Regulation of amyloid precursor protein (APP) processing by protein kinase C (PKC) and phosphotyrosine pathways was investigated in cultured human astrocytes. Phorbol 12, 13-dibutyrate (PDBu), a PKC activator, increased secretion of APPalpha 2-3-fold over control values, and GF109203X, a PKC inhibitor, blocked this effect. Similarly, platelet derived growth factor (PDGF) increased the secreted form of APPalpha (sAPPalpha) level two-fold, and genistein, a tyrosine kinase inhibitor, blocked the stimulatory effect of PDGF. Co-treatment of PDGF and PDBu resulted in a five-fold increase in the sAPPalpha production, and genistein and GF109203X did not block the stimulatory effects of PDBu and PDGF, respectively. These results indicate that both PKC and phosphotyrosine pathways are involved in APP processing in human astrocytes, but they act independently. The two pathways appear to converge to mitogen-activated protein kinase (MAPK) because PD98059, a MAPK inhibitor, blocked the effects of PDBu and PDGF on APPa secretion. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.