Abstract
Nerve growth factor (NGF) induces sustained activation of classical MAP kinase (MAPK, also known as ERK) and neuronal differentiation in PC12 cells, whereas epidermal growth factor (EGF) induces transient activation of ERK/MAPK and stimulates proliferation of the cells. Although previous studies showed that sustained activation of ERK/MAPK is important for neuronal differentiation of the cells, a recent report revealed that inhibition of the sustained phase of ERK/MAPK activation alone does not block neurite outgrowth caused by NGF. These results suggest requirement for an additional signaling pathway(s) triggered by NGF in neuronal differentiation. Here we show that NGF induces sustained activation of p38, a subfamily member of the MAPK superfamily, and that inhibition of the p38 pathway blocks neurite outgrowth in PC12 cells. Surprisingly, expression of constitutively active MAPK/ERK kinase (MAPKK, also known as MEK) results in p38 activation as well as ERK/MAPK activation, and a p38 inhibitor blocks neurite outgrowth caused by the constitutively active MAPKK/MEK. Moreover, constitutive activation of p38 is able to induce neurite outgrowth when combined with EGF treatment. These results reveal an essential role of p38 in neuronal differentiation in PC12 cells.
Highlights
A recent finding that the sustained activation of ERK/MAPK results from activation of Rap1, expression of a mutant Rap1 that blocks the sustained phase of ERK/MAPK activation does not inhibit neurite outgrowth triggered by Nerve growth factor (NGF) demonstrates that neurite outgrowth by NGF does not require sustained activation of ERK/MAPK [9]
We have shown that NGF treatment induces rapid and relatively long activation of p38 and that inhibition of p38 by a specific inhibitor SB203580 or by expression of dominant-negative constructs of the p38 pathway blocks neurite outgrowth in PC12 cells
An immune complex kinase assay for p38 in extracts of PC12 cells treated with NGF revealed that p38 became activated within 5 min of the treatment, and the activity was maximal at 10 min and gradually decreased (Fig. 1A, left)
Summary
Growth [7, 8]. a recent finding that the sustained activation of ERK/MAPK results from activation of Rap1, expression of a mutant Rap1 that blocks the sustained phase of ERK/MAPK activation does not inhibit neurite outgrowth triggered by NGF demonstrates that neurite outgrowth by NGF does not require sustained activation of ERK/MAPK [9]. We have shown that NGF treatment induces rapid and relatively long activation of p38 and that inhibition of p38 by a specific inhibitor SB203580 or by expression of dominant-negative constructs of the p38 pathway blocks neurite outgrowth in PC12 cells. We have shown that constitutive activation of p38 is able to induce neurite outgrowth when combined with EGF treatment, which induces transient activation of ERK/MAPK and p38.
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