Function of the Nucleotide Exchange Activity of Vav1 in T Cell Development and Activation

Saveliev, Alexander; Vanes, Lesley; Ksionda, Olga; Rapley, Jonathan; Smerdon, Stephen J.; Rittinger, Katrin; Tybulewicz, Victor L. J.

doi:10.1126/scisignal.2000420

Cited by 69 publications

(98 citation statements)

References 59 publications

(106 reference statements)

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“…Knock-in mice expressing a GEF-deficient form of Vav1 exhibit a block in T cell development at the DP to SP transition, which is similar to the phenotype of Themis1 −/− mice (20). We therefore suspected that the impaired T cell development observed in Themis1 −/− mice might result, in part, from a defect in Vav1 GEF activity.…”

Section: Themis1 Enhances Vav1 Activity In Thymocytesmentioning

confidence: 78%

Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability

et al. 2016

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The T cell signaling protein Themis1 is essential for the positive and negative selection of thymocytes in the thymus. Although the developmental defect that results from the loss of Themis1 suggests that it enhances T cell receptor (TCR) signaling, Themis1 also recruits Src homology 2 domain-containing phosphatase-1 (SHP-1) to the vicinity of TCR signaling complexes, suggesting that it has an inhibitory role in TCR signaling. We used TCR signaling reporter mice and quantitative proteomics to explore the role of Themis1 in developing T cells. We found that Themis1 acted mostly as a positive regulator of TCR signaling in vivo when receptors were activated by positively selecting ligands. Proteomic analysis of the Themis1 interactome identified SHP-1, the TCR-associated adaptor protein Grb2, and the guanine nucleotide exchange factor Vav1 as the principal interacting partners of Themis1 in isolated mouse thymocytes. Analysis of TCR signaling in Themis1-deficient and Themis1-overexpressing mouse thymocytes demonstrated that Themis1 promoted Vav1 activity both in vitro and in vivo. The reduced activity of Vav1 and the impaired T cell development in Themis1 −/− mice were due in part to increased degradation of Grb2, which suggests that Themis1 is required to maintain the steady-state abundance of Grb2 in thymocytes. Together, these data suggest that Themis1 acts as a positive regulator of TCR signaling in developing T cells, and identify a mechanism by which Themis1 regulates thymic selection.

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Section: Themis1 Enhances Vav1 Activity In Thymocytesmentioning

confidence: 78%

Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability

et al. 2016

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“…of the suboptimal deletion of the Nck2 flox alleles in DN thymocytes. Notably, a partial block at the DN3 stage is shared by other deletional models of direct and indirect binding partners of Nck; namely, WASP (32), Vav (33), and the CD3ε.PRS, although, in this case, in some (13,22) but not all (12,14) models investigated.…”

Section: Discussionmentioning

confidence: 99%

Fine Tuning of the Threshold of T Cell Selection by the Nck Adapters

Roy

Togbé

Holdorf

et al. 2010

The Journal of Immunology

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Thymic selection shapes the T cell repertoire to ensure maximal antigenic coverage against pathogens while preventing autoimmunity. Recognition of self-peptides in the context of peptide-MHC complexes by the TCR is central to this process, which remains partially understood at the molecular level. In this study we provide genetic evidence that the Nck adapter proteins are essential for thymic selection. In vivo Nck deletion resulted in a reduction of the thymic cellularity, defective positive selection of low-avidity T cells, and impaired deletion of thymocytes engaged by low-potency stimuli. Nck-deficient thymocytes were characterized by reduced ERK activation, particularly pronounced in mature single positive thymocytes. Taken together, our findings identify a crucial role for the Nck adapters in enhancing TCR signal strength, thereby fine-tuning the threshold of thymocyte selection and shaping the preimmune T cell repertoire.

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“…Alternatively, Vav3 might play a GEF activityindependent role in chemotaxis. Some GEF activity-independent roles have been described for the Vav family in other cell types; for example, a GEF-dead version of Vav1 can mediate TCR-induced calcium flux and cellular polarization in T cells (40).…”

Section: Discussionmentioning

confidence: 99%

P-Rex1 and Vav1 Cooperate in the Regulation of Formyl-Methionyl-Leucyl-Phenylalanine–Dependent Neutrophil Responses

Lawson

Donald

Anderson

et al. 2011

The Journal of Immunology

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G protein-coupled receptor (GPCR) activation elicits neutrophil responses such as chemotaxis and reactive oxygen species (ROS) formation, which depend on the small G protein Rac and are essential for host defense. P-Rex and Vav are two families of guanine-nucleotide exchange factors (GEFs) for Rac, which are activated through distinct mechanisms but can both control GPCR-dependent neutrophil responses. It is currently unknown whether they play specific roles or whether they can compensate for each other in controlling these responses. In this study, we have assessed the function of neutrophils from mice deficient in P-Rex and/or Vav family GEFs. We found that both the P-Rex and the Vav family are important for LPS priming of ROS formation, whereas particle-induced ROS responses and cell spreading are controlled by the Vav family alone. Surprisingly, fMLF-stimulated ROS formation, adhesion, and chemotaxis were synergistically controlled by P-Rex1 and Vav1. These responses were more severely impaired in neutrophils lacking both P-Rex1 and Vav1 than those lacking the entire P-Rex family, the entire Vav family, or both P-Rex1 and Vav3. P-Rex1/Vav1 (P1V1) double-deficient cells also showed the strongest reduction in fMLF-stimulated activation of Rac1 and Rac2. This reduction in Rac activity may be sufficient to cause the defects observed in fMLF-stimulated P1V1 neutrophil responses. Additionally, Mac-1 surface expression was reduced in P1V1 cells, which might contribute further to defects in responses involving integrins, such as GPCR-stimulated adhesion and chemotaxis. We conclude that P-Rex1 and Vav1 together are the major fMLFR -dependent Dbl family Rac-GEFs in neutrophils and cooperate in the control of fMLF-stimulated neutrophil responses.

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Function of the Nucleotide Exchange Activity of Vav1 in T Cell Development and Activation

Cited by 69 publications

References 59 publications

Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability

Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability

Fine Tuning of the Threshold of T Cell Selection by the Nck Adapters

P-Rex1 and Vav1 Cooperate in the Regulation of Formyl-Methionyl-Leucyl-Phenylalanine–Dependent Neutrophil Responses

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