期刊
MOLECULAR BIOLOGY OF THE CELL
卷 24, 期 7, 页码 1068-1082出版社
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E12-09-0661
关键词
-
类别
资金
- Canadian Institutes of Health Research [MOP-97774, MOP-106625]
- Kidney Foundation of Canada
- Grant Miller Cancer Research grant from the University of Toronto
- KRESCENT New Investigator Award (a joint award of the Kidney Foundation of Canada, Canadian Nephrology Society, and Canadian Institute of Health Research)
- Early Researcher Award from the Ontario Ministry of Research and Innovation
- Li Ka Shing scholarship
- University of Toronto open scholarship
- Grants-in-Aid for Scientific Research [23790090] Funding Source: KAKEN
Transactivation of the epidermal growth factor receptor (EGFR) by tumor necrosis factor-alpha (TNF-alpha) is a key step in mediating RhoA activation and cytoskeleton and junction remodeling in the tubular epithelium. In this study we explore the mechanisms underlying TNF-alpha-induced EGFR activation. We show that TNF-alpha stimulates the TNF-alpha convertase enzyme (TACE/a disintegrin and metalloproteinase-17), leading to activation of the EGFR/ERK pathway. TACE activation requires the mitogen-activated protein kinase p38, which is activated through the small GTPase Rac. TNF-alpha stimulates both Rac and RhoA through the guanine nucleotide exchange factor (GEF)-H1 but by different mechanisms. EGFR- and ERK-dependent phosphorylation at the T678 site of GEF-H1 is a prerequisite for RhoA activation only, whereas both Rac and RhoA activation require GEF-H1 phosphorylation on S885. Of interest, GEF-H1-mediated Rac activation is upstream from the TACE/EGFR/ERK pathway and regulates T678 phosphorylation. We also show that TNF-alpha enhances epithelial wound healing through TACE, ERK, and GEF-H1. Taken together, our findings can explain the mechanisms leading to hierarchical activation of Rac and RhoA by TNF-alpha through a single GEF. This mechanism could coordinate GEF functions and fine-tune Rac and RhoA activation in epithelial cells, thereby promoting complex functions such as sheet migration.
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