PKCθ links proximal T cell and Notch signaling through localized regulation of the actin cytoskeleton
Notch is a critical regulator of T cell differentiation and is activated through proteolytic cleavage in response to ligand engagement. Using murine myelin-reactive CD4 T cells, we demonstrate that proximal T cell signaling modulates Notch activation by a spatiotemporally constrained mechanism. The...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2017-01-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/20003 |
| _version_ | 1828195612710928384 |
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| author | Graham J Britton Rachel Ambler Danielle J Clark Elaine V Hill Helen M Tunbridge Kerrie E McNally Bronwen R Burton Philomena Butterweck Catherine Sabatos-Peyton Lea A Hampton-O’Neil Paul Verkade Christoph Wülfing David Cameron Wraith |
| author_facet | Graham J Britton Rachel Ambler Danielle J Clark Elaine V Hill Helen M Tunbridge Kerrie E McNally Bronwen R Burton Philomena Butterweck Catherine Sabatos-Peyton Lea A Hampton-O’Neil Paul Verkade Christoph Wülfing David Cameron Wraith |
| author_sort | Graham J Britton |
| collection | DOAJ |
| description | Notch is a critical regulator of T cell differentiation and is activated through proteolytic cleavage in response to ligand engagement. Using murine myelin-reactive CD4 T cells, we demonstrate that proximal T cell signaling modulates Notch activation by a spatiotemporally constrained mechanism. The protein kinase PKCθ is a critical mediator of signaling by the T cell antigen receptor and the principal costimulatory receptor CD28. PKCθ selectively inactivates the negative regulator of F-actin generation, Coronin 1A, at the center of the T cell interface with the antigen presenting cell (APC). This allows for effective generation of the large actin-based lamellum required for recruitment of the Notch-processing membrane metalloproteinase ADAM10. Such enhancement of Notch activation is critical for efficient T cell proliferation and Th17 differentiation. We reveal a novel mechanism that, through modulation of the cytoskeleton, controls Notch activation at the T cell:APC interface thereby linking T cell receptor and Notch signaling pathways. |
| first_indexed | 2024-04-12T09:45:29Z |
| format | Article |
| id | doaj.art-75afcfe3d41645f7a11ec23c03da7a47 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T09:45:29Z |
| publishDate | 2017-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-75afcfe3d41645f7a11ec23c03da7a472022-12-22T03:37:57ZengeLife Sciences Publications LtdeLife2050-084X2017-01-01610.7554/eLife.20003PKCθ links proximal T cell and Notch signaling through localized regulation of the actin cytoskeletonGraham J Britton0Rachel Ambler1https://orcid.org/0000-0002-6647-4116Danielle J Clark2Elaine V Hill3Helen M Tunbridge4Kerrie E McNally5Bronwen R Burton6Philomena Butterweck7Catherine Sabatos-Peyton8Lea A Hampton-O’Neil9https://orcid.org/0000-0002-9665-170XPaul Verkade10Christoph Wülfing11https://orcid.org/0000-0002-6156-9861David Cameron Wraith12https://orcid.org/0000-0003-2147-5614School of Cellular and Molecular Medicine, University of Bristol, Bristol, United KingdomSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, United KingdomSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, United KingdomSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, United KingdomSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, United KingdomSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, United KingdomSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, United KingdomSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, United KingdomSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, United KingdomSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, United KingdomSchool of Biochemistry, University of Bristol, Bristol, United KingdomSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, United KingdomSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, United KingdomNotch is a critical regulator of T cell differentiation and is activated through proteolytic cleavage in response to ligand engagement. Using murine myelin-reactive CD4 T cells, we demonstrate that proximal T cell signaling modulates Notch activation by a spatiotemporally constrained mechanism. The protein kinase PKCθ is a critical mediator of signaling by the T cell antigen receptor and the principal costimulatory receptor CD28. PKCθ selectively inactivates the negative regulator of F-actin generation, Coronin 1A, at the center of the T cell interface with the antigen presenting cell (APC). This allows for effective generation of the large actin-based lamellum required for recruitment of the Notch-processing membrane metalloproteinase ADAM10. Such enhancement of Notch activation is critical for efficient T cell proliferation and Th17 differentiation. We reveal a novel mechanism that, through modulation of the cytoskeleton, controls Notch activation at the T cell:APC interface thereby linking T cell receptor and Notch signaling pathways.https://elifesciences.org/articles/20003CD4 T cellcell signallingcytoskeleton |
| spellingShingle | Graham J Britton Rachel Ambler Danielle J Clark Elaine V Hill Helen M Tunbridge Kerrie E McNally Bronwen R Burton Philomena Butterweck Catherine Sabatos-Peyton Lea A Hampton-O’Neil Paul Verkade Christoph Wülfing David Cameron Wraith PKCθ links proximal T cell and Notch signaling through localized regulation of the actin cytoskeleton eLife CD4 T cell cell signalling cytoskeleton |
| title | PKCθ links proximal T cell and Notch signaling through localized regulation of the actin cytoskeleton |
| title_full | PKCθ links proximal T cell and Notch signaling through localized regulation of the actin cytoskeleton |
| title_fullStr | PKCθ links proximal T cell and Notch signaling through localized regulation of the actin cytoskeleton |
| title_full_unstemmed | PKCθ links proximal T cell and Notch signaling through localized regulation of the actin cytoskeleton |
| title_short | PKCθ links proximal T cell and Notch signaling through localized regulation of the actin cytoskeleton |
| title_sort | pkcθ links proximal t cell and notch signaling through localized regulation of the actin cytoskeleton |
| topic | CD4 T cell cell signalling cytoskeleton |
| url | https://elifesciences.org/articles/20003 |
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