Prosaposin treatment induces PC12 entry in the S phase of the cell cycle and prevents apoptosis: activation of ERKs and sphingosine kinase

We report that prosaposin treatment induced extracellular signal-regulated kinases (ERKs) and sphingosine kinase activity, increased DNA synthesis, an d prevented cell apoptosis. Prosaposin treatment induced pheochromocytoma c ells (PC12) to enter the S phase of the cell cycle; this effect was inhibit ed by the MEK inhibitor PD98059, indicating that prosaposin-induced ERK pho sphorylation is required for stimulation of DNA synthesis. The prosaposin e ffect was also inhibited by pertussis toxin, indicating that the prosaposin receptor is a G-protein-coupled receptor. Prosaposin rescued PC12 cells fr om apoptosis induced by staurosporine or ceramide. Sphingosine kinase activ ity was increased by prosaposin treatment. We propose that this effect is a mechanism underlying the proliferative and anti-apoptotic functions of pro saposin. Prosaposin appears to be a key regulatory factor in the ceramide-S -l-P rheostat, which regulates cell fate.