PKC? 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 PKC? is a critical mediator of signaling by the T cell antigen receptor and the principal costimulatory receptor CD28. PKC? 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.

SUBMITTER: Britton GJ 

PROVIDER: S-EPMC5310840 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature