The Lsc RhoGEF mediates signaling from thromboxane A2 to actin polymerization and apoptosis in thymocytes

Harenberg, Anke; Girkontaitė, Irutė; Giehl, Klaudia; Fischer, Klaus–Dieter

doi:10.1002/eji.200425769

Cited by 29 publications

(23 citation statements)

References 46 publications

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“…The Rac-GTP pull-down was performed essentially as described with some modifications (23). Thymocytes were resuspended in PBS plus 0.1% BSA, washed once, and lysed with RIPA buffer.…”

Section: Protein Analysismentioning

confidence: 99%

αPIX RhoGEF Supports Positive Selection by Restraining Migration and Promoting Arrest of Thymocytes

Korthals

Schilling

Reichardt

et al. 2014

The Journal of Immunology

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Thymocytes mature in a series of stages by migrating through specific areas of the thymus and interacting with other cells to receive the necessary developmental signals; however, little is known about the molecular mechanisms governing this migration. We report that murine thymocytes with a knockout mutation in α-PAK (p21-activated kinase)-interacting exchange factor (PIX; Arhgef6), an activator of Rho GTPases, showed greatly increased motility and altered morphology in two-dimensional migration on ICAM-1. αPIX was also required for efficient positive selection, but not negative selection, of thymocytes. TCR signaling was normal in αPix− thymocytes, indicating that the effects of αPIX on positive selection are largely independent of TCR signaling. αPix− thymocytes also paused less during migration in the thymic cortex, interacted less with ICAM-1 coated beads, and could overcome TCR stop signals, consistent with defective scanning behavior. These results identify αPIX as a regulator of thymocyte migration and subsequent arrest that is linked to positive selection.

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“…The Rac-GTP pull-down was performed essentially as described with some modifications (23). Thymocytes were resuspended in PBS plus 0.1% BSA, washed once, and lysed with RIPA buffer.…”

Section: Protein Analysismentioning

confidence: 99%

αPIX RhoGEF Supports Positive Selection by Restraining Migration and Promoting Arrest of Thymocytes

Korthals

Schilling

Reichardt

et al. 2014

The Journal of Immunology

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“…In addition to MLC phosphorylation, ROCK activation mediates other molecular events in PMA-treated apoptotic cells such as prevention of nuclear distribution of phospho-ERK, inhibition of induction of the cell cycle inhibitor p21 (Cip1/Waf1) [68], and cytosolic translocation of heterogeneous nuclear ribonucleoprotein C1 and C2, which are two nuclear restricted pre-mRNA binding proteins [72]. In primary thymocytes, apoptosis induced by activation of the receptor for thromboxane A(2), which is coupled to Gα(12/13) subunits, is inhibited by deletion of Lsc RhoGEF (an activator of GTPases of the Rho family), associated with inactivation of Rho/ROCK and increased Akt phosphorylation [47]. Ethanol is an important teratogen that induces marked central nervous system dysfunctions and ethanol-induced ROCK activation in astrocytes promotes MLC phosphorylation and actomyosin contraction thereby leading to apoptosis induced by loss of anchorage [89].…”

Section: In Vitro Evidencementioning

confidence: 99%

Rho kinase in the regulation of cell death and survival

Shi

Wei

2007

Arch. Immunol. Ther. Exp.

219

183

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SummaryRho kinase (ROCK) belongs to a family of serine/threonine kinases that are activated via interaction with Rho GTPases. ROCK is involved in a wide range of fundamental cellular functions such as contraction, adhesion, migration, and proliferation. Recent studies have shown that ROCK plays an important role in the regulation of apoptosis in various cell types and animal disease models. Two ROCK isoforms, ROCK1 and ROCK2, are assumed to be function redundant, based largely on kinase construct overexpression, and chemical inhibitors (Y27632 and fasudil), which inhibit both ROCK1 and ROCK2. Gene targeting and RNA interference approaches allow further dissection of distinct cellular, physiological and patho-physiological functions of the two ROCK isoforms. This review, based on recent molecular, cellular and animal studies, focuses on the current understanding of ROCK signaling in the regulation of apoptosis and highlights the new findings from recently generated ROCK-deficient mice.

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“…Considering the similarity of the phenotype between mice lacking Rho GDI␣␤ and Lsc, part of their physiological function appears to overlap especially in regulating Rho activation. Importantly, Lsc Ϫ/Ϫ mice on a BALB/c background showed increased numbers of thymocytes and hyperplasia of the thymus, implicating Lsc in thromboxane (TXA) 2 signaling to T cells (42). Since TXA2 activates apoptosis of immature thymocytes, it is intriguing whether Rho GDI␣␤ Ϫ/Ϫ mice on a BALB/c background will develop hyperplasia of the thymus because of decreased TXA2-mediated apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Defective Chemokine-Directed Lymphocyte Migration and Development in the Absence of Rho Guanosine Diphosphate-Dissociation Inhibitors α and β

Ishizaki

Togawa²,

Tanaka-Okamoto

et al. 2006

The Journal of Immunology

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Rho family small GTP-binding proteins, including Rho, Rac, and Cdc42, are key determinants of cell movement and actin-dependent cytoskeletal morphogenesis. Rho GDP-dissociation inhibitor (GDI) α and Rho GDIβ (or D4/Ly-GDI), closely related regulators for Rho proteins, are both expressed in hemopoietic cell lineages. Nevertheless, the functional contributions of Rho GDIs remain poorly understood in vivo. In this study, we report that combined disruption of both the Rho GDIα and Rho GDIβ genes in mice resulted in reduction of marginal zone B cells in the spleen, retention of mature T cells in the thymic medulla, and a marked increase in eosinophil numbers. Furthermore, these mice showed lower CD3 expression and impaired CD3-mediated proliferation of T cells. While B cells showed slightly enhanced chemotactic migration in response to CXCL12, peripheral T cells showed markedly reduced chemotactic migration in response to CCL21 and CCL19 associated with decreased receptor levels of CCR7. Overall, Rho protein levels were reduced in the bone marrow, spleen, and thymus but sustained activation of the residual part of RhoA, Rac1, and Cdc42 was detected mainly in the bone marrow and spleen. Rho GDIα and Rho GDIβ thus play synergistic roles in lymphocyte migration and development by modulating activation cycle of the Rho proteins in a lymphoid organ-specific manner.

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The Lsc RhoGEF mediates signaling from thromboxane A2 to actin polymerization and apoptosis in thymocytes

Cited by 29 publications

References 46 publications

αPIX RhoGEF Supports Positive Selection by Restraining Migration and Promoting Arrest of Thymocytes

αPIX RhoGEF Supports Positive Selection by Restraining Migration and Promoting Arrest of Thymocytes

Rho kinase in the regulation of cell death and survival

Defective Chemokine-Directed Lymphocyte Migration and Development in the Absence of Rho Guanosine Diphosphate-Dissociation Inhibitors α and β

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