PI3K/Akt/mTOR, a Pathway Less Recognized for Staphylococcal Superantigen-Induced Toxicity

Krakauer, Teresa

doi:10.3390/toxins4111343

Cited by 17 publications

(12 citation statements)

References 144 publications

(202 reference statements)

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“…In some regards, this PG102-induced altered CD40 signaling resembles the "alternative" signaling pathways that bacterial superantigens are reported to trigger when they bind TCR/MHC complexes (reviewed in Ref. 53).…”

Section: Discussionmentioning

confidence: 79%

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

Bankert

Oxley

Smith

et al. 2015

The Journal of Immunology

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Blocking the interaction of CD40 with its ligand CD154 is a desirable goal of therapies for preventing and/or ameliorating autoimmune diseases and transplant rejection. CD154-blocking mAbs used in human clinical trials resulted in unanticipated vascular complications, leading to heightened interest in the therapeutic potential of antagonist mAbs specific for human CD40. Abs that do not require physical competition with CD154 to inhibit CD40 signaling have particular therapeutic promise. In this study, we demonstrate that the antagonist anti-human CD40 mAb PG102 fails to trigger CD40-mediated activation, as well as impairs CD154-mediated CD40 activation, via a distinct nonstimulatory CD40 signaling mechanism. PG102 did not induce early CD40-induced signaling events, and it inhibited early kinase and transcription factor activation by CD154 or agonist anti-CD40 mAbs. However, PG102 stimulated normal CD40-mediated TNFR-associated factor (TRAF)2 and TRAF3 degradation. PG102 induced the formation of a CD40 signaling complex that contained decreased amounts of both TRAF2 and TRAF3 and TRAF2-associated signaling proteins. Additionally, PG102-induced CD40 signaling complexes failed to recruit TRAF6 to detergent-insoluble membrane fractions. Fab fragments of PG102, while retaining CD40 binding, did not induce TRAF degradation, nor could they inhibit CD154-stimulated B cell signaling, indicating that CD40 aggregation is required for the signaling inhibition induced by PG102. The antagonistic impact of PG102 on CD40 signaling reveals that the manner of CD40 ligation can determine sharply different outcomes for CD40 signaling and suggests that such information can be used to therapeutically manipulate these outcomes.

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Section: Discussionmentioning

confidence: 79%

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

Bankert

Oxley

Smith

et al. 2015

The Journal of Immunology

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“…In our study, the phosphorylation level of JAK1, JAK3, STAT1, STAT3, STAT5A and STAT5B is all decreased dramatically, which indicated TPD7 inhibited JAK/STAT signalling pathway via suppressing the expression of IL‐2R (Figure ). Furthermore, the PI3K/AKT/mTOR signalling pathway can also be activated by IL‐2R, which is relevant to tumour growth, cell survival, cell proliferation, cell cycle progression and apoptosis . In addition, it has been revealed that the essential tumour suppressor gene PTEN encodes a phosphatase protein against the PI3K/AKT anti‐apoptotic pathway .…”

Section: Discussionmentioning

confidence: 99%

TPD7 inhibits the growth of cutaneous T cell lymphoma H9 cell through regulating IL‐2R signalling pathway

Zhu

Liu

Shi

et al. 2019

J Cellular Molecular Medi

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IL‐2R pathway is a key regulator in the development of immune cells and has emerged as a promising drug target in cancer treatment, but there is a scarcity of related inhibitors. TPD7 is a novel biphenyl urea taspine derivate, which has been shown anti‐cancer effect. Here, we demonstrated the anti‐cancer activity of TPD7 in cutaneous T cell lymphoma and investigated the underlying mechanism of TPD7 through IL‐2R signalling. The inhibitory effect of TPD7 on cell viability exhibited a strong correlation with the expression level of IL‐2R, and cutaneous T cell lymphoma H9 and HUT78 cells were most sensitive to TPD7. TPD7 was nicely bound to IL‐2R and down‐regulated the mRNA and protein levels of IL‐2R. Furthermore, TPD7 suppressed the downstream cascades of IL‐2R including JAK/STAT, PI3K/AKT/mTOR and PLCγ/Raf/MAPK signalling, resulting in Bcl‐2 mitochondrial apoptosis pathway and cell cycle proteins CDK/Cyclins regulation. And, these were verified by flow cytometry analysis that TPD7 facilitated cell apoptosis in H9 cells via mitochondrial pathway and impeded cell cycle progression at G2/M phase. TPD7 is a novel anti‐cancer agent and may be a potential candidate for cutaneous T cell lymphoma treatment by regulating IL‐2R signalling pathway.

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“…A description of these signal transduction pathways upon superantigen binding to host cell receptors was presented recently (Figure 1) [70]. Phosphorylation and dephosphorylation events modulate all three cascades with specific kinases and phosphatases.…”

Section: Cross-talk Among Key Signaling Pathwaysmentioning

confidence: 99%

Update on Staphylococcal Superantigen-Induced Signaling Pathways and Therapeutic Interventions

Krakauer

2013

Toxins

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Staphylococcal enterotoxin B (SEB) and related bacterial toxins cause diseases in humans and laboratory animals ranging from food poisoning, acute lung injury to toxic shock. These superantigens bind directly to the major histocompatibility complex class II molecules on antigen-presenting cells and specific Vβ regions of T-cell receptors (TCR), resulting in rapid hyper-activation of the host immune system. In addition to TCR and co-stimulatory signals, proinflammatory mediators activate signaling pathways culminating in cell-stress response, activation of NFκB and mammalian target of rapamycin (mTOR). This article presents a concise review of superantigen-activated signaling pathways and focuses on the therapeutic challenges against bacterial superantigens.

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PI3K/Akt/mTOR, a Pathway Less Recognized for Staphylococcal Superantigen-Induced Toxicity

Cited by 17 publications

References 144 publications

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

TPD7 inhibits the growth of cutaneous T cell lymphoma H9 cell through regulating IL‐2R signalling pathway

Update on Staphylococcal Superantigen-Induced Signaling Pathways and Therapeutic Interventions

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