Persistent versus transient map kinase (ERK) activation in the proliferation of lung epithelial type 2 cells

Type 2 pneumocytes are progenitor cells of alveolar epithelium and importan t for re-epithelialization following lung injury. This study examined the r ole of persistent versus transient mitogen-activated protein (MAP) kinase ( extracellular signal-regulated kinase; ERK) in type 2 cell proliferation. T hree different types of agents; epidermal growth factor (EGF), 12-O-tetrade canoylphorbol-13-acetate (TPA), and fetal bovine serum (FBS) induced differ ent patterns of ERK activation. FBS induced a strong and persistent MAP kin ase response, whereas the effects of EGF was transient with a strong activa tion at 5 minutes and only a slight stimulation at 4 hours. The TPA respons e was more prolonged than the EGF response, but not by far as strong and pe rsistent as the FBS response. Activation by EGF and TPA and the early respo nse induced by FBS were strongly reduced by the MEK inhibitor PD98059. The sustained FBS-induced ERK activation was inhibited by similar to 50%. The t otal number of cells, the percentage of cells in S and G(2)/M phase of the cell cycle and the incorporation of H-3-thymidine into DNA were strongly in creased in response to FBS, whereas EGF and TPA were without effect. The pr oliferation was reduced by similar to 50% after pretreatment with PD98059. The results indicate that a persistent ERK activation of a critical size le ads to type 2 cell proliferation, and that thr proliferative response may a lso depend un a MEK-independent ERK activation.