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

Hye-Jin Lee; Ji-Hye Yoon; Ji-Seon Ahn; Eun-Hye Jo; Mi-Yeon Kim; Young Chul Lee; Jin Woo Kim; Eun-Jung Ann; Hee-Sae Park

doi:10.1016/j.bbamcr.2015.08.009

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

Biochim Biophys Acta. 2015 Nov;1853(11 Pt A):2918-28. doi: 10.1016/j.bbamcr.2015.08.009. Epub 2015 Aug 12.

Authors

Hye-Jin Lee¹, Ji-Hye Yoon¹, Ji-Seon Ahn¹, Eun-Hye Jo¹, Mi-Yeon Kim¹, Young Chul Lee², Jin Woo Kim², Eun-Jung Ann³, Hee-Sae Park⁴

Affiliations

¹ Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
² Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
³ Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea. Electronic address: eunjung36@gmail.com.
⁴ Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea. Electronic address: proteome@jnu.ac.kr.

PMID: 26276215
DOI: 10.1016/j.bbamcr.2015.08.009

Abstract

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 of Jagged1. 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.

Keywords: Fe65; Jagged1; Lysosome; Neuralized-like 1; Proteasome; Protein degradation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calcium-Binding Proteins / genetics
Calcium-Binding Proteins / metabolism*
HEK293 Cells
Humans
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / metabolism*
Jagged-1 Protein
Lysosomes / genetics
Lysosomes / metabolism
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
NIH 3T3 Cells
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Proteasome Endopeptidase Complex / genetics
Proteasome Endopeptidase Complex / metabolism
Protein Stability
Serrate-Jagged Proteins
Signal Transduction / physiology*
Transcription Factor AP-1 / genetics
Transcription Factor AP-1 / metabolism
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination / physiology

Substances

APBB1 protein, human
Apbb1 protein, mouse
Calcium-Binding Proteins
Intercellular Signaling Peptides and Proteins
JAG1 protein, human
Jag1 protein, mouse
Jagged-1 Protein
Membrane Proteins
Nerve Tissue Proteins
Nuclear Proteins
Serrate-Jagged Proteins
Transcription Factor AP-1
NEURL1 protein, human
Ubiquitin-Protein Ligases
Proteasome Endopeptidase Complex