Caspase-dependent cleavage and inactivation of the Vav1 proto-oncogene product during apoptosis prevents IL-2 transcription

Hofmann, Thomas G.; Hehner, Steffen P.; Dröge, Wulf; Schmitz, M. Lienhard

doi:10.1038/sj.onc.1203406

Cited by 32 publications

(23 citation statements)

References 53 publications

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“…To test this hypothesis, we examined the ability of Vav1, Vav2, and Vav3 to synergize with TCR signaling to activate transcription of an NFAT-or NFBdependent luciferase reporter gene. Consistent with previously reported results (19,49,50), stimulation of Jurkat T cells with anti-CD3 antibodies resulted in activation of both NFAT-and NFB-dependent transcription, which was strongly potentiated by overexpression of Vav1 in each case (Fig. 6).…”

Section: Resultssupporting

confidence: 80%

Vav Family Proteins Couple to Diverse Cell Surface Receptors

Moores

Selfors²,

Fredericks³

et al. 2000

Molecular and Cellular Biology

140

108

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Section: Resultssupporting

confidence: 80%

Vav Family Proteins Couple to Diverse Cell Surface Receptors

Moores

Selfors²,

Fredericks³

et al. 2000

Molecular and Cellular Biology

140

108

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“…Other components of the T cell receptor signalling cascade such as Vav and HPK1 have also been identi®ed as caspase 3 substrates in lymphocytes (Chen et al, 1999;Hofmann et al, 2000). Cleavage of these signalling enzymes leads to alterations in their catalytic activity.…”

Section: Discussionmentioning

confidence: 99%

Caspase-dependent cleavage of the hematopoietic specific adaptor protein Gads alters signalling from the T cell receptor

et al. 2001

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Gads is a SH2 and SH3 domain-containing, hematopoietic-speci®c adaptor protein that functions in signalling from the T cell receptor. Gads acts by linking SLP-76, bound by the carboxy-terminal Gads SH3 domain, to tyrosine phosphorylated LAT which contains binding sites for the Gads SH2 domain. Gads is distinguished from Grb2 and the closely related Grap protein by the presence of a 120 amino acid unique region between the SH2 domain and the carboxy terminal SH3 domain. Here we demonstrate that the unique region of Gads contains a capase cleavage site. Induction of apoptosis in lymphocytes results in detectable Gads cleavage by 60 min. Gads cleavage is blocked in vivo by treating cells with a caspase 3 inhibitor. A putative caspase 3 cleavage site was identi®ed within the unique region and mutation of this site prevented Gads cleavage in vitro, and in vivo. The Gads cleavage products retained the predicted binding speci®city for SLP-76 and LAT. Expression of the Gads cleavage products in Jurkat T cells inhibited NFAT activation following TCR cross linking. These ®ndings indicate that cleavage of Gads in vivo could function to alter signalling downstream of the T cell receptor by disrupting cross talk between SLP-76 and LAT. Oncogene (2001) 20, 1203 ± 1211.

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“…It was shown that caspase 8 and caspase 3 are activated in anti-CD3-stimulated T-cells (Alam et al 1999;Kennedy et al 1999). Together with the evidence showing that proteins involved in the TCR signaling cascade such as Gads, SLP-76, LAT, SLAP-130/Fyb (Berry et al 2001), vav1 (Hofmann et al 2000), and HPK1 (Chen et al 1999) are substrates for caspase processing, it is tempting to speculate that caspase 8 plays a role in maintaining optimal proximal signaling of the TCR-CD3 complex. Alternatively, caspase 8 may be required for modulation of proper cytokine responsiveness.…”

Section: Caspase 8 Function In T-cell Activation and Proliferationmentioning

confidence: 99%

Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity

Salmena¹,

Lemmers²,

Hakem³

et al. 2003

Genes Dev.

433

466

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Defects in death receptor-mediated apoptosis have been linked to cancer and autoimmune disease in humans.The in vivo role of caspase 8, a component of this pathway, has eluded analysis in postnatal tissues because of the lack of an appropriate animal model. Targeted disruption of caspase 8 is lethal in utero. We generated mice with a targeted caspase 8 mutation that is restricted to the T-cell lineage. Despite normal thymocyte development in the absence of caspase 8, we observed a marked decrease in the number of peripheral T-cells and impaired T-cell response ex vivo to activation stimuli. caspase 8 ablation protected thymocytes and activated T-cells from CD95 ligand but not anti-CD3-induced apoptosis, or apoptosis activated by agents that are known to act through the mitochondria. caspase 8 mutant mice were unable to mount an immune response to viral infection, indicating that caspase 8 deletion in T-cells leads to immunodeficiency. These findings identify an essential, cell-stage-specific role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. This is consistent with the recent identification of caspase 8 mutations in human immunodeficiency.

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Caspase-dependent cleavage and inactivation of the Vav1 proto-oncogene product during apoptosis prevents IL-2 transcription

Cited by 32 publications

References 53 publications

Vav Family Proteins Couple to Diverse Cell Surface Receptors

Vav Family Proteins Couple to Diverse Cell Surface Receptors

Caspase-dependent cleavage of the hematopoietic specific adaptor protein Gads alters signalling from the T cell receptor

Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity

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