Rho proteins are signalling molecules that control cellular dynamics, movement and morphological changes. They are activated by Rho guanine-nucleotide exchange factors (Rho GEFs) that transduce upstream signals into Rho-mediated activation of downstream processes. Fgd5 is a Rho GEF involved in angiogenesis and its target Rho protein for this process has been linked to Cdc42 activation. Here, we examined the function of purified Fgd5, specifically, which Rho proteins it activates and pinpoint the structural domains required for enzymatic activity. Using a GEF enzyme assay, we found that purified Fgd5 showed preferential activation of Rac1 and direct binding of Rac1 in pull-down and co-immunoprecipitation assays. Structural comparisons showed that the Fgd5 DH domain is highly similar to the Rac1 GEF, TrioN, supporting a role for Fgd5 as a Rac1 GEF. Compounds that bind to purified Fgd5 DH-PH protein were identified by screening a small molecule library via surface plasmon resonance. The effects of eleven ligands were further examined for their ability to inhibit the Fgd5 GEF enzymatic activity and Rac1 interaction. From these studies, we found that the compound aurintricarboxylic acid, and to a lesser extent mitoxantrone dihydrochloride, inhibited both Fgd5 GEF activation of Rac1 and their interaction. Aurintricarboxylic acid had no effect on the activity or binding of the Rac1 GEF, TrioN, thus demonstrating the feasibility of selectively disrupting Rho GEF activators. Abbreviations: a.a.: amino acid; ATA: aurintricarboxylic acid; DH: Dbl homology; DOCK: dictator of cytokinesis; Fgd: faciogenital dysplasia; GEF: guanine-nucleotide exchange factor; GST: glutathione S-transferase; LOPAC: library of pharmacologically active compounds; PH: pleckstrin homology; PDB: protein data bank; s.e.m.: standard error of the mean; SPR: surface plasmon resonance.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"12 1","pages":"147-160"},"PeriodicalIF":0.0,"publicationDate":"2021-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42750169","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

Small GTPases of the Ras superfamily and glycogen phosphorylase regulation in T cells. Ras超家族的小GTP酶和T细胞中糖原磷酸化酶的调节

Small GTPases Pub Date : 2021-03-01 Epub Date: 2019-09-12 DOI: 10.1080/21541248.2019.1665968

Francisco Llavero, Alazne Arrazola Sastre, Miriam Luque Montoro, Miguel A Martín, Joaquín Arenas, Alejandro Lucia, José L Zugaza

{"title":"Small GTPases of the Ras superfamily and glycogen phosphorylase regulation in T cells.","authors":"Francisco Llavero, Alazne Arrazola Sastre, Miriam Luque Montoro, Miguel A Martín, Joaquín Arenas, Alejandro Lucia, José L Zugaza","doi":"10.1080/21541248.2019.1665968","DOIUrl":"10.1080/21541248.2019.1665968","url":null,"abstract":"Small GTPases, together with their regulatory and effector molecules, are key intermediaries in the complex signalling pathways that control almost all cellular processes, working as molecular switches to transduce extracellular cues into cellular responses that drive vital functions, such as intracellular transport, biomolecule synthesis, gene activation and cell survival. How all of these networks are linked to metabolic pathways is a subject of intensive study. Because any response to cellular action requires some form of energy input, elucidating how cells coordinate the signals that lead to a tangible response involving metabolism is central to understand cellular activities. In this review, we summarize recent advances in our understanding of the molecular basis of the crosstalk between small GTPases of the Ras superfamily, specifically Rac1 and Ras/Rap1, and glycogen phosphorylase in T lymphocytes. Abbreviations: ADCY: adenylyl cyclase; ADCY6: adenylyl cyclase 6; BCR: B cell receptor; cAMP: 3',5'-cyclic adenosine monophosphate; CRIB: Cdc42/Rac binding domain; DLPFC: dysfunction of the dorsolateral prefrontal cortex; EGFR: epidermal growth factor receptor; Epac2: exchange protein directly activated by cAMP; GDP: guanodine-5'-diphosphate; GPCRs: G protein-coupled receptors; GTP: guanodin-5'-triphosphate; IL2: interleukin 2; IL2-R: interleukin 2 receptor; JAK: janus kinases; MAPK: mitogen-activated protein kinase; O-GlcNAc: O-glycosylation; PAK1: p21 activated kinase 1; PI3K: phosphatidylinositol 3-kinase; PK: phosphorylase kinase; PKA: cAMP-dependent protein kinase A; PKCθ: protein kinase Cθ; PLCγ: phospholipase Cγ; Src: proto-oncogene tyrosine-protein kinase c; STAT: signal transducer and activator of transcription proteins.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"12 1","pages":"106-113"},"PeriodicalIF":0.0,"publicationDate":"2021-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42566011","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

Paradoxical regulation of glucose-induced Rac1 activation and insulin secretion by RhoGDIβ in pancreatic β-cells. 胰腺β细胞中 RhoGDIβ 对葡萄糖诱导的 Rac1 激活和胰岛素分泌的矛盾调控。

Small GTPases Pub Date : 2021-03-01 Epub Date: 2019-07-03 DOI: 10.1080/21541248.2019.1635403

Vijayalakshmi Thamilselvan, Anjaneyulu Kowluru

{"title":"Paradoxical regulation of glucose-induced Rac1 activation and insulin secretion by RhoGDIβ in pancreatic β-cells.","authors":"Vijayalakshmi Thamilselvan, Anjaneyulu Kowluru","doi":"10.1080/21541248.2019.1635403","DOIUrl":"10.1080/21541248.2019.1635403","url":null,"abstract":"Small GTPases (e.g., Rac1) play key roles in glucose-stimulated insulin secretion (GSIS) in the β-cell. We investigated regulation by RhoGDIβ of glucose-induced activation of Rac1 and insulin secretion. RhoGDIβ is expressed in INS-1 832/13 cells, rodent and human islets. siRNA-mediated knockdown of RhoGDIβ in INS-1 832/13 cells significantly attenuated glucose-induced Rac1 activation without affecting its translocation and membrane association. Further, suppression of RhoGDIβ expression exerted minimal effects on GSIS at the height of inhibition of Rac1 activation, suggesting divergent effects of RhoGDIβ on Rac1 activation and insulin secretion in the glucose-stimulated β-cell. We provide the first evidence for the expression of RhoGDIβ in rodent and human β-cells, and its differential regulatory roles of this protein in G protein activation and GSIS. Abbreviations: Arf6: ADP ribosylation factor; Cdc42: Cell Division Cycle; GAP: GTPase-activating protein; GDI: GDP dissociation inhibitor; GDIα: GDP dissociation inhibitorα; GDIβ: GDP dissociation inhibitorβ; GEF: Guanine nucleotide exchange factor; GSIS: Glucose-stimulated insulin secretion; Rac1: Ras-Related C3 Botulinum Toxin Substrate 1.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":" ","pages":"114-121"},"PeriodicalIF":0.0,"publicationDate":"2021-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849774/pdf/KSGT_12_1635403.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37393756","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

Correction. 更正。

Small GTPases Pub Date : 2021-01-01 Epub Date: 2020-01-11 DOI: 10.1080/21541248.2020.1713572

引用次数: 0

Anchorage-independent growth conditions reveal a differential SOS2 dependence for transformation and survival in RAS-mutant cancer cells. 锚定依赖性生长条件揭示了 RAS 突变癌细胞的转化和存活对 SOS2 的不同依赖性。

Small GTPases Pub Date : 2021-01-01 Epub Date: 2019-05-07 DOI: 10.1080/21541248.2019.1611168

Erin Sheffels, Nancy E Sealover, Patricia L Theard, Robert L Kortum

{"title":"Anchorage-independent growth conditions reveal a differential SOS2 dependence for transformation and survival in RAS-mutant cancer cells.","authors":"Erin Sheffels, Nancy E Sealover, Patricia L Theard, Robert L Kortum","doi":"10.1080/21541248.2019.1611168","DOIUrl":"10.1080/21541248.2019.1611168","url":null,"abstract":"The RAS family of genes (HRAS, NRAS, and KRAS) is mutated in around 30% of human tumours. Wild-type RAS isoforms play an important role in mutant RAS-driven oncogenesis, indicating that RasGEFs may play a significant role in mutant RAS-driven transformation. We recently reported a hierarchical requirement for SOS2 in mutant RAS-driven transformation in mouse embryonic fibroblasts, with KRAS>NRAS>HRAS (Sheffels et al., 2018). However, whether SOS2 deletion differentially affects mutant RAS isoform-dependent transformation in human tumour cell lines has not been tested. After validating sgRNAs that efficiently deleted HRAS and NRAS, we showed that the differential requirement for SOS2 to support anchorage-independent (3D) growth, which we previously demonstrated in MEFs, held true in cancer cells. KRAS-mutant cells showed a high dependence on SOS2 for 3D growth, as previously shown, whereas HRAS-mutant cells did not require SOS2 for 3D growth. This differential requirement was not due to differences in RTK-stimulated WT RAS activation, as SOS2 deletion reduced RTK-stimulated WT RAS/PI3K/AKT signalling in both HRAS and KRAS mutated cell lines. Instead, this differential requirement of SOS2 to promote transformation was due to the differential sensitivity of RAS-mutated cancer cells to reductions in WT RAS/PI3K/AKT signalling. KRAS mutated cancer cells required SOS2/PI3K signaling to protect them from anoikis, whereas survival of both HRAS and NRAS mutated cancer cells was not altered by SOS2 deletion. Finally, we present an integrated working model of SOS signaling in the context of mutant KRAS based on our findings and those of others.","PeriodicalId":22139,"journal":{"name":"Small GTPases","volume":"12 1","pages":"67-78"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781674/pdf/KSGT_12_1611168.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37381698","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

Effects of RhoA and RhoC upon the sensitivity of prostate cancer cells to glutamine deprivation. RhoA 和 RhoC 对前列腺癌细胞对谷氨酰胺剥夺敏感性的影响。

Small GTPases Pub Date : 2021-01-01 Epub Date: 2018-11-18 DOI: 10.1080/21541248.2018.1546098

Luciana Bueno De Paiva, Vanessa Aline Bernusso, João Agostinho Machado-Neto, Fabiola Traina, Anne J Ridley, Sara Teresinha Olalla-Saad, Mariana Lazarini

引用次数: 0