期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 287, 期 18, 页码 15066-15075出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.327262
关键词
-
资金
- National Institutes of Health [DK60729, P50 DK 64539, DK43207, DK39957, JCCC/P30 CA016042, CURE/P30 DK041301]
- National Health and Medical Research Council Australia [633033]
- Blinder Research Foundation for Crohn's Disease
- Eli and Edythe Broad Chair
The neuropeptide/hormone neurotensin (NT) mediates intestinal inflammation and cell proliferation by binding of its high affinity receptor, neurotensin receptor-1 (NTR1). NT stimulates IL-8 expression in NCM460 human colonic epithelial cells by both MAP kinase-and NF-kappa B-dependent pathways. Although the mechanism of NTR1 endocytosis has been studied, the relationship between NTR1 intracellular trafficking and inflammatory signaling remains to be elucidated. In the present study, we show that in NCM460 cells exposed to NT, beta-arrestin-1 (beta ARR1), and beta-arrestin-2 (beta ARR2) translocate to early endosomes together with NTR1. Endothelin-converting enzyme-1 (ECE-1) degrades NT in acidic conditions, and its activity is crucial for NTR1 recycling. Pretreatment of NCM460 cells with the ECE-1 inhibitor SM19712 or gene silencing of beta ARR1 or beta ARR2 inhibits NT-stimulated ERK1/2 and JNK phosphorylation, NF-kappa B p65 nuclear translocation and phosphorylation, and IL-8 secretion. Furthermore, NT-induced cell proliferation, but not IL-8 transcription, is attenuated by the JNK inhibitor, JNK(AII). Thus, NTR1 internalization and recycling in human colonic epithelial cells involves beta ARRs and ECE-1, respectively. Our results also indicate that beta ARRs and ECE-1-dependent recycling regulate MAP kinase and NF-kappa B signaling as well as cell proliferation in human colonocytes in response to NT.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据