| First Author | Stützer I | Year | 2013 |
| Journal | J Biol Chem | Volume | 288 |
| Issue | 15 | Pages | 10536-47 |
| PubMed ID | 23430253 | Mgi Jnum | J:336904 |
| Mgi Id | MGI:6839643 | Doi | 10.1074/jbc.M112.444703 |
| Citation | Stutzer I, et al. (2013) Systematic proteomic analysis identifies beta-site amyloid precursor protein cleaving enzyme 2 and 1 (BACE2 and BACE1) substrates in pancreatic beta-cells. J Biol Chem 288(15):10536-47 |
| abstractText | Expansion of functional islet beta-cell mass is a physiological process to compensate for increased insulin demand. Deficiency or pharmacological inhibition of the plasma membrane protease BACE2 enhances pancreatic beta-cell function and proliferation, and therefore BACE2 is a putative target for the therapeutic intervention under conditions of beta-cell loss and dysfunction. To gain a molecular understanding of BACE2 function, we performed a systematic and quantitative proteomic analysis to map the natural substrate repertoire of BACE2 and its homologue BACE1 in beta-cells. Loss- and gain-of-function studies of in vitro and in vivo models identified specific and functionally heterogeneous targets. Our analysis revealed non-redundant roles of BACE1/2 in ectodomain shedding with BACE1 regulating a broader and BACE2 a more distinct set of beta-cell-enriched substrates including two proteins of the seizure 6 protein family (SEZ6L and SEZ6L2). Lastly, our study provides insights into the global beta-cell sheddome and secretome, an important prerequisite to uncover novel mechanisms contributing to beta-cell homeostasis and a resource for therapeutic target and biomarker discoveries. |
