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Growth arrest of PC12 cells by nerve growth factor is dependent on the phosphatidylinositol 3‐kinase/Akt pathway via p75 neurotrophin receptor

We recently isolated mutant PC12 cell clones (PC84 cells) by transfection of PC12 cells with nerve growth factor (NGF) cDNA. These cells secreted active NGF and extended short processes, but proliferated faster than the parental PC12 cells. Because the expression level of p75, a low‐affinity receptor for NGF, was significantly low, we suspected that NGF signaling via p75 was necessary for the growth arrest of the PC12 cells, and this was shown to be the case by repressing p75 function in PC12 cells. In this study, we examined the downstream signaling of p75, which would ultimately evoke the growth arrest. NGF is known to induce rapid phosphorylation of MAP kinase and Akt in PC12 cells, whereas in PC84 cells, MAP kinase was phosphorylated but the phosphorylation level of Akt was very low under the serum‐free condition. This finding suggested that the low expression level of p75 in PC84 cells was the reason for the low Akt activation. Because Akt is known to be activated via phosphatidylinositol (PI) 3‐kinase, we treated PC12 cells with a PI3‐kinase inhibitor, Wortmannin, and found these cells did not cease proliferation in the presence of NGF. Furthermore, anti‐p75 neutralizing antibody reduced NGF‐induced phosphorylation of Akt in PC12 cells under the serum‐free condition. Because we had already shown that PC12 cells treated with anti‐p75 neutralizing antibody did not cease proliferation in the presence of NGF, these results suggest that NGF activates Akt via p75, which is necessary for the NGF‐induced growth arrest of PC12 cells. © 2003 Wiley‐Liss, Inc.