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Cancer-associated mutations in VAV1 trigger variegated signaling outputs and drive T cell lymphomagenesis

ABSTRACT: Mutations in VAV1, a multifunctional signaling protein essential for T lymphocytes, have been recently found in peripheral T cell lymphoma (PTCL) and other tumors. However, their pathobiological significance remains unsettled. Here, we show that these mutations belong to several subclasses according to the spectra of VAV1 signaling branches deregulated by them. These mutations target both known and new regulatory hotspots as well as transitional activation states of the protein. The most frequent VAV1 mutant subclass drives PTCL formation in mice by exacerbating normal VAV1- dependent signaling responses in follicular helper T cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE165006 | GEO | 2021/09/01

REPOSITORIES: GEO

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Cancer-associated mutations in VAV1 trigger variegated signaling outputs and drive T cell lymphomagenesis

Project description:Cancer-associated mutations in VAV1 trigger variegated signaling outputs and drive T cell lymphomagenesis

| PRJNA692770 | ENA

Cancer-associated mutations in VAV1 trigger variegated signaling outputs and T-cell lymphomagenesis.

Project description:Mutations in VAV1, a gene that encodes a multifunctional protein important for lymphocytes, are found at different frequencies in peripheral T-cell lymphoma (PTCL), non-small cell lung cancer, and other tumors. However, their pathobiological significance remains unsettled. After cataloguing 51 cancer-associated VAV1 mutations, we show here that they can be classified in five subtypes according to functional impact on the three main VAV1 signaling branches, GEF-dependent activation of RAC1, GEF-independent adaptor-like, and tumor suppressor functions. These mutations target new and previously established regulatory layers of the protein, leading to quantitative and qualitative changes in VAV1 signaling output. We also demonstrate that the most frequent VAV1 mutant subtype drives PTCL formation in mice. This process requires the concurrent engagement of two downstream signaling branches that promote the chronic activation and transformation of follicular helper T cells. Collectively, these data reveal the genetic constraints associated with the lymphomagenic potential of VAV1 mutant subsets, similarities with other PTCL driver genes, and potential therapeutic vulnerabilities.

| S-EPMC8591544 | biostudies-literature

CANCER-ASSOCIATED MUTATIONS IN VAV1 TRIGGER VARIEGATED SIGNALING OUTPUTS AND T CELL LYMPHOMAGENESIS

Project description:Mutations in VAV1, a gene that encodes a multifunctional protein important for lymphocytes, are found at different frequencies in peripheral T cell lymphoma (PTCL), non-small cell lung cancer and other tumors. However, their pathobiological significance remains unsettled. After cataloguing 51 cancer-associated VAV1 mutations, we show here that they can be classified in five subtypes according to functional impact on the three main VAV1 signaling branches, GEF-dependent activation of RAC1, GEF-independent adapter-like as well as tumor suppressor functions. These mutations target new and previously established regulatory layers of the protein, leading to quantitative and qualitative changes in VAV1 signaling output. We also demonstrate that the most frequent VAV1 mutant subtype drives PTCL formation in mice. This process requires the concurrent engagement of two downstream signaling branches that promote the chronic activation and transformation of follicular helper T cells. Collectively, these data reveal the genetic constraints associated with the lymphomagenic potential of VAV1 mutant subsets, similarities with other PTCL driver genes, and potential therapeutic vulnerabilities.

| S-SCDT-EMBOJ-2021-108125 | biostudies-other

Characterization of the spectrum of trivalent VAV1 mutation-driven tumors using a gene-edited mouse model

Project description:VAV1 mutations have been recently found in peripheral T cell lymphoma and non-small cell lung cancer. To understand their pathogenic potential, we generated a gene-edited mouse model that expresses a Vav1 mutant protein that recapitulates the signaling alterations present the VAV1 mutant subclass most frequently found in tumors. We could not detect any overt tumorigenic process in those mice. However, the concurrent elimination of the Trp53 tumor suppressor gene in them drives T cell lymphomagenesis. This process represents an exacerbation of the normal functions that wild-type Vav1 plays in follicular helper T cells. We also found that, in combination with an oncogenic Kras mutation, the Vav1 mutant version favors progression of non-small cell lung cancer. These data indicate that VAV1 mutations play critical, although highly cell typespecific roles in tumorigenesis. They also indicate that such functions are contingent on the mutational landscape of the tumors involved.

2022-10-12 | GSE189221 | GEO

Genome-wide analysis of gene expression in VAV1-/- versus VAV1+/+ bone marrow (BM)-macrophages

Project description:Analysis of differential gene expression profiles in VAV1-/- versus VAV+/+ BM-macrophages , respectively. A distinct expression profile in VAV1-/- versus VAV1+/+ (wild-type) BM-macrophages allows to resolve molecular mechanisms. Total RNA was obtained froms BM-macrophages of VAV1+/+ and VAV1-/- mice

2013-03-08 | E-GEOD-36123 | biostudies-arrayexpress

Genome-wide analysis of gene expression in VAV1-/- versus VAV1+/+ bone marrow (BM)-macrophages

2013-03-08 | GSE36123 | GEO

EXPRESSION OF VAV1 IN GLIOBLASTOMA MULTIFORME

Project description:Background: Even though much progress has been made in the understanding of the molecular nature of glioma, the survival rates of patients affected of this tumour have not changed significantly during these years. Thus, a deeper understanding of this malignancy is still needed in order to predict its outcome and improve patient treatment. Here, we report that VAV1, a GDP/GTP exchange factor for Rho/Rac proteins with oncogenic potential that is involved in the regulation of cytoskeletal dynamics and cell migration. Methodology/Principal Findings: VAV1 is overexpressed in 32 patients diagnosed with high-grade glioma. Such overexpression is linked to the parallel upregulation of a number of genes coding for proteins also involved in cell invasion- and migration-related processes. Unexpectedly, immunohistochemical experiments revealed that VAV1 is not expressed in glioma cells. Instead, VAV1 is found in non-tumoral astrocyte-like cells that are located either peritumoraly or perivascularly, suggesting that its expression is linked to synergistic signalling cross-talk between cancer and infiltrating cells. Conclusions/Significance: Interestingly, we show that the pattern of expression of VAV1 is a good prognostic factor to unveil populations of high-grade glioma patients with different survival and progression free survival rates.

2010-09-30 | GSE24072 | GEO

Analysis of the Vav1 interactome in primary T cells

Project description:In this study, we combined mouse genetics and quantitative proteomics to characterize in a comprehensive manner the VAV1 interactome. A line of knock-in mouse expressing endogenous VAV1 molecules with a genetic tag permitting affinity purification was generated and combined with affinity purification and mass spectrometry (AP-MS) to analyze the VAV1 signaling complex that assembles in primary CD4+ T cells over 300 s of activation. This allowed us to describe in a time-resolved manner the interactome of VAV1 in primary CD4+ T cells and to identify 44 previously unknown bindings partners of VAV1. The dataset contains mass spectrometry results from the analysis of AP-MS purifications (based on affinity purification on Streptactin beads of One-Strep-tagged proteins) starting from CD4+ T cells which were either non stimulated or stimulated with pervanadate for different time lengths. Control samples for each time point were prepared from wild-type mice. 8 different conditions were thus analyzed: - VAV1-OST transgenic mice, CD4+ T cells non stimulated (noted Vav_0) - VAV1-OST transgenic mice, CD4+ T cells stimulated 30s (noted Vav_30) - VAV1-OST transgenic mice, CD4+ T cells stimulated 120s (noted Vav_120) - VAV1-OST transgenic mice, CD4+ T cells stimulated 300s (noted Vav_300) - WT mice, CD4+ T cells non stimulated (noted WT_0) - WT mice, CD4+ T cells stimulated 30s (noted WT_30) - WT mice, CD4+ T cells stimulated 120s (noted WT_120) - WT mice, CD4+ T cells stimulated 300s (noted WT_300) Four biological replicates were prepared for these 8 different conditions (noted S1, S2, S3, S4), yielding 32 analyzed samples. Three technical nanoLC-MS runs were acquired for each sample (noted R1, R2, R3), except for some samples of the biological series S4 for which 2 technical nanoLC-MS runs were performed. This led to 91 nanoLC-MS raw files composing the dataset.

2018-06-26 | PXD004217 | Pride

Themis1-mediated repression of SHP-1 activity promotes regulatory T cell suppressive functions through a Vav1-RelA signaling axis

Project description:Regulatory T cells (Tregs) expressing the transcription factor Foxp3 constitute a unique T cell lineage committed to suppressive functions and are crucial for suppressing aberrant immune responses in autoimmunity and allergy. Treg transcriptional landscape is tightly controlled by Foxp3-binding partners, including RelA. Although those DNA-binding complexes have been well characterized, the TCR signaling events that coordinate those dynamic molecular assembly are still poorly understood. Using a combination of genetic models, we show that the suppressive function of Tregs is controlled by a tri-molecular interplay between the signaling proteins Themis1, Vav1 and SHP-1. We identify the tyrosine phosphatase SHP-1 as a central component of an inhibitory circuit, which leads to the dephosphorylation of Vav1, which in turn is associated with a dramatic reduction of RelA activity and Treg suppressive function. Themis1 disconnects this circuit by blocking SHP-1 catalytic activity. Collectively, our results reveal a previously unappreciated pathway, whereby Themis1-mediated repression of SHP-1 activity promotes Tregs suppressive functions through a Vav1-RelA signaling axis.

2021-06-01 | GSE165882 | GEO

Vav1 regulates T cell activation through a feedback mechanism and crosstalk between the T cell receptor and CD28 in CD3-stimulated T cells

Project description:Vav1, a Rac/Rho guanine nucleotide exchange factor and a critical component of the T cell receptor (TCR) signaling cascade, is rapidly tyrosine phosphorylated in response to T cell activation. Previous studies using Vav1 knockout models have demonstrated its importance in TCR signaling. Although Vav1 has established roles in proliferation, cytokine secretion, Ca2+ responses, and cytoskeletal regulation, its function in the regulation of phosphorylation of TCR components, including the ζ chain, the CD3 δ, ε, γ chains, and the associated kinases Lck, and ZAP-70 is not well established. To obtain a more comprehensive picture of the role of Vav1 in receptor proximal signaling, we performed a wide-scale characterization of Vav1-dependent tyrosine phosphorylation events using quantitative phosphoproteomic analysis of Vav1-deficient T cells across a time course of TCR stimulation. Among the 642 tyrosine phosphorylation sites identified and quantified in cells with or without Vav1, we observed statistically significant alterations in phosphorylation on proteins implicated in canonical actin cytoskeletal rearrangement and cell cycle progression, supporting the previously established role of Vav1 in these functions of TCR signaling. Critically, this study revealed a new role for Vav1 in negative feedback regulation of the phosphorylation of immunoreceptor tyrosine-based activation motifs within the ζ chains, CD3 δ, ε, γ chains, as well as activation sites on the critical T cell tyrosine kinases Itk, Lck, and ZAP-70. Our study also uncovered a previously unappreciated role for Vav1 in crosstalk between the CD28 and TCR signaling pathways.

2016-05-31 | PXD002022 | Pride

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