Fe65 negatively regulates Jagged1 signaling by decreasing Jagged1 protein stability through the E3 ligase Neuralized-like 1

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Fe65 is a highly conserved adaptor protein that interacts with several binding partners. Fe65 binds proteins to mediate various cellular processes. But the interacting partner and the regulatory mechanisms controlled by Fe65 are largely unknown. In this study, we found that Fe65 interacts with the C-terminus of Jagged1. Furthermore, Fe65 negatively regulates AP1-mediated Jagged1 intercellular domain transactivation in a Tip60-independent manner. We found that Fe65 triggers the degradation of Jagged1, but not the Jagged1 intracellular domain (JICD), through both proteasome and lysosome pathways. We also showed that Fe65 promotes recruitment of the E3 ligase Neuralized-like 1 (Neurl1) to membrane-tethered Jagged1 and monoubiquitination ofJagged1. These three proteins form a stable trimeric complex, thereby decreasing Jagged1 targeting by ubiquitin-mediated degradation. Consequently, Jagged1 is a novel binding partner of Fe65, and Fe65 may act as a novel effector of Jagged1 signaling.
Publisher
ELSEVIER SCIENCE BV
Issue Date
2015-11
Language
English
Article Type
Article
Keywords

AMYLOID PRECURSOR PROTEIN; INTRACELLULAR DOMAIN; ALZHEIMERS-DISEASE; NOTCH LIGANDS; APP; CANCER

Citation

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v.1853, no.11, pp.2918 - 2928

ISSN
0167-4889
DOI
10.1016/j.bbamcr.2015.08.009
URI
http://hdl.handle.net/10203/203668
Appears in Collection
BS-Journal Papers(저널논문)
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