NGF INDUCES TRANSIENT BUT NOT SUSTAINED ACTIVATION OF ERK IN PC12 MUTANT-CELLS INCAPABLE OF DIFFERENTIATING

Activation of receptor tyrosine kinases stimulates a diverse array of cellular responses such as proliferation and differentiation. The firs t events in the signal transduction pathways mediated by different rec eptor tyrosine kinases are similar and include activation of the mitog en-activated protein kinase (MAPK) pathway and the induction of immedi ate early genes. The precise signaling pathways leading to each of the cellular responses mediated by receptor tyrosine kinases are still un known, although it has been proposed that sustained activation of the MAPK pathway by receptor tyrosine kinases such as the nerve growth fac tor (NGF) receptor TrkA is sufficient to induce differentiation in PC1 2 cells. In the present study we examined the effect of NGF on mutant PC12 cells that were derived spontaneously in our cultures. NGF induce d normal activation of immediate early genes in these cells, whereas t he activation of some delayed response genes, as well as neurite outgr owth, was impaired. Furthermore, activation of the NGF-induced extrace llular signal-regulated kinase (ERK)in these cells was transient, not sustained. These results support the hypothesis that sustained activat ion of ERK plays an important role in activating the induction of dela yed response genes. However, sustained ERK activation is not a mandato ry condition for the promotion of all the features of differentiated P C12 cells, as NCF could induce transcription of the delayed response g ene, transin, in PC12 mutant cells. Taken together, our results sugges t that NGF induces differentiation of PC12 cells via several signaling pathways, an important one of which is the MAPK pathway. J. Cell. Bio chem. 70.325-432, 1998. (C) 1998 Wiley-Liss, Inc.