P38 is a negative regulator of growth factor-induced ERK1/2 activation

摘要

Growth factor-induced activation of extracellular-regulated kinases 1 and 2 (ERK1/2) is an integral step in cellular proliferation, differentiation, survival or transformation. These biological responses are counter regulated by stress factors and inflammatory cytokines which activate stress-activated protein kinases, p38 and c-Jun amino-terminal protein kinases (JNK). However, there is considerable crosstalk between these pathways. Treatment of various cultured cells with insulin, epidermal growth (EGF) and nerve growth factor (NGF) results in strong ERK1/2 but only weak p38 activation, and inhibition of p38, using the specific inhibitor SB203580, results in enhanced and prolonged ERK1/2 activation by these factors. In contrast, we find that in cells expressing constitutively active MKK6, causing upregulation of p38 activity, there is reduced growth factor induced activation of ERK1/2. Consistent with these results, the pre-treatment of PC12 cells with SB203580 produces a sustained ERK1/2 activation by EGF, resulting in the differentiation of PC 12 cells, similar to that produced by NGF. Based on the activity of Ras, Raf-1 and MEK1/2, the target for p38-mediated inhibition of growth factor-induced ERK1/2 activation was identified as most likely being Raf. These data show that p38 inhibits ERK1/2 activity and might therefore, in addition to its suggested role in apoptosis, be an important regulator of various biological responses including cell proliferation and differentiation.