Amyloid precursor protein processing is separately regulated by protein kinase C and tyrosine kinase in human astrocytes.
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 APPalpha secretion.
Kim
Chul
C
Brain Disease Research Center, Ajou University School of Medicine, San 5, Woncheon-dong, Paldal-gu, 442-721 Suwon, South Korea.
Jang
Chang Hwan
CH
Bang
Jung Hee
JH
Jung
Min Whan
MW
Joo
Insoo
I
Kim
Seung Up
SU
Mook-Jung
Inhee
I
D000544:Alzheimer Disease / Q000201:enzymology* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology*; D001921:Brain / Q000201:enzymology* / Q000503:physiopathology; D002478:Cells, Cultured; D004347:Drug Interactions / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D005419:Flavonoids / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008301:Maleimides / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D005419:Flavonoids; D005904:Glial Fibrillary Acidic Protein; D007211:Indoles; D008301:Maleimides; D010982:Platelet-Derived Growth Factor; D015240:Phorbol 12,13-Dibutyrate; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; C070515:bisindolylmaleimide I; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one