RhoH is important for positive thymocyte selection and T-cell receptor signaling

Dorn, Tatjana; Kuhn, Ursula; Bungartz, Gerd; Stiller, Sebastian B.; Bauer, Martina; Ellwart, Joachim W.; Peters, Thorsten; Scharffetter‐­Kochanek, Karin; Semmrich, Monika; Laschinger, Melanie; Holzmann, Bernhard; Klinkert, Wolfgang E. F.; Straten, Per thor; Køllgaard, Tania; Sixt, Michael; Brakebusch, Cord

doi:10.1182/blood-2006-04-019034

Cited by 78 publications

(105 citation statements)

References 35 publications

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“…These binding proteins may also participate in signal transduction. Among such binding proteins, we identified RhoH, a member of the Rho family of small GTPases that is known to be expressed in hematopoietic cells [31]. Overexpression of RhoH potentiated the effect of BCR stimulation on the overall level of protein tyrosine-phosphorylation in Namalwa cells (Figs.…”

Section: Identification Of Rhoh As a Binding Partner For Phosphorylatmentioning

confidence: 96%

Large‐scale proteomic analysis of tyrosine‐phosphorylation induced by T‐cell receptor or B‐cell receptor activation reveals new signaling pathways

et al. 2009

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Activation of the T-cell receptor (TCR) and that of the B-cell receptor (BCR) elicits tyrosinephosphorylation of proteins that belongs to similar functional categories, but result in distinct cellular responses. Large-scale analyses providing an overview of the signaling pathways downstream of TCR or BCR have not been described, so it has been unclear what components of these pathways are shared and which are specific. We have now performed a systematic analysis and provide a comprehensive list of tyrosine-phosphorylated proteins (PY proteome) with quantitative data on their abundance in T cell, B cell, and nonlymphoid cell lines. Our results led to the identification of novel tyrosine-phosphorylated proteins and signaling pathways not previously implicated in immunoreceptor signal transduction, such as clathrin, zonula occludens 2, eukaryotic translation initiation factor 3, and RhoH, suggesting that TCR or BCR signaling may be linked to downstream processes such as endocytosis, cell adhesion, and translation. Thus comparative and quantitative studies of tyrosine-phosphorylation have the potential to expand knowledge of signaling networks and to promote understanding of signal transduction at the system level.

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Section: Identification Of Rhoh As a Binding Partner For Phosphorylatmentioning

confidence: 96%

Large‐scale proteomic analysis of tyrosine‐phosphorylation induced by T‐cell receptor or B‐cell receptor activation reveals new signaling pathways

et al. 2009

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“…In contrast, little is known about the function of the many other members of the Rho family, such as RhoH/TTF. Recently published work suggests that RhoH/TTF plays a key role in TCR signaling (13,30). For instance, it has been demonstrated that RhoH/TTF is required for recruitment of ZAP70 to the TCR.…”

Section: Discussionmentioning

confidence: 99%

“…Ϫ/Ϫ mice were generated and provided by Dr. C. Brakebusch (Department of Molecular Pathology, University of Copenhagen, Copenhagen, Denmark) (13). For all experiments, 6-to 8-wk-old mice with a C57BL/6J background were used.…”

Section: Mice Rhohmentioning

confidence: 99%

RhoH/TTF Negatively Regulates Leukotriene Production in Neutrophils

Daryadel

Yousefi

Troi

et al. 2009

The Journal of Immunology

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Leukotriene B4 (LTB4) is an important proinflammatory lipid mediator generated by neutrophils upon activation. GM-CSF stimulation is known to enhance agonist-mediated LTB4 production of neutrophils within minutes, a process called “priming”. In this study, we demonstrate that GM-CSF also limits the production of LTB4 by neutrophils via a transcriptional mechanism at later time points. We identified hemopoietic-specific Ras homologous (RhoH)/translocation three four (TTF), which was induced following GM-CSF stimulation in neutrophils, as a key regulator in this process. Neutrophils derived from RhoH/TTF-deficient (Rhoh−/−) mice demonstrated increased LTB4 production upon activation compared with normal mouse neutrophils. Moreover, neutrophils from cystic fibrosis patients expressed enhanced levels of RhoH/TTF and generated less LTB4 upon activation compared with normal human neutrophils. Taken together, these data suggest that RhoH/TTF represents an inducible feedback inhibitor in neutrophils that is involved in the limitation of innate immune responses.

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“…A role for RhoH downstream of CXCR4 signaling is identified by a failure to activate PAK1 in response to strong stimulation via CXCR4 in the absence of RhoH (13), further linking RhoH with regulation of the cytoskeleton by Rac GTPases. However, constitutive activation of Rac1 increases proliferation of thymocytes in DN3 and an accelerated transition from DN3 to DN4 (20), whereas RhoH-deficient cells reveal diminished signaling and a block at this stage even in the presence of activated Rac1 (21), suggesting that regulation by RhoH is more complicated than only cytoskeletal effects. Defects in thymic selection, alongside studies of proximal TCR signals implicate RhoH as an important player in conjunction with Zap70 (9,21).…”

Section: Discussionmentioning

confidence: 96%

“…However, constitutive activation of Rac1 increases proliferation of thymocytes in DN3 and an accelerated transition from DN3 to DN4 (20), whereas RhoH-deficient cells reveal diminished signaling and a block at this stage even in the presence of activated Rac1 (21), suggesting that regulation by RhoH is more complicated than only cytoskeletal effects. Defects in thymic selection, alongside studies of proximal TCR signals implicate RhoH as an important player in conjunction with Zap70 (9,21). Zap70 is also reported to be involved in outside-in signaling for high-affinity LFA-1-mediated adhesion (22).…”

Section: Discussionmentioning

confidence: 96%

Opposing roles for RhoH GTPase during T-cell migration and activation

Baker¹,

Comrie²,

Hyun³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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T cells spend the majority of their time perusing lymphoid organs in search of cognate antigen presented by antigen presenting cells (APCs) and then quickly recirculate through the bloodstream to another lymph node. Therefore, regulation of a T-cell response is dependent upon the ability of cells to arrive in the correct location following chemokine gradients ("go" signal) as well as to receive appropriate T-cell receptor (TCR) activation signals upon cognate antigen recognition ("stop" signal). However, the mechanisms by which T cells regulate these go and stop signals remain unclear. We found that overexpression of the hematopoietic-specific RhoH protein in the presence of chemokine signals resulted in decreased Rap1-GTP and LFA-1 adhesiveness to ICAM-1, thus impairing T-cell chemotaxis; while in the presence of TCR signals, there were enhanced and sustained Rap1-GTP and LFA-1 activation as well as prolonged T:APC conjugates. RT-PCR analyses of activated CD4 + T cells and live images of T-cell migration and immunological synapse (IS) formation revealed that functions of RhoH took place primarily at the levels of transcription and intracellular distribution. Thus, we conclude that RhoH expression provides a key molecular determinant that allows T cells to switch between sensing chemokine-mediated go signals and TCR-dependent stop signals.

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RhoH is important for positive thymocyte selection and T-cell receptor signaling

Cited by 78 publications

References 35 publications

Large‐scale proteomic analysis of tyrosine‐phosphorylation induced by T‐cell receptor or B‐cell receptor activation reveals new signaling pathways

Large‐scale proteomic analysis of tyrosine‐phosphorylation induced by T‐cell receptor or B‐cell receptor activation reveals new signaling pathways

RhoH/TTF Negatively Regulates Leukotriene Production in Neutrophils

Opposing roles for RhoH GTPase during T-cell migration and activation

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