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The Tec kinase ITK optimizes differential NFAT, NF-κB, and Erk1/2 signaling to regulate graded gene induction in mouse CD8+ T cells

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE167304 | GEO | 2021/02/23

REPOSITORIES: GEO

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The Tec kinase ITK optimizes differential NFAT, NF-κB, and Erk1/2 signaling to regulate graded gene induction in mouse CD8+ T cells [RNA-seq]

Project description:In this study we generated SMART-seq cDNA libraries from mouse CD8+ OT-I T cells that were stimulated with WT splenocytes loaded with OVA peptide or OVA peptide variants, with or without presence of ITK inhibitor PRN-694 at early time points (0, 30min, 60min, or 120min).

2021-02-23 | GSE167303 | GEO

The Tec kinase ITK optimizes differential NFAT, NF-κB, and Erk1/2 signaling to regulate graded gene induction in mouse CD8+ T cells [ATAC-seq]

Project description:In this study we generated ATAC-seq libraries from mouse CD8+ OT-I T cells that were stimulated with WT splenocytes loaded with OVA peptide or OVA peptide variants, with or without presence of ITK inhibitor PRN-694 at early time points (0, 30min, 60min, or 120min).

2021-02-23 | GSE167302 | GEO

The Tec kinase ITK optimizes differential NFAT, NF-κB, and Erk1/2 signaling to regulate graded gene induction in mouse CD8+ T cells

Project description:The Tec kinase ITK optimizes differential NFAT, NF-κB, and Erk1/2 signaling to regulate graded gene induction in mouse CD8+ T cells

| PRJNA704110 | ENA

The Tec kinase ITK optimizes differential NFAT, NF-κB, and Erk1/2 signaling to regulate graded gene induction in mouse CD8+ T cells [ATAC-seq]

Project description:The Tec kinase ITK optimizes differential NFAT, NF-κB, and Erk1/2 signaling to regulate graded gene induction in mouse CD8+ T cells [ATAC-seq]

| PRJNA704175 | ENA

The Tec kinase ITK optimizes differential NFAT, NF-κB, and Erk1/2 signaling to regulate graded gene induction in mouse CD8+ T cells [RNA-seq]

Project description:The Tec kinase ITK optimizes differential NFAT, NF-κB, and Erk1/2 signaling to regulate graded gene induction in mouse CD8+ T cells [RNA-seq]

| PRJNA704176 | ENA

Activation of the Tec Kinase ITK Controls Graded IRF4 Expression in Response to Variations in TCR Signal Strength.

Project description:TCR signal strength is critical for CD8+ T cell clonal expansion after Ag stimulation. Levels of the transcription factor IRF4 control the magnitude of this process through the induction of genes involved in proliferation and glycolytic metabolism. The signaling mechanism connecting graded TCR signaling to the generation of varying amounts of IRF4 is not well understood. In this study, we show that Ag potency regulates the kinetics but not the magnitude of NFAT1 activation in single mouse CD8+ T cells. Consequently, T cells that transduce weaker TCR signals exhibit a marked delay in Irf4 mRNA induction, resulting in decreased overall IRF4 expression in individual cells and increased heterogeneity within the clonal population. We further show that the activity of the tyrosine kinase ITK acts as a signaling catalyst that accelerates the rate of the cellular response to TCR stimulation, controlling the time to onset of Irf4 gene transcription. These findings provide insight into the function of ITK in TCR signal transduction that ultimately regulates IRF4 expression levels in response to variations in TCR signal strength.

| S-EPMC7343623 | biostudies-literature

SH2-dependent autophosphorylation within the Tec family kinase Itk.

Project description:The Tec family kinase, Itk (interleukin-2 tyrosine kinase), undergoes an in cis autophosphorylation on Y180 within its Src homology 3 (SH3) domain. Autophosphorylation of the Itk SH3 domain by the Itk kinase domain is strictly dependent on the presence of the intervening Src homology 2 (SH2) domain. A direct docking interaction between the Itk kinase and SH2 domains brings the Itk SH3 domain into the active site where Y180 is then phosphorylated. We now identify the residues on the surface of the Itk SH2 domain responsible for substrate docking and show that this SH2 surface mediates autophosphorylation in the full-length Itk molecule. The canonical phospholigand binding site on the SH2 domain is not involved in substrate docking, instead the docking site consists of side chains from three loop regions (AB, EF and BG) and part of the betaD strand. These results are extended into Btk (Bruton's tyrosine kinase), a Tec family kinase linked to the B-cell deficiency X-linked agammaglobulinemia (XLA). Our results suggest that some XLA-causing mutations might impair Btk phosphorylation.

| S-EPMC2722949 | biostudies-literature

T-cell signaling regulated by the Tec family kinase, Itk.

Project description:The Tec family tyrosine kinases regulate lymphocyte development, activation, and differentiation. In T cells, the predominant Tec kinase is Itk, which functions downstream of the T-cell receptor to regulate phospholipase C-gamma. This review highlights recent advances in our understanding of Itk kinase structure and enzymatic regulation, focusing on Itk protein domain interactions and mechanisms of substrate recognition. We also discuss the role of Itk in the development of conventional versus innate T-cell lineages, including both alphabeta and gammadelta T-cell subsets. Finally, we describe the complex role of Itk signaling in effector T-cell differentiation and the regulation of cytokine gene expression. Together, these data implicate Itk as an important modulator of T-cell signaling and function.

| S-EPMC2890196 | biostudies-literature

The Tec family kinase Itk exists as a folded monomer in vivo.

Project description:Tec family tyrosine kinases transduce signals from antigen and other receptors. In particular, Itk plays an important role in T-cell development and activation. Itk has an N-terminal pleckstrin homology domain, a Tec Homology domain with a proline-rich region, SH3 and SH2 domains and a kinase domain, the structure each of which has been determined. However, the full structure of Itk and other Tec kinases remain elusive. Models of Itk suggest either a head to tail dimer, with the SH2 domain interacting with the SH3 domain, or a folded monomer with the SH3 domain interacting with the proline-rich region. We show here that in vivo Itk exists as a monomer, with the pleckstrin homology domain less than 80 A from the C terminus. Zn2+ coordinating residues in the Tec Homology domain, not the proline-rich region, are critical for this intramolecular interaction. These data have implications for our understanding of Tec family kinase structure.

| S-EPMC2785618 | biostudies-literature

The Tec kinase ITK regulates thymic expansion, emigration, and maturation of ?? NKT cells.

Project description:The Tec family tyrosine kinase, Itk, regulates signaling downstream of the TCR. The absence of Itk in CD4(+) T cells results in impaired Th2 responses along with defects in maturation, cytokine production, and survival of iNKT cells. Paradoxically, Itk(-/-) mice have spontaneously elevated serum IgE levels, resulting from an expansion of the V?1.1(+)V?6.3(+) subset of ?? T cells, known as ?? NKT cells. Comparisons between ?? NKT cells and ?? iNKT cells showed convergence in the pattern of cell surface marker expression, cytokine profiles, and gene expression, suggesting that these two subsets of NKT cells undergo similar differentiation programs. Hepatic ?? NKT cells have an invariant TCR and are derived predominantly from fetal progenitors that expand in the thymus during the first weeks of life. The adult thymus contains these invariant ?? NKT cells plus a heterogeneous population of V?1.1(+)V?6.3(+) T cells with diverse CDR3 sequences. This latter population, normally excluded from the liver, escapes the thymus and homes to the liver when Itk is absent. In addition, Itk(-/-) ?? NKT cells persistently express high levels of Zbtb16 (PLZF) and Il4, genes that are normally downregulated in the most mature subsets of NKT cells. These data indicate that Itk signaling is required to prevent the expansion of ?? NKT cells in the adult thymus, to block their emigration, and to promote terminal NKT cell maturation.

| S-EPMC3594397 | biostudies-literature

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