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Tumor necrosis factor-a 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 syn-thesized 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. | Eur. J. Biochem. 270 2386-2393 2003 FEBS 2003 doi 10.1046 j.1432-1033.2003.03606.x Tumor necrosis factor-a converting enzyme is processed by proprotein-convertases to its mature form which is degraded upon phorbol ester stimulation Kristina Endres Andreas Anders Elzbieta Kojro Sandra Gilbert Falk Fahrenholz and Rolf Postina Institute of Biochemistry Johannes Gutenberg-University Mainz Germany Tumor necrosis factor-a 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. Keywords ADAM10 Alzheimer s disease furin PC7 TACE. ADAMs a disintegrin and metalloproteinases are a family of
