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

ABSTRACT We report that prosaposin treatment induced extracellular signal‐regulated kinases (ERKs) and sphingosine kinase activity, increased DNA synthesis, and prevented cell apoptosis. Prosaposin treatment induced pheochromocytoma cells (PC12) to enter the S phase of the cell cycle;this effect was inhibited by the MEK inhibitor PD98059, indicating that prosaposin‐induced ERK phosphorylation is required for stimulation of DNA synthesis. The prosaposin effect was also inhibited by pertussis toxin, indicating that the prosaposin receptor is a G‐protein‐coupled receptor. Prosaposin rescued PC12 cells from apoptosis induced by staurosporine or ceramide. Sphingosine kinase activity was increased by prosaposin treatment. We propose that this effect is a mechanism underlying the proliferative and anti‐apoptotic functions of prosaposin. Prosaposin appears to be a key regulatory factor in the ceramide‐S‐1‐P rheostat, which regulates cell fate.—Misasi, R., Sorice, M., Di Marzio, L., Campana, W. M., Molinari, S., Cifone, M. G., Pavan, A., Pontieri, G. M., O'Brien, J. S. Prosaposin treatment induces PC12 entry in the S phase of the cell cycle and prevents apoptosis: activation of ERKs and sphingosine kinase. FASEB J. 15, 467‐474 (2001)