PI3 kinase function is vital for the function but not formation of LAT-mediated signaling complexes

Cruz-Orcutt, Noemi; Houtman, Jon C. D.

doi:10.1016/j.molimm.2009.04.006

Cited by 17 publications

(24 citation statements)

References 47 publications

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“…In conventional ␣␤T cells, Vav1 regulates the phosphorylation of PLC-␥1 and plays a central role in the regulation of lymphocyte development, activation, and proliferation (13). Vav1 regulates PLC-␥1 phosphorylation via PI3K-dependent and -independent pathways (41,42,51,52). In the present study we found that the phosphorylation of PLC-␥1 was unaffected by the PI3K inhibitor, indicating that Vav1 might regulate the phosphorylation of PLC-␥1 through the PI3K-independent pathway in ␥␦T cells.…”

Section: Discussionsupporting

confidence: 51%

Vav1-phospholipase C-γ1 (Vav1-PLC-γ1) Pathway Initiated by T Cell Antigen Receptor (TCRγδ) Activation Is Required to Overcome Inhibition by Ubiquitin Ligase Cbl-b during γδT Cell Cytotoxicity

Yin

Zhang

Mao

et al. 2013

Journal of Biological Chemistry

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Background: TCR␥␦ and NKG2D are two important receptors for ␥␦T cell cytotoxicity. Results: ␥␦T cell cytotoxicity is TCR␥␦-dependent and requires the activation of Vav1-PLC-␥1 pathway. Conclusion: ␥␦T cell cytotoxicity requires a strong signal to overcome the inhibitory threshold set by Cbl-b. Significance: Our finding provides new insights into the molecular mechanisms underlying the activation of ␥␦T cell cytotoxicity.

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Section: Discussionsupporting

confidence: 51%

Vav1-phospholipase C-γ1 (Vav1-PLC-γ1) Pathway Initiated by T Cell Antigen Receptor (TCRγδ) Activation Is Required to Overcome Inhibition by Ubiquitin Ligase Cbl-b during γδT Cell Cytotoxicity

Yin

Zhang

Mao

et al. 2013

Journal of Biological Chemistry

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“…The activity of the PI3K was shown to be essential to the signaling capacity of LAT-mediated complexes. 60 In support of the possible interplay between LAT and the BP4-BP5 mapping loci, copy number variants of the BP4-BP5 interval was associated with LAT differential expression in human lymphoblastoid cell lines. 45 Our findings suggest that LAT, like CD247 and ZAP70, [41][42][43][44] plays a role in neurogenesis and that perturbation of this pathway may lead to neurodevelopmental phenotypes.…”

Section: Discussionmentioning

confidence: 93%

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

Loviglio

Arbogast

Jønch³

et al. 2017

The American Journal of Human Genetics

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Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0.5%-1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220 kb BP2-BP3 CNV is likewise a potent driver of neuropsychiatric, anatomical, and metabolic pathologies. These two CNVs are engaged in complex reciprocal chromatin looping, intimating a functional relationship between genes in these regions that might be relevant to pathomechanism. We assessed the drivers of the distal 16p11.2 duplication by overexpressing each of the nine encompassed genes in zebrafish. Only overexpression of LAT induced a reduction of brain proliferating cells and concomitant microcephaly. Consistently, suppression of the zebrafish ortholog induced an increase of proliferation and macrocephaly. These phenotypes were not unique to zebrafish; Lat knockout mice show brain volumetric changes. Consistent with the hypothesis that LAT dosage is relevant to the CNV pathology, we observed similar effects upon overexpression of CD247 and ZAP70, encoding members of the LAT signalosome. We also evaluated whether LAT was interacting with KCTD13, MVP, and MAPK3, major driver and modifiers of the proximal 16p11.2 600 kb BP4-BP5 syndromes, respectively. Co-injected embryos exhibited an increased microcephaly, suggesting the presence of genetic interaction. Correspondingly, carriers of 1.7 Mb BP1-BP5 rearrangements that encompass both the BP2-BP3 and BP4-BP5 loci showed more severe phenotypes. Taken together, our results suggest that LAT, besides its well-recognized function in T cell development, is a major contributor of the 16p11.2 220 kb BP2-BP3 CNV-associated neurodevelopmental phenotypes.

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“…TCR induction alone can lead to the activation of Akt (Chapman et al, 2013; Cruz-Orcutt and Houtman, 2009; Kalland et al, 2011; Kane and Weiss, 2003; Seminario et al, 2004; Shim et al, 2011), but costimulatory receptor activation can enhance TCR-induced Akt induction (Kalland et al, 2011). Interestingly, TCR-induced Akt phosphorylation was significantly greater in HuT78 T cells and APBTs that were pretreated with flagellin compared to untreated cells (Figure 5 and Figure 6).…”

Section: Resultsmentioning

confidence: 99%

Prior TLR5 induction in human T cells results in a transient potentiation of subsequent TCR-induced cytokine production

Tremblay

Bilal

Houtman

2014

Molecular Immunology

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Activation of TLRs by components required for pathogen viability results in increased inflammation and an enhanced immune response to infection. Unlike their effects on other immune cells, TLR activation in the absence of T cell antigen receptor (TCR) induction has little effect on T cell activity. Instead, the simultaneous induction of TLR and TCR results in increased cytokine release compared to TCR treatment alone. Thus, the current model states that TLRs alter T cell function only if activated at the same time as the TCR. In this study, we tested the novel hypothesis that prior TLR induction can also alter TCR-mediated functions. We found that human T cells responded to ligands for TLR2 and TLR5. However, only prior TLR5 induction potentiated subsequent TCR-mediated cytokine production in human T cells. This response required at least 24 hours of TLR5 induction and lasted for approximately 24–36 hours after removal of a TLR5 ligand. Interestingly, prior TLR5 induction enhanced TCR-mediated activation of Akt without increasing Lck, LAT or ERK kinase phosphorylation. Together, our studies show that TLR5 induction leads to a transient increase in the sensitivity of T cells to TCR stimulation by selectively enhancing TCR-mediated Akt function, highlighting that timeframe when TLR5 can potentiate TCR-induced downstream functions are significantly longer that previously appreciated.

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PI3 kinase function is vital for the function but not formation of LAT-mediated signaling complexes

Cited by 17 publications

References 47 publications

Vav1-phospholipase C-γ1 (Vav1-PLC-γ1) Pathway Initiated by T Cell Antigen Receptor (TCRγδ) Activation Is Required to Overcome Inhibition by Ubiquitin Ligase Cbl-b during γδT Cell Cytotoxicity

Vav1-phospholipase C-γ1 (Vav1-PLC-γ1) Pathway Initiated by T Cell Antigen Receptor (TCRγδ) Activation Is Required to Overcome Inhibition by Ubiquitin Ligase Cbl-b during γδT Cell Cytotoxicity

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

Prior TLR5 induction in human T cells results in a transient potentiation of subsequent TCR-induced cytokine production

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