BACE1 Regulates Notch Signaling by Controlling the Cleavage of Jag1 and Jag2 [Neurobiology]

June 6th, 2014 by He, W., Jinxuan, H., Xia, Y., Yan, R.

BACE1 is a type I transmembrane aspartyl protease that cleaves amyloid precursor protein (APP) at the β-secretase site to initiate the release of β-amyloid peptide (Aβ). As a secretase, BACE1 also cleaves additional membrane-bound molecules by exerting various cellular functions. In this study, we showed that BACE1 can effectively shed the membrane-anchored signaling molecule Jagged 1 (Jag1). We also mapped the cleavage sites of Jag1 by ADAM10 and ADAM17. Although Jag1 shares a high degree of homology with Jag2 in the ectodomain region, BACE1 fails to cleave Jag2 effectively, indicating a selective cleavage of Jag1. Abolished cleavage of Jag1 in BACE1-null mice leads to enhanced astrogenesis and concomitantly reduced neurogenesis. This characterization provides biochemical evidence that the Jag1-Notch pathway is under the control of BACE1 activity.