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TACE Activation by MAPK-Mediated Regulation of Cell Surface Dimerization and TIMP3 Association
- Source :
- Science Signaling. 5
- Publication Year :
- 2012
- Publisher :
- American Association for the Advancement of Science (AAAS), 2012.
-
Abstract
- Ectodomain shedding mediated by tumor necrosis factor–α (TNF-α)–converting enzyme [TACE; also known as ADAM17 (a disintegrin and metalloproteinase 17)] provides an important switch in regulating cell proliferation, inflammation, and cancer progression. TACE-mediated ectodomain cleavage is activated by signaling of the mitogen-activated protein kinases (MAPKs) p38 and ERK (extracellular signal– regulated kinase). Here, we found that under basal conditions, TACE was predominantly present as dimers at the cell surface, which required its cytoplasmic domain and enabled efficient association with tissue inhibitor of metalloproteinase-3 (TIMP3) and silencing of TACE activity. Upon activation of the ERK or p38 MAPK pathway, the balance shifted from TACE dimers to monomers, and this shift was associated with increased cell surface presentation of TACE and decreased TIMP3 association, which relieved the inhibition of TACE by TIMP3 and increased TACE-mediated proteolysis of transforming growth factor–α. Thus, cell signaling altered the dimer-monomer equilibrium and inhibitor association to promote activation of TACE-mediated ectodomain shedding, a regulatory mechanism that may extend to other ADAM proteases.
- Subjects :
- MAPK/ERK pathway
Cell signaling
MAP Kinase Signaling System
p38 mitogen-activated protein kinases
CHO Cells
ADAM17 Protein
p38 Mitogen-Activated Protein Kinases
Biochemistry
Article
Cricetulus
Cricetinae
Disintegrin
Animals
Humans
Molecular Biology
Tissue Inhibitor of Metalloproteinase-3
biology
Cell growth
Kinase
Cell Biology
Transforming Growth Factor alpha
Molecular biology
Protein Structure, Tertiary
Cell biology
Enzyme Activation
ADAM Proteins
Ectodomain
biology.protein
Protein Multimerization
Subjects
Details
- ISSN :
- 19379145 and 19450877
- Volume :
- 5
- Database :
- OpenAIRE
- Journal :
- Science Signaling
- Accession number :
- edsair.doi.dedup.....e00b082e0b526b1efc06509c72e59ca4