Central role of the exchange factor GEF-H1 in TNF-α–induced sequential activation of Rac, ADAM17/TACE, and RhoA in tubular epithelial cells
| Autor: | Pam Speight, Qinghong Dan, Yasaman Amoozadeh, Susumu Tanimura, Andras Kapus, Yuqian Zhang, Katalin Szászi, Faiza Waheed |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
mitogen activated protein kinase p38
MAPK/ERK pathway RHOA Swine wound healing animal cell environment and public health Western blotting Kidney Tubules Proximal Transactivation 0302 clinical medicine guanine nucleotide exchange factor h1 protein cleavage Guanine Nucleotide Exchange Factors guanine nucleotide exchange factor rat enzyme phosphorylation Phosphorylation Extracellular Signal-Regulated MAP Kinases 0303 health sciences tumor necrosis factor alpha tumor necrosis factor alpha converting enzyme kidney tubule cell article Articles guanosine triphosphatase protein function rac GTP-Binding Proteins unclassified drug enzyme activity 3. Good health Cell biology ErbB Receptors priority journal 030220 oncology & carcinogenesis RNA Interference RhoA guanine nucleotide binding protein Guanine nucleotide exchange factor biological phenomena cell phenomena and immunity Signal transduction signal transduction animal structures matrix metalloproteinase p38 mitogen-activated protein kinases Blotting Western ADAM17 Protein Biology 03 medical and health sciences Rac protein Animals controlled study protein interaction Protein kinase A Molecular Biology 030304 developmental biology nonhuman Dose-Response Relationship Drug membrane depolarization Tumor Necrosis Factor-alpha fungi Epithelial Cells enzyme activation Cell Biology Signaling Matrix Metalloproteinases molecular dynamics ADAM Proteins enzymes and coenzymes (carbohydrates) Microscopy Fluorescence protein analysis Mutation biology.protein LLC-PK1 Cells rhoA GTP-Binding Protein epidermal growth factor receptor epithelium |
| Zdroj: | Molecular Biology of the Cell |
| ISSN: | 1939-4586 1059-1524 |
| DOI: | 10.1091/mbc.e12-09-0661 |
| Popis: | Transactivation of the epidermal growth factor receptor (EGFR) by tumor necrosis factor-α (TNF-α) 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-α-induced EGFR activation. We show that TNF-α stimulates the TNF-α 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-α 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-α 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-α 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. Molecular Biology of the Cell, 24(7), pp.1068-1082; 2013 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|