Thrombin promotes sustained signaling and inflammatory gene expression through the CDC25 and Ras-associating domains of phospholipase Cϵ.

The Journal of Biological Chemistry
Stephanie S DusabanJoan Heller Brown

Abstract

Phospholipase C-epsilon (PLCϵ) plays a critical role in G-protein-coupled receptor-mediated inflammation. In addition to its ability to generate the second messengers inositol 1,4,5-trisphosphate and diacylglycerol, PLCϵ, unlike the other phospholipase C family members, is activated in a sustained manner. We hypothesized that the ability of PLCϵ to function as a guanine nucleotide exchange factor (GEF) for Rap1 supports sustained downstream signaling via feedback of Rap1 to the enzyme Ras-associating (RA2) domain. Using gene deletion and adenoviral rescue, we demonstrate that both the GEF (CDC25 homology domain) and RA2 domains of PLCϵ are required for long term protein kinase D (PKD) activation and subsequent induction of inflammatory genes. PLCϵ localization is largely intracellular and its compartmentalization could contribute to its sustained activation. Here we show that localization of PLCϵ to the Golgi is required for activation of PKD in this compartment as well as for subsequent induction of inflammatory genes. These data provide a molecular mechanism by which PLCϵ mediates sustained signaling and by which astrocytes mediate pathophysiological inflammatory responses.

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Citations

Jul 3, 2016·American Journal of Physiology. Lung Cellular and Molecular Physiology·Kaiser M BijliArshad Rahman
Sep 10, 2016·PloS One·Peter V DiStefanoAngela J Glading
Jun 5, 2017·Journal of Neuroinflammation·Stephanie S DusabanJoan Heller Brown
Sep 20, 2020·The Journal of Biological Chemistry·Monita SiengAngeline M Lyon
Jan 11, 2021·Chemistry and Physics of Lipids·Kaushik MuralidharanAngeline M Lyon
Jan 18, 2021·The Journal of Biological Chemistry·Monita SiengAngeline M Lyon

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