Signal transduction pathway related to activation of extracellular signal-regulated kinase by ionizing radiation

Abstract

Exposure of MDA-MB-468 cells to ionizing radiation (IR) caused biphasic activation of extracellular signal-regulated kinase (ERK) as indicated by its phosphorylation at Thr202/Tyr204. ERK1/2 became activated 2-5 min and 6 h after 0.5-10 Gy irradiation. Enhanced phosphorylation of ERK1/2 observed 2-5 min after irradiation was at the same level in the dose range of 0.1-10 Gy. A specific inhibitor of the epidermal growth factor receptor (EGFR) AG1478 inhibited IR induced activation of ERK1/2. However, in response to IR, EGFR did not become phosphorylated at Tyr992 and Try1045, and phosphorylation of Tyr845 and Tyr1068 was decreased 2-30 min after irradiation with increase at 6 h after irradiation. Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP-2), which positively regulates EGFR/Ras/Raf/ERK signaling cascade, became activated 2 min and 2-4 h after irradiation as indicated by its phosphorylation at Tyr542. Src and protein tyrosine phosphatase α (PTP α) became activated 1-6 h after irradiation as indicated by their phosphorylation at Tyr789 or Tyr426 respectively. These results suggest that ERK1/2 activation by IR is mediated through activation of SHP-2 and EGFR.