A protein kinase Cδ-dependent protein kinase D pathway modulates ERK1/2 and JNK1/2 phosphorylation and bim-associated apoptosis by asbestos

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Abstract

Inhalation of asbestos and oxidant-generating pollutants causes injury and compensatory proliferation of lung epithelium, but the signaling mechanisms that lead to these responses are unclear. We hypothesized that a protein kinase (PK)Cδ-dependent PKD pathway was able to regulate downstream mitogen-activated protein kinases, affecting pro- and anti-apoptotic responses to asbestos. Elevated levels of phosphorylated PKD (p-PKD) were observed in distal bronchiolar epithelial cells of mice inhaling asbestos. In contrast, PKCδ-/- mice showed significantly lower levels of p-PKD in lung homogenates and in situ after asbestos inhalation. In a murine lung epithelial cell line, asbestos caused significant increases in the phosphorylation of PKCδ-dependent PKD, ERK1/2, and JNK1/2/c-Jun that occurred with decreases in the BH3-only pro-apoptotic protein, Bim. Silencing of PKCδ, PKD, and use of small molecule inhibitors linked the ERK1/2 pathway to the prevention of Bim-associated apoptosis as well as the JNK1/2/c-Jun pathway to the induction of apoptosis. Our studies are the first to show that asbestos induces PKD phosphorylation in lung epithelial cells both in vivo and in vitro. PKCδ-dependent PKD phosphorylation by asbestos is causally linked to a cellular pathway that involves the phosphorylation of both ERK1/2 and JNK1/2, which play opposing roles in the apoptotic response induced by asbestos. Copyright © American Society for Investigative Pathology.

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Buder-Hoffmann, S. A., Shukla, A., Barrett, T. F., MacPherson, M. B., Lounsbury, K. M., & Mossman, B. T. (2009). A protein kinase Cδ-dependent protein kinase D pathway modulates ERK1/2 and JNK1/2 phosphorylation and bim-associated apoptosis by asbestos. American Journal of Pathology, 174(2), 449–459. https://doi.org/10.2353/ajpath.2009.080180

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