PKCθ links proximal T cell and Notch signaling through localized regulation of the actin cytoskeleton

Britton, Graham J.; Ambler, Rachel; Clark, Danielle J; Hill, E.; Tunbridge, Helen M; McNally, Kerrie E.; Burton, Bronwen R; Butterweck, Philomena; Sabatos-Peyton, Catherine; Hampton-O'Neil, Lea A; Verkade, Paul; Wülfing, Christoph; Wraith, David C.

doi:10.7554/elife.20003

Cited by 20 publications

(17 citation statements)

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“…Once PKC has been activated, it induces activity of ADAM10 and ADAM17. It has recently been shown, in agreement with our study, that PKCθ regulates Notch processing downstream of TCR signal and upstream of ADAM activity ( 112 ). Cleavage of the Notch receptor at the S2 site by ADAMs is required for Notch activation.…”

Section: A Model Of Tcr-activated Notch Signalingsupporting

confidence: 93%

A Review of Notch Processing With New Insights Into Ligand-Independent Notch Signaling in T-Cells

Steinbuck

Winandy

2018

Front. Immunol.

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The Notch receptor is an evolutionarily highly conserved transmembrane protein essential to a wide spectrum of cellular systems, and its deregulation has been linked to a vast number of developmental disorders and malignancies. Regulated Notch function is critical for the generation of T-cells, in which abnormal Notch signaling results in leukemia. Notch activation through trans-activation of the receptor by one of its ligands expressed on adjacent cells has been well defined. In this canonical ligand-dependent pathway, Notch receptor undergoes conformational changes upon ligand engagement, stimulated by a pulling-force on the extracellular fragment of Notch that results from endocytosis of the receptor-bound ligand into the ligand-expressing cell. These conformational changes in the receptor allow for two consecutive proteolytic cleavage events to occur, which release the intracellular region of the receptor into the cytoplasm. It can then travel to the nucleus, where it induces gene transcription. However, there is accumulating evidence that other pathways may induce Notch signaling. A ligand-independent mechanism of Notch activation has been described in which receptor processing is initiated via cell-internal signals. These signals result in the internalization of Notch into endosomal compartments, where chemical changes existing in this microenvironment result in the conformational modifications required for receptor processing. This review will present mechanisms underlying both canonical ligand-dependent and non-canonical ligand-independent Notch activation pathways and discuss the latter in the context of Notch signaling in T-cells.

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Section: A Model Of Tcr-activated Notch Signalingsupporting

confidence: 93%

A Review of Notch Processing With New Insights Into Ligand-Independent Notch Signaling in T-Cells

Steinbuck

Winandy

2018

Front. Immunol.

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“…To investigate whether impaired cell couple maintenance results in loss of cytolytic effector function, Clone 4 CTLs were treated with a low concentration (40nM) of Jasplakinolide. At this concentration cell coupling was not impaired (25, 26), but the percentage of CTLs displaying a peripheral F-actin ring was markedly reduced to levels similar to those achieved among Clone 4 TILs (Fig. 3C to E, fig.…”

Section: Resultssupporting

confidence: 62%

PD-1 suppresses the maintenance of cell couples between cytotoxic T cells and tumor target cells within the tumor

Ambler

Edmunds

Toti

et al. 2018

Preprint

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CD8+ T cell killing of tumor cells is suppressed by the tumor microenvironment. Inhibitory receptors, prominently PD-1, are key mediators of this suppression. To discover cellular defects triggered by tumor exposure and associated PD-1 signaling, we have established an ex vivo imaging approach to investigate CD8+ tumor infiltrating lymphocytes (TILs) interacting with tumor targets. Whilst TIL:tumor cell couples formed effectively, couple stability deteriorated within 1-2 minutes. This was associated with excessive cofilin recruitment to the cellular interface, coincident deterioration of f-actin structures, increased TIL locomotion, and impaired tumor cell killing. Diminished engagement of PD-1 within the tumor, but not acute ex vivo blockade, partially restored cell couple maintenance and killing. PD-1 thus suppresses TIL function by inducing a polarization-impaired state.

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“…Atypical protein kinase C (aPKC) enhances relocalization of Notch from late endosomes to the nucleus, thus augmenting signaling, but in contrast promotes internalization of Notch receptors that are not engaged in signaling (655). aPKC (PKC) also regulates Notch via remodeling the actin skeleton and increased recruitment of ADAM10 (75). PIM kinase also enhances the level of nuclear Notch1 ICD via phosphorylation of one of the Notch1 ICD nuclear localization sequences (612).…”

Section: Notch Receptorsmentioning

confidence: 99%

Notch Signaling in Development, Tissue Homeostasis, and Disease

Siebel

Lendahl

2017

Physiological Reviews

772

677

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Notch signaling is an evolutionarily highly conserved signaling mechanism, but in contrast to signaling pathways such as Wnt, Sonic Hedgehog, and BMP/TGF-β, Notch signaling occurs via cell-cell communication, where transmembrane ligands on one cell activate transmembrane receptors on a juxtaposed cell. Originally discovered through mutations in more than 100 yr ago, and with the first Notch gene cloned more than 30 yr ago, we are still gaining new insights into the broad effects of Notch signaling in organisms across the metazoan spectrum and its requirement for normal development of most organs in the body. In this review, we provide an overview of the Notch signaling mechanism at the molecular level and discuss how the pathway, which is architecturally quite simple, is able to engage in the control of cell fates in a broad variety of cell types. We discuss the current understanding of how Notch signaling can become derailed, either by direct mutations or by aberrant regulation, and the expanding spectrum of diseases and cancers that is a consequence of Notch dysregulation. Finally, we explore the emerging field of Notch in the control of tissue homeostasis, with examples from skin, liver, lung, intestine, and the vasculature.

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PKCθ links proximal T cell and Notch signaling through localized regulation of the actin cytoskeleton

Cited by 20 publications

References 50 publications

A Review of Notch Processing With New Insights Into Ligand-Independent Notch Signaling in T-Cells

A Review of Notch Processing With New Insights Into Ligand-Independent Notch Signaling in T-Cells

PD-1 suppresses the maintenance of cell couples between cytotoxic T cells and tumor target cells within the tumor

Notch Signaling in Development, Tissue Homeostasis, and Disease

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