The many faces of the guanine-nucleotide exchange factor trio

Rijssel, Jos van; Buul, Jaap D. van

doi:10.4161/cam.21418

Cited by 50 publications

(46 citation statements)

References 67 publications

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“…4, B-E, gray traces). We observed this small response previously (van Unen et al, 2015a), and it can most likely be attributed to the activation of the endogenous guanine exchange factor trio (van Rijssel and van Buul, 2012) by endogenous H 1 R receptors. We repeated this experiment in human embryonic kidney 293 (HEK293) cells, which do not contain endogenous H 1 R receptors, and found similar results for the activation of RhoA by ectopically expressed H 1 R, but no change in YFP/CFP FRET ratio for the control condition (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 84%

Quantitative Single-Cell Analysis of Signaling Pathways Activated Immediately Downstream of Histamine Receptor Subtypes

Unen

Rashidfarrokhi

Hoogendoorn

et al. 2016

Molecular Pharmacology

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Genetically encoded biosensors based on Förster resonance energy transfer (FRET) can visualize responses of individual cells in real time. Here, we evaluated whether FRET-based biosensors provide sufficient contrast and specificity to measure activity of G-protein-coupled receptors. The four histamine receptor subtypes (H 1 R, H 2 R, H 3 R, and H 4 R) respond to the ligand histamine by activating three canonical heterotrimeric G-protein-mediated signaling pathways with a reported high degree of specificity. Using FRET-based biosensors, we demonstrate that H 1 R activates Gaq. We also observed that H 1 R activates Gai, albeit at a 10-fold lower potency. In addition to increasing cAMP levels, most likely via Gas, we found that the H 2 R induces Gaq-mediated calcium release. The H 3 R and H 4 R activated Gai with high specificity and a high potency. We demonstrate that a number of FRET sensors provide sufficient contrast to: 1) analyze the specificity of the histamine receptor subtypes for different heterotrimeric G-protein families with single-cell resolution, 2) probe for antagonist specificity, and 3) allow the measurement of single-cell concentration-response curves.

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Section: Resultsmentioning

confidence: 84%

Quantitative Single-Cell Analysis of Signaling Pathways Activated Immediately Downstream of Histamine Receptor Subtypes

Unen

Rashidfarrokhi

Hoogendoorn

et al. 2016

Molecular Pharmacology

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“…TRIO A, B, and D are strongly expressed in brain tissue, whereas TRIO C is exclusively expressed in the cerebellum during development. 45 The study of TRIO and its orthologs in C. elegans, Drosophila, and mice demonstrates that DH1 of TRIO plays a vital role in neurite outgrowth and axon guidance during the development of the neuronal system. C. elegans TRIOlike unc-73 is deeply involved in cell migration regulation, 46 whereas in Drosophila, dosage-sensitive interaction between TRIO and the tyrosine-protein kinase Abl determines the axon pathfinding.…”

Section: Discussionmentioning

confidence: 99%

Incorporating Functional Information in Tests of Excess De Novo Mutational Load

Jiang

Han

Petrovski

et al. 2015

The American Journal of Human Genetics

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A number of recent studies have investigated the role of de novo mutations in various neurodevelopmental and neuropsychiatric disorders. These studies attempt to implicate causal genes by looking for an excess load of de novo mutations within those genes. Current statistical methods for assessing this excess are based on the implicit assumption that all qualifying mutations in a gene contribute equally to disease. However, it is well established that different mutations can have radically different effects on the ultimate protein product and, as a result, on disease risk. Here, we propose a method, fitDNM, that incorporates functional information in a test of excess de novo mutational load. Specifically, we derive score statistics from a retrospective likelihood that incorporates the probability of a mutation being damaging to gene function. We show that, under the null, the resulting test statistic is distributed as a weighted sum of Poisson random variables and we implement a saddlepoint approximation of this distribution to obtain accurate p values. Using simulation, we have shown that our method outperforms current methods in terms of statistical power while maintaining validity. We have applied this approach to four de novo mutation datasets of neurodevelopmental and neuropsychiatric disorders: autism spectrum disorder, epileptic encephalopathy, schizophrenia, and severe intellectual disability. Our approach also implicates genes that have been implicated by existing methods. Furthermore, our approach provides strong statistical evidence supporting two potentially causal genes: SUV420H1 in autism spectrum disorder and TRIO in a combined analysis of the four neurodevelopmental and neuropsychiatric disorders investigated here.

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“…Thus, it is unlikely that Vav1 and Vav3 are involved in the activation of RhoG in platelets. A more recent study demon- strated that another Rho guanine nucleotide exchange factor, Trio, is able to exchange GTP on RhoG and that it regulates lamellipodial formation to mediate cell spreading and migration in other cells (41). Trio is ubiquitously expressed, but the role of Trio in platelet function has not been established.…”

Section: Discussionmentioning

confidence: 99%

RhoG Protein Regulates Glycoprotein VI-Fc Receptor γ-Chain Complex-mediated Platelet Activation and Thrombus Formation

Kim

Dangelmaier

Bhavanasi

et al. 2013

Journal of Biological Chemistry

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Background: RhoG is a ubiquitously expressed member of the Rho family of GTPases. Results: RhoG-deficient platelets display severely impaired GPVI-dependent platelet activation. Conclusion: RhoG plays an important role in GPVI-FcR␥ complex-mediated platelet activation and thrombus formation. Significance: Our study enhances the understanding of the molecular mechanisms of GPVI-FcR␥ complex activation.

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The many faces of the guanine-nucleotide exchange factor trio

Cited by 50 publications

References 67 publications

Quantitative Single-Cell Analysis of Signaling Pathways Activated Immediately Downstream of Histamine Receptor Subtypes

Quantitative Single-Cell Analysis of Signaling Pathways Activated Immediately Downstream of Histamine Receptor Subtypes

Incorporating Functional Information in Tests of Excess De Novo Mutational Load

RhoG Protein Regulates Glycoprotein VI-Fc Receptor γ-Chain Complex-mediated Platelet Activation and Thrombus Formation

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