Signals from the AT(2) (angiotensin type 2) receptor of angiotensin II inhibit p21(ras) and activate MAPK (mitogen-activated protein kinase) to induce morphological neuronal differentiation in NG108-15 cells

In a previous study, we had shown that activation of the AT(2) (angiotensin type 2) receptor of angiotensin II (Ang II) induced morphological differen tiation of the neuronal cell line NG108-15. In the present study, we invest igated the nature of the possible intracellular mediators involved in the A T(2) effect. We found that stimulation of AT(2) receptors in NG108-15 cells resulted in time-dependent modulation of tyrosine phosphorylation of a num ber of cytoplasmic proteins. Stimulation of NG108-15 cells with Ang II indu ced a decrease in GTP-bound p21(ras) but a sustained increase in the activi ty of p42(mapk) and p44(mapk) as well as neurite outgrowth. Similarly, neur ite elongation, increased polymerized tubulin levels, and increased mitogen -activated protein kinase (MAPK) activity were also observed in a stably tr ansfected NG108-15 cell line expressing the dominant-negative mutant of p21 (ras), RasN17. These results support the observation that inhibition of p21 (ras) did not impair the effect of Ang II on its ability to stimulate MARK activity. While 10 mu M of the MEK inhibitor, PD98059, only moderately affe cted elongation, 50 mu M PD98059 completely blocked the Ang II- and the Ras N17-mediated induction of neurite outgrowth, These results demonstrate that some of the events associated with the AT(2) receptor-induced neuronal mor phological differentiation of NG108-15 cells not only include inhibition of p21(ras) but an increase in MARK activity as well, which is essential for neurite outgrowth.