Marambaud P, Wilk S, Checler F
IPMC du CNRS, UPR411, Valbonne, France.
J Neurochem. 1996 Dec;67(6):2616-9. doi: 10.1046/j.1471-4159.1996.67062616.x.
The beta-amyloid precursor protein undergoes a physiological cleavage by alpha-secretase that leads to the release of a secreted C-terminally truncated fragment called APP alpha and likely concomitantly reduces the formation of the amyloidogenic A beta peptide. Here we demonstrate that APP alpha secretion is increased by the protein kinase A (PKA) effectors 8-bromo cyclic AMP and forskolin in human embryonic kidney cells (HK293), and that this can be prevented by a proteasome inhibitor. Furthermore, we establish that PKA effectors but not protein kinase C agonists increase the chymotrypsin-like activity and phosphorylation state of the proteasome in vitro and in vivo in HK293 cells. Altogether, this report demonstrates that the alpha-secretase pathway is under the control of PKA in human cells and that the proteasome likely contributes, either directly or through yet unknown intermediates, to the PKA-stimulated APP alpha secretion in human cells.
β-淀粉样前体蛋白经α-分泌酶进行生理性切割，导致释放出一种称为APPα的C末端截短的分泌片段，并且可能同时减少淀粉样蛋白生成性Aβ肽的形成。在此，我们证明在人胚肾细胞（HK293）中，蛋白激酶A（PKA）效应物8-溴环磷酸腺苷和福斯高林可增加APPα的分泌，而蛋白酶体抑制剂可阻止这种增加。此外，我们证实PKA效应物而非蛋白激酶C激动剂可在体外和HK293细胞体内增加蛋白酶体的胰凝乳蛋白酶样活性和磷酸化状态。总之，本报告表明α-分泌酶途径在人细胞中受PKA调控，并且蛋白酶体可能直接或通过尚未知晓的中间体，对人细胞中PKA刺激的APPα分泌起作用。
