ERK activation and mitogenesis in human airway smooth muscle cells

Asthmatic airways are characterized by an increase in smooth muscle mass, d ue mainly to hyperplasia. Many studies suggest that extracellular signal-re gulated kinases 1 and 2 (ERK1 and ERK2, respectively), one group of the mit ogen-activated protein (MAP) kinase superfamily, play a key role in the sig nal transduction pathway leading to cell proliferation. PGE(2) and forskoli n inhibited mitogen-induced ERK activation. Inhibition of MAP kinase kinase s 1 and 2 (MEK1 and MEK2, respectively), which are upstream from ERK, with the specific MEK inhibitor U-0126 blocked both cell proliferation and ERK a ctivation. In addition, U-0126 inhibited mitogen-induced activation of p90 ribosomal S6 kinase and expression of c-Fos and cyclin D1, all of which are downstream from ERK in the signaling cascade that leads to cell proliferat ion. Antisense oligodeoxynucleotides directed to ERK1 and -2 mRNAs reduced ERK protein and cell proliferation. These results indicate that ERK is requ ired for human airway smooth muscle cell proliferation. Thus targeting the control of ERK activation may provide a new therapeutic approach for hyperp lasia seen in asthma.