title: Tumor necrosis factor-alpha converting enzyme is processed by proprotein-convertases to its mature form which is degraded upon phorbol ester stimulation.
abstract: Tumor necrosis factor-alpha converting enzyme (TACE or ADAM17) is a member of the ADAM (a disintegrin and metalloproteinase) family of type I membrane proteins and mediates the ectodomain shedding of various membrane-anchored signaling and adhesion proteins. TACE is synthesized as an inactive zymogen, which is subsequently proteolytically processed to the catalytically active form. We have identified the proprotein-convertases PC7 and furin to be involved in maturation of TACE. This maturation is negatively influenced by the phorbol ester phorbol-12-myristate-13-acetate (PMA), which decreases the cellular amount of the mature form of TACE in PMA-treated HEK293 and SH-SY5Y cells. Furthermore, we found that stimulation of protein kinase C or protein kinase A signaling pathways did not influence long-term degradation of mature TACE. Interestingly, PMA treatment of furin-deficient LoVo cells did not affect the degradation of mature TACE. By examination of furin reconstituted LoVo cells we were able to exclude the possibility that PMA modulates furin activity. Moreover, the PMA dependent decrease of the mature enzyme form is specific for TACE, as the amount of mature ADAM10 was unaffected in PMA-treated HEK293 and SH-SY5Y cells. Our results indicate that the activation of TACE by the proprotein-convertases PC7 and furin is very similar to the maturation of ADAM10 although there is a significant difference in the cellular stability of the mature enzyme forms after phorbol ester treatment.
authors.affiliation: Institute of Biochemistry, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Endres
authors.forename: Andreas
authors.initials: A
authors.lastname: Anders
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Kojro
authors.forename: Sandra
authors.initials: S
authors.lastname: Gilbert
authors.forename: Falk
authors.initials: F
authors.lastname: Fahrenholz
authors.forename: Rolf
authors.initials: R
authors.lastname: Postina
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D015153:Blotting, Western; D002417:Cattle; D002448:Cell Adhesion; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D045683:Furin; D005822:Genetic Vectors; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry; D010703:Phorbol Esters / Q000378:metabolism*; D043484:Proprotein Convertases; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013381:Subtilisins / Q000737:chemistry / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D018076:DNA, Complementary; D010446:Peptide Fragments; D010703:Phorbol Esters; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; C099101:PCSK7 protein, human; C490931:Pcsk7 protein, rat; D043484:Proprotein Convertases; D013381:Subtilisins; D045683:Furin; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606464:Adam17 protein, rat; D013755:Tetradecanoylphorbol Acetate