ASBESTOS CAUSES STIMULATION OF THE EXTRACELLULAR SIGNAL-REGULATED KINASE-1 MITOGEN-ACTIVATED PROTEIN-KINASE CASCADE AFTER PHOSPHORYLATION OF THE EPIDERMAL GROWTH-FACTOR RECEPTOR

Asbestos fibers are human carcinogens with undefined mechanisms of act ion. In studies here, we examined signal transduction events induced b y asbestos in target cells of mesothelioma and potential cell surface origins for these cascades. Asbestos fibers, but not their nonfibrous analogues, induced protracted phosphorylation of the mitogen-activated protein (MAP) kinases and extracellular signal-regulated kinases (ERK ) 1 and 2, and increased kinase activity of ERK2. ERK1 and ERK2 phosph orylation and activity were initiated by addition of exogenous epiderm al growth factor (EGF) and transforming growth factor-alpha, but not b y isoforms of platelet-derived growth factor or insulin-like growth fa ctor-1 in mesothelial cells. MAP kinase activation by asbestos was att enuated by suramin, which inhibits growth factor receptor interactions , or tyrphostin AG 1478, a specific inhibitor of EGF receptor tyrosine kinase activity (IC50 = 3 nM). Moreover, asbestos caused autophosphor ylation of the EGF receptor, an event triggering the ERK cascade. Thes e studies are the first to establish that a MAP kinase signal transduc tion pathway is initiated after phosphorylation of a peptide growth fa ctor receptor following exposure to asbestos fibers.