title: PKCθ links proximal T cell and Notch signaling through localized regulation of the actin cytoskeleton.
abstract: 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.
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Britton
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Rachel
authors.identifier: 0000-0002-6647-4116
authors.initials: R
authors.lastname: Ambler
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Danielle J
authors.initials: DJ
authors.lastname: Clark
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Elaine V
authors.initials: EV
authors.lastname: Hill
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Tunbridge
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Kerrie E
authors.initials: KE
authors.lastname: McNally
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Bronwen R
authors.initials: BR
authors.lastname: Burton
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Philomena
authors.initials: P
authors.lastname: Butterweck
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: Sabatos-Peyton
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Lea A
authors.identifier: 0000-0002-9665-170X
authors.initials: LA
authors.lastname: Hampton-O'Neil
authors.affiliation: School of Biochemistry, University of Bristol, Bristol, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Verkade
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Christoph
authors.identifier: 0000-0002-6156-9861
authors.initials: ChC
authors.lastname: Wülfing
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: David Cameron
authors.identifier: 0000-0003-2147-5614
authors.initials: DC
authors.lastname: Wraith
mesh_terms: D000072197:ADAM10 Protein / Q000378:metabolism; D008841:Actin Cytoskeleton / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D000074121:Protein Kinase C-theta / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018106:CD28 Antigens; D008565:Membrane Proteins; D008840:Microfilament Proteins; D011948:Receptors, Antigen, T-Cell; D051880:Receptors, Notch; C072061:coronin proteins; D000074121:Protein Kinase C-theta; D053829:Amyloid Precursor Protein Secretases; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse
keywords: CD4 T cell; cell biology; cell signalling; cytoskeleton; immunology; mouse