title: TACE activation by MAPK-mediated regulation of cell surface dimerization and TIMP3 association.
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.
authors.affiliation: Department of Cell and Tissue Biology, Programs in Cell Biology and Developmental Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Pinglong
authors.initials: P
authors.lastname: Xu
authors.forename: Jianming
authors.initials: J
authors.lastname: Liu
authors.forename: Masayo
authors.initials: M
authors.lastname: Sakaki-Yumoto
authors.forename: Rik
authors.initials: R
authors.lastname: Derynck
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D055503:Protein Multimerization / Q000502:physiology*; D017434:Protein Structure, Tertiary; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D016211:Transforming Growth Factor alpha; D048051:p38 Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human