Asbestos-induced phosphorylation of epidermal growth factor receptor is linked to c-fosand apoptosis

Abstract

We examined the mechanisms of interaction of crocidolite asbestos fibers with the epidermal growth factor (EGF) receptor (EGFR) and the role of the EGFR-extracellular signal-regulated kinase (ERK) signaling pathway in early-response protooncogene (c- fos/c- jun) expression and apoptosis induced by asbestos in rat pleural mesothelial (RPM) cells. Asbestos fibers, but not the nonfibrous analog riebeckite, abolished binding of EGF to the EGFR. This was not due to a direct interaction of fibers with ligand, inasmuch as binding studies using fibers and EGF in the absence of membranes showed that EGF did not adsorb to the surface of asbestos fibers. Exposure of RPM cells to asbestos caused a greater than twofold increase in steady-state message and protein levels of EGFR ( P < 0.05). The tyrphostin AG-1478, which inhibits the tyrosine kinase activity of the EGFR, but not the tyrphostin A-10, which does not affect EGFR activity, significantly ameliorated asbestos-induced increases in mRNA levels of c- fos but not of c- jun. Pretreatment of RPM cells with AG-1478 significantly reduced apoptosis in cells exposed to asbestos. Our findings suggest that asbestos-induced binding to EGFR initiates signaling pathways responsible for increased expression of the protooncogene c- fos and the development of apoptosis. The ability to block asbestos-induced elevations in c- fos mRNA levels and apoptosis by small-molecule inhibitors of EGFR phosphorylation may have therapeutic implications in asbestos-related diseases.

Increased Phosphorylated Extracellular Signal-Regulated Kinase Immunoreactivity Associated with Proliferative and Morphologic Lung Alterations after Chrysotile Asbestos Inhalation in Mice

“…6 Activation of ERK signaling was subsequently observed to be mediated through phosphorylation of EGF-R and linked to apoptosis and/or cell proliferation. 6,7,25,26 Our observation that ERK phosphorylation is focally induced in developing fibrotic lesions after 14 and 30 days of asbestos inhalation provides further evidence that ERK signaling cascades may be key mediators in the development of asbestos-associated lung disease through regulation of cell proliferation or apoptosis.…”

Src-dependent ERK5 and Src/EGFR-dependent ERK1/2 activation is required for cell proliferation by asbestos

“…Figure 14 presents a hypothetical schema for the findings reported here and our previous work showing that ERK1/2 expression precedes the advent of DNA synthesis in C10 cells exposed to asbestos (Buder-Hoffmann et al, 2001). Asbestos fibers cause aggregation of the EGFR, a phenomenon leading to phosphorylation of the EGFR (Zanella et al, 1996(Zanella et al, , 1999, which is critical to ERK1/2 activation. Alternatively, Src activation by asbestos (or H 2 O 2 and EGF) may lead to phosphorylation of the EGFR and/or downstream events linked to ERK5 phosphorylation.…”

“…pTYR 1173 was detected using a rabbit polyclonal anti-pTyr 1173 antibody and electrochemical luminescence Figure 12 Asbestos-induced proliferation is inhibited by blocking Src, ERK1/2 and ERK5 pathways. (Pache et al, 1998) and induce its phosphorylation (Zanella et al, 1996) as well as its increased biosynthesis (Zanella et al, 1999). Our work here focused on signaling pathways critical to MAPK activation by asbestos, a physiologically relevant oxidant stress ubiquitous in the environment, and the role of the EGFR and the Src pathway in these events.…”

“…Recently, cell injury and S-phase alterations by asbestos have been linked to phosphorylation of the epidermal growth factor receptor (EGFR) and the protracted activation of the extracellular signal-regulated (ERK1/2) pathway (Zanella et al, 1996(Zanella et al, , 1999Jimenez et al, 1997;Buder-Hoffmann et al, 2001). Mitogen-activated protein kinase (MAPK) signal transduction pathways, including the extracellular signalregulated protein kinases (ERKs 1/2), c-Jun N-terminal kinases (JNKs), p38 and big mitogen kinase 1 (BMK1/ ERK5), are activated in response to various agents such as growth factors, tumor promoters and oxidants.…”

Persistent Localization of Activated Extracellular Signal-Regulated Kinases (ERK1/2) Is Epithelial Cell-Specific in an Inhalation Model of Asbestosis

“…5 Work to date suggests that crocidolite asbestos fibers cause activation of ERK1/2 via phosphorylation and aggregation of the epidermal growth factor receptor (EGFR). [5][6][7][8][9] In this regard, asbestos is one of several nonligands including polycations, 10 ultraviolet irradiation, 11 X-irradiation, 12 and H 2 O 2 , 13 that activate growth factor receptors and signaling cascades leading to cell injury and/or proliferation.…”