| RRC ID |
43733
|
| 著者 |
Fukuda S, Nishida-Fukuda H, Nakayama H, Inoue H, Higashiyama S.
|
| タイトル |
Monoubiquitination of pro-amphiregulin regulates its endocytosis and ectodomain shedding.
|
| ジャーナル |
Biochem Biophys Res Commun
|
| Abstract |
All members of epidermal growth factor (EGF) family are expressed as transmembrane precursors on cell surfaces and then proteolytically converted to soluble ligands for EGF receptor (EGFR) by a disintegrin and metalloproteases (ADAMs). As enzyme-substrate complex formation is essential for this "ectodomain shedding", alteration of cell surface retention could affect their physical interaction with ADAMs and eventually contribute to shedding efficiency. Here, we showed that monoubiquitination of pro-amphiregulin (pro-AREG, an EGFR ligand) accelerated its half-life on cell surface. Monoubiquitination occurred at lysine 240 of pro-AREG as the primary acceptor site. Using a chimeric protein of pro-AREG and a monomeric ubiquitin mutant (pro-AREGmUb), immunocytochemical analysis and a cell surface biotinylation assay revealed that a significant portion of pro-AREGmUb was expressed on the cell surface, immediately endocytosed, and predominantly localized to early endosomes. Importantly, ectodomain shedding of pro-AREGmUb induced by tetradecanoyl phorbol acetate was significantly reduced in comparison to wild-type pro-AREG. These results suggested that pro-AREG monoubiquitination and the subsequent trafficking to intracellular organelles is a novel shedding regulatory mechanism that contributes to the secretion of EGFR ligands in growth factor signaling.
|
| 巻・号 |
420(2)
|
| ページ |
315-20
|
| 公開日 |
2012-4-6
|
| DOI |
10.1016/j.bbrc.2012.02.156
|
| PII |
S0006-291X(12)00430-5
|
| PMID |
22425981
|
| MeSH |
Amphiregulin
Cell Line, Tumor
EGF Family of Proteins
Endocytosis*
ErbB Receptors / metabolism
Glycoproteins / genetics
Glycoproteins / metabolism*
Half-Life
Humans
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / metabolism*
Lysine / genetics
Lysine / metabolism
Protein Transport
Ubiquitination*
|
| IF |
2.985
|
| 引用数 |
7
|
|
WOS 分野
|
BIOPHYSICS
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
|
