Stimulation-induced Down-regulation of Tumor Necrosis Factor-α Converting Enzyme

The extracellular domains of many proteins, including growth factors, cytokines, receptors, and adhesion molecules, are proteolytically released from cells, a process termed “shedding.” Tumor necrosis factor-α converting enzyme (TACE/ADAM-17) is a metalloprotease-disintegrin that sheds tumor necrosis factor-α and other proteins. To study the regulation of TACE-mediated shedding, we examined the effects of stimulation of cells on TACE localization and expression. Immunofluorescence microscopy revealed a punctate distribution of TACE on the surface of untreated cells, and stimulation of monocytic cells with lipopolysaccharide did not affect TACE staining. Phorbol 12-myristate 13-acetate (PMA), a potent inducer of shedding, decreased cell-surface staining for TACE. Surface biotinylation experiments confirmed and extended this observation; PMA decreased the half-life of surface-biotinylated TACE without increasing the turnover of total cell-surface proteins. Soluble fragments of TACE were not detected in the medium of cells that had down-regulated TACE, and TACE was not down-regulated when endocytosis was inhibited. Antibody uptake experiments suggested that cell-surface TACE was internalized in response to PMA. Surprisingly, a metalloprotease inhibitor prevented the PMA-induced turnover of TACE. Thus, PMA activates shedding and causes the down-regulation of a major “sheddase,” suggesting that induced shedding may be regulated by a mechanism that decreases the amount of active TACE on the cell surface. The extracellular domains of many proteins, including growth factors, cytokines, receptors, and adhesion molecules, are proteolytically released from cells, a process termed “shedding.” Tumor necrosis factor-α converting enzyme (TACE/ADAM-17) is a metalloprotease-disintegrin that sheds tumor necrosis factor-α and other proteins. To study the regulation of TACE-mediated shedding, we examined the effects of stimulation of cells on TACE localization and expression. Immunofluorescence microscopy revealed a punctate distribution of TACE on the surface of untreated cells, and stimulation of monocytic cells with lipopolysaccharide did not affect TACE staining. Phorbol 12-myristate 13-acetate (PMA), a potent inducer of shedding, decreased cell-surface staining for TACE. Surface biotinylation experiments confirmed and extended this observation; PMA decreased the half-life of surface-biotinylated TACE without increasing the turnover of total cell-surface proteins. Soluble fragments of TACE were not detected in the medium of cells that had down-regulated TACE, and TACE was not down-regulated when endocytosis was inhibited. Antibody uptake experiments suggested that cell-surface TACE was internalized in response to PMA. Surprisingly, a metalloprotease inhibitor prevented the PMA-induced turnover of TACE. Thus, PMA activates shedding and causes the down-regulation of a major “sheddase,” suggesting that induced shedding may be regulated by a mechanism that decreases the amount of active TACE on the cell surface. tumor necrosis factor-α tumor necrosis factor-α converting enzyme a disintegrin and metalloprotease heparin-binding epidermal growth factor-like growth factor protein kinase C tissue inhibitor of metalloproteases lipopolysaccharide phorbol 12-myristate 13-acetate Immunex compound 3 phosphate-buffered saline polyacrylamide gel electrophoresis horseradish peroxidase 4-morpholineethanesulfonic acid A wide variety of proteins, including cytokines, growth factors, and their receptors, as well as cell adhesion molecules, are synthesized as transmembrane proteins that can be released from cells by proteolysis, a process termed “ectodomain shedding” (reviewed in Ref. 1.Hooper N.M. Karran E.H. Turner A.J. Biochem. J. 1997; 321: 265-279Crossref PubMed Scopus (560) Google Scholar). Release of soluble growth factors and cytokines, in addition to relaxing spatial constraints on their action, may qualitatively change their biological activities (2.Suda T. Hashimoto H. Tanaka M. Ochi T. Nagata S. J. Exp. Med. 1997; 186: 2045-2050Crossref PubMed Scopus (444) Google Scholar, 3.Tanaka M. Itai T. Adachi M. Nagata S. Nat. Med. 1998; 4: 31-36Crossref PubMed Scopus (611) Google Scholar, 4.Brannan C.I. Lyman S.D. Williams D.E. Eisenman J. Anderson D.M. Cosman D. Bedell M.A. Jenkins N.A. Copeland N.G. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 4671-4674Crossref PubMed Scopus (257) Google Scholar, 5.Grell M. Douni E. Wajant H. Lohden M. Clauss M. Maxeiner B. Georgopoulos S. Lesslauer W. Kollias G. Pfizenmaier K. Scheurich P. Cell. 1995; 83: 793-802Abstract Full Text PDF PubMed Scopus (1160) Google Scholar). Shedding of transmembrane receptors may render cells unresponsive to particular ligands, and the resulting soluble receptors may act to modulate the activity of their ligands (6.McDermott M.F. Aksentijevich I. Galon J. McDermott E.M. Ogunkolade B.W. Centola M. Mansfield E. Gadina M. Karenko L. Pettersson T. McCarthy J. Frucht D.M. Aringer M. Torosyan Y. Teppo A.M. Wilson M. Karaarslan H.M. Wan Y. Todd I. Wood G. Schlimgen R. Kumarajeewa T.R. Cooper S.M. Vella J.P. Amos C.I. Mulley J. Quane K.A. Molloy M.G. Ranki A. Powell R.J. Hitman G.A. O'Shea J.J. Kastner D.L. Cell. 1999; 97: 133-144Abstract Full Text Full Text PDF PubMed Scopus (1109) Google Scholar, 7.Engelmann H. Aderka D. Rubinstein M. Rotman D. Wallach D. J. Biol. Chem. 1989; 264: 11974-11980Abstract Full Text PDF PubMed Google Scholar). Thus, the process of ectodomain shedding may regulate the interaction of cells with their environment in multiple ways (8.Werb Z. Yan Y. Science. 1998; 282: 1279-1280Crossref PubMed Google Scholar). The importance of ectodomain shedding in mammalian development was underscored by the observation of perinatal lethality in mice lacking activity of the first identified “sheddase,” tumor necrosis factor-α (TNF-α)1converting enzyme (TACE) (9.Peschon J.J. Slack J.L. Reddy P. Stocking K.L. Sunnarborg S.W. Lee D.C. Russell W.E. Castner B.J. Johnson R.S. Fitzner J.N. Boyce R.W. Nelson N. Kozlosky C.J. Wolfson M.F. Rauch C.T. Cerretti D.P. Paxton R.J. March C.J. Black R.A. Science. 1998; 282: 1281-1284Crossref PubMed Scopus (1363) Google Scholar). TACE (ADAM-17) is a member of the ADAM (adisintegrin and metalloprotease) family of metalloprotease-disintegrins. It was originally identified by its ability to cleave transmembrane proTNF-α resulting in the release of mature, soluble TNF-α from cells (10.Black R.A. Rauch C.T. Kozlosky C.J. Peschon J.J. Slack J.L. Wolfson M.F. Castner B.J. Stocking K.L. Reddy P. Srinivasan S. Nelson N. Boiani N. Schooley K.A. Gerhart M. Davis R. Fitzner J.N. Johnson R.S. Paxton R.J. March C.J. Cerretti D.P. Nature. 1997; 385: 729-733Crossref PubMed Scopus (2715) Google Scholar, 11.Moss M.L. Jin S.L. Milla M.E. Bickett D.M. Burkhart W. Carter H.L. Chen W.J. Clay W.C. Didsbury J.R. Hassler D. Hoffman C.R. Kost T.A. Lambert M.H. Leesnitzer M.A. McCauley P. McGeehan G. Mitchell J. Moyer M. Pahel G. Rocque W. Overton L.K. Schoenen F. Seaton T. Su J.L. Warner J. Willard D. Becherer J.D. Nature. 1997; 385: 733-736Crossref PubMed Scopus (1485) Google Scholar). Subsequent studies using mice and cell lines lacking TACE activity implicated TACE in the shedding of transforming growth factor-α, L-selectin, and the p75 TNF-receptor (9.Peschon J.J. Slack J.L. Reddy P. Stocking K.L. Sunnarborg S.W. Lee D.C. Russell W.E. Castner B.J. Johnson R.S. Fitzner J.N. Boyce R.W. Nelson N. Kozlosky C.J. Wolfson M.F. Rauch C.T. Cerretti D.P. Paxton R.J. March C.J. Black R.A. Science. 1998; 282: 1281-1284Crossref PubMed Scopus (1363) Google Scholar). Both ADAM-10 and TACE may also participate in the α-secretase processing of β-amyloid precursor protein (12.Lammich S. Kojro E. Postina R. Gilbert S. Pfeiffer R. Jasionowski M. Haass C. Fahrenholz F. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3922-3927Crossref PubMed Scopus (985) Google Scholar, 13.Buxbaum J.D. Liu K.N. Luo Y. Slack J.L. Stocking K.L. Peschon J.J. Johnson R.S. Castner B.J. Cerretti D.P. Black R.A. J. Biol. Chem. 1998; 273: 27765-27767Abstract Full Text Full Text PDF PubMed Scopus (838) Google Scholar). Another ADAM, ADAM-9 (meltrin-γ, MDC9), has recently suggested to the shedding of heparin-binding epidermal growth factor-like growth factor Y. M. H. R. T. K. Y. T. A. S. E. J. 1998; PubMed Scopus Google Scholar). the of mammalian is to release the from cells H. N. W. P. T. S. Science. 1999; PubMed Scopus Google and may also be for of D. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, ADAM proteins metalloprotease domains may a family of that regulate and release soluble and receptors from The by shedding is regulated are shedding are induced by phorbol N.M. Karran E.H. Turner A.J. Biochem. J. 1997; 321: 265-279Crossref PubMed Scopus (560) Google suggesting a for protein kinase C a of shedding induced by other are to that are multiple of the shedding of a particular S.M. G. M.A. M. J. Cell. Biochem. 1998; PubMed Scopus Google Scholar, M. G. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, R. S. Black T. G. 1999; PubMed Google Scholar). is not induced shedding of metalloproteases in the localization of with the of and is for phorbol shedding in cells, suggesting that may in response to phorbol Y. M. H. R. T. K. Y. T. A. S. E. J. 1998; PubMed Scopus Google Scholar). shedding can be induced by of A. B. M.A. J. PubMed Scopus Google by of cells with are to the of with the of J. B. M.A. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). induced shedding the of the has C. M. Wallach D. J. Biol. Chem. Full Text PDF PubMed Google Scholar, A. P. J. Exp. Med. 1995; PubMed Scopus Google Scholar, Biol. Cell. PubMed Scopus Google Scholar, C. Black R.A. J. Exp. Med. 1995; PubMed Scopus Google Scholar, M.A. M.L. Lee D.C. Biol. Cell. 1997; PubMed Scopus Google Scholar, J. W. F. E. E. L. S. J. Google Scholar, R. R. I. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar, Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). Shedding are also to be regulated by ADAM proteins are synthesized as The is to the metalloprotease in a a mechanism is by F. C. R. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, F. B.J. E. R. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, processing of may regulate TACE is by tissue inhibitor of A. A. M. B.J. C. M. A.J. G. 1998; PubMed Scopus Google and can a of shedding F. J. G. J. Russell J. 1998; PubMed Scopus Google Scholar, H. Y. 1997; PubMed Scopus Google Scholar, G. G. A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). can the shedding of protein S.M. G. M.A. M. J. Cell. Biochem. 1998; PubMed Scopus Google Scholar). other can be suggesting that and the shedding activity of a to the mechanism by TACE-mediated shedding are we examined the effects of lipopolysaccharide and phorbol on the localization and of cell-surface TACE. of monocytic cells to on TACE Surprisingly, TACE was down-regulated in cells with PMA. down-regulation the and of TACE TACE in untreated The PMA-induced and of TACE was by a metalloprotease and the of TACE was down-regulated in response to suggesting that shedding may be and cells were in medium and cells were in medium as cell lines were in a was from a with TACE extracellular the and to the (10.Black R.A. Rauch C.T. Kozlosky C.J. Peschon J.J. Slack J.L. Wolfson M.F. Castner B.J. Stocking K.L. Reddy P. Srinivasan S. Nelson N. Boiani N. Schooley K.A. Gerhart M. Davis R. Fitzner J.N. Johnson R.S. Paxton R.J. March C.J. Cerretti D.P. Nature. 1997; 385: 729-733Crossref PubMed Scopus (2715) Google Scholar). The was from a with the TACE extracellular The was as E. D. A on a of TACE extracellular The was from a with a to of TACE the of The was from were from TACE extracellular and was from of cells that had with a of TACE. The protein of the The and of TACE has K. C. R. H. G.A. Reddy P. Wolfson M.F. Rauch C.T. Castner B.J. Davis R. M. Fitzner J.N. Cerretti D.P. March C.J. Paxton R.J. Black R.A. W. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). A protein the of TACE of to was from the of Phorbol 12-myristate 13-acetate and lipopolysaccharide were from was from Immunex compound 3 was Immunex (10.Black R.A. Rauch C.T. Kozlosky C.J. Peschon J.J. Slack J.L. Wolfson M.F. Castner B.J. Stocking K.L. Reddy P. Srinivasan S. Nelson N. Boiani N. Schooley K.A. Gerhart M. Davis R. Fitzner J.N. Johnson R.S. Paxton R.J. March C.J. Cerretti D.P. Nature. 1997; 385: 729-733Crossref PubMed Scopus (2715) Google Scholar). TACE extracellular and protein were on and by The were with a of and in phosphate-buffered saline for and with in and for The and were a of The were for with and in horseradish peroxidase as the were using cells as were for The cells were in of and for on cells, was as a to was to cells, were not as to staining. The cells were in to a of in and for on soluble TACE extracellular was as a a of in the with the cells were in in a of in for and in in for were with to in for in the with with the cells were on in a of in on using were and on a using a and from as were for with and and for with in The cells were 3 with of on the the cells were to medium and as were from cells by the cells in and and on for was in a for and the resulting was to a were by of total protein were as for were with of for were on protein for with the were with as The were in to for and the resulting were by on were by and proteins were detected by with to with were using and to with were using and were on a in cells were and in medium lacking a of in the of PMA. To the of soluble TACE the and of the TACE extracellular protein was to the medium of a the cells were and were in and The were using of the cell and were by and as To the of the of of untreated cells were in and in to and The were with the to with a of the as for of cells were in medium medium medium with to a of in the of PMA and as a the cells were with and with a to a of in a on the cells were and with were and with as for of TACE. The cell were in and on a cells were to cells were and in the of the the medium was and with medium PMA and as The cells were for with and with in for by a in was by in in for The cells were with and for microscopy as of cells were with in medium lacking for The cells were with with acid and with were with and by as of cells were with to in medium PMA and as the cells were and with The cells were with for and in and by and the extracellular of TACE were in mice and with a TACE extracellular To the resulting we examined their on of fragments of TACE. A the of TACE. of proteins the the domains were with the The detected the protein and the protein not the protein Thus, the of TACE. The proteins. this that the and domains of TACE. cells to the of the of TACE. and and of TACE on of cell cell of TACE the were identified by with a a from the of TACE. and also and of TACE the of TACE was detected when of surface-biotinylated cells were with of the and and of TACE, TACE is on the surface of cells, as has suggested (10.Black R.A. Rauch C.T. Kozlosky C.J. Peschon J.J. Slack J.L. Wolfson M.F. Castner B.J. Stocking K.L. Reddy P. Srinivasan S. Nelson N. Boiani N. Schooley K.A. Gerhart M. Davis R. Fitzner J.N. Johnson R.S. Paxton R.J. March C.J. Cerretti D.P. Nature. 1997; 385: 729-733Crossref PubMed Scopus (2715) Google Scholar). cells to the of the for of cell-surface TACE. The a punctate of staining on the surface of cells of staining was not with and including soluble TACE as a in the the cell-surface staining to TACE on the surface of To to the mechanism by shedding is we the and distribution of TACE on the surface of cells by of monocytic cells with of transmembrane is by TACE, resulting in the release of TNF-α the TNF-α is to and regulation K. Google Scholar). is not of TACE is a of the regulation of TNF-α biotinylation experiments that did not the amount of TACE on the of (10.Black R.A. Rauch C.T. Kozlosky C.J. Peschon J.J. Slack J.L. Wolfson M.F. Castner B.J. Stocking K.L. Reddy P. Srinivasan S. Nelson N. Boiani N. Schooley K.A. Gerhart M. Davis R. Fitzner J.N. Johnson R.S. Paxton R.J. March C.J. Cerretti D.P. Nature. 1997; 385: 729-733Crossref PubMed Scopus (2715) Google Scholar). To the of TNF-α is regulated the of shedding, we examined the of on and localization of cell-surface TACE in of the cells for 3 with the cells are of soluble TNF-α the R. and R. A. did not affect the amount distribution of cell-surface TACE, as detected by Thus, the and distribution of TACE may be to TNF-α from monocytic cells, and the of on this may be to of is released by TACE Phorbol as PMA are potent of ectodomain PMA-induced shedding and PMA is to protein M. S. W.E. J. Biol. Chem. Full Text PDF PubMed Google Scholar, R. S. I. M. F. Y. G. A. A. M.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google we that the of shedding by PMA be to of active TACE from to the To this we examined the of PMA on cell-surface and localization of TACE by cells, in response to were with with and examined by microscopy as The distribution of TACE on the surface of cells was to that for cells, the amount of TACE was on Surprisingly, PMA in staining for cell-surface TACE cells a of TACE in response to PMA and To that TACE was from the surface of cells, we examined the effects of PMA on TACE by cell-surface was the for cells, the of TACE was detected on the surface of the of cells with PMA to a down-regulation of cell-surface TACE as by biotinylation and 3 A down-regulation was in cells 3 experiments that a variety of cell lines down-regulated cell-surface TACE in response to including and not suggesting that the of TACE is a of the response of cells to a of cells of To the of TACE in cells, we the in the that cells were surface-biotinylated with PMA. is to a TACE on the surface of cells are with the of the and their is the of surface-biotinylated TACE was in cells, with a half-life of PMA decreased the half-life of surface-biotinylated TACE to without the of total cell-surface proteins C that cell-surface TACE is to in response to and that the of TACE not a turnover of cell-surface proteins, total surface-biotinylated proteins not a in The of TACE from the cell surface in response to PMA the that TACE is shedding of TACE has not the domains of are to be by T. T. T. K. Y. A. Nature. 1995; PubMed Scopus Google Scholar, P. J. Biol. PubMed Scopus Google Scholar, L. Biol. 1997; PubMed Scopus Google Scholar). TACE were in we to a transmembrane and a soluble of TACE. did not fragments of TACE in from cell using the of TACE also to soluble of TACE in the of first TACE was in response to the amount of TACE in the medium were The detected of TACE in of untreated cells the was identified as TACE, on its with the was a from the of TACE. The amount of TACE in cell decreased in response to PMA with that the of TACE detected with was not to the of the particular by the PMA decreased the of TACE without the amount of TACE soluble of TACE were detected in the of untreated cells when were TACE protein to cell the with PMA was of the the medium was to suggesting that a soluble of TACE by the cells detected by this we of the TACE in cells cell this we did not soluble TACE on of the Thus, cells TACE, the of TACE is a of the amount in untreated cells, is in by a mechanism that not affect TACE the we did not soluble of TACE in of cells, we that TACE be internalized in response to PMA. To for a of endocytosis in the down-regulation of TACE, we the of endocytosis Anderson J. Biol. 1989; PubMed Scopus Google on TACE in PMA induced the of TACE from cells in medium cells in medium did not TACE in response to PMA To that was the we also endocytosis and medium decreased and the of was in the of PMA was by cells in medium medium was to shedding of cell-surface L-selectin, as has A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). was by PMA that the cells had not the ability to to PMA. The metalloprotease inhibitor a that TACE other by to its active and a for activity K. C. R. H. G.A. Reddy P. Wolfson M.F. Rauch C.T. Castner B.J. Davis R. M. Fitzner J.N. Cerretti D.P. March C.J. Paxton R.J. Black R.A. W. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google prevented the and the PMA-induced of from the of shedding is not for the down-regulation TACE, and the of TACE is that To the that TACE was we the uptake of by cells with PMA. and cells were in the of PMA in medium the cells were as cells, their was to of protein distribution that of of the cells were and with and by TACE staining was detected on the surface of untreated cells of with surface staining was detected the had in to with in the of PMA surface staining for TACE and a of staining The in cells may of TACE a of induced by the of to TACE on the cell surface. for with in the of PMA did not surface staining that the of not be to uptake of induced by PMA. cells also uptake of punctate in response to PMA and The in staining the cell may in from in the of monocytic cells and cells are the cells were in the to a of of the cells in a the observation that PMA of was the cell Thus, PMA to the of cell-surface TACE we that TACE be in response to we the effects of the metalloprotease inhibitor (10.Black R.A. Rauch C.T. Kozlosky C.J. Peschon J.J. Slack J.L. Wolfson M.F. Castner B.J. Stocking K.L. Reddy P. Srinivasan S. Nelson N. Boiani N. Schooley K.A. Gerhart M. Davis R. Fitzner J.N. Johnson R.S. Paxton R.J. March C.J. Cerretti D.P. Nature. 1997; 385: 729-733Crossref PubMed Scopus (2715) Google on the PMA-induced down-regulation of TACE. Surface biotinylation experiments that the PMA-induced of TACE of the of proteins by is of the in that TACE is not in response to PMA. we not in the for a of metalloproteases in that prevented the down-regulation of TACE by endocytosis we the of on and cells were with PMA in the of for of and was to and had on that its on cell-surface TACE was not to a of is that TACE from by TACE The experiments were in to the by ectodomain shedding is stimulation of cells to on TACE localization suggesting that the of TACE activity may be for the release of TNF-α from of cells to proTNF-α of TNF-α their medium in the of stimulation J. C. S. Cosman D. Black R.A. J. 1995; Google Scholar). Thus, shedding may not be in the of TNF-α The shedding of other TACE is by PMA. we that of cells with PMA causes the down-regulation of TACE of cells with PMA a in the amount of cell-surface TACE, as by microscopy and cell-surface biotinylation and a in the total amount of TACE, as by The of cell-surface TACE to be the shedding response PMA-induced shedding of M.A. Science. 1989; PubMed Scopus Google Scholar). a of TACE is detected in cells of with PMA 3 and Thus, the PMA-induced of TACE is not with the of TACE as a Antibody uptake experiments and the of induced TACE turnover by medium suggested that PMA induced the of TACE the that TACE is in response to to we to soluble fragments of TACE that shedding be to The of TACE may the of TACE a of H. T. Biol. 1997; Full Text PDF PubMed Scopus Google and the PMA-induced of TACE was when cells were in and endocytosis Anderson J. Biol. 1989; PubMed Scopus Google Scholar). the metalloprotease inhibitor prevented the PMA-induced of TACE The of was not to of did not affect uptake of is a metalloprotease we not of TACE is to PMA-induced the of may be TACE metalloproteases other TACE act to TACE a metalloprotease in the of internalized TACE the to the cell surface of TACE that be metalloproteases not identified in mammalian cells, this The interaction of with TACE TACE from and of to TACE the of the TACE extracellular in a that the of TACE. TACE activity be for its TACE with the transmembrane of proteins, and be internalized and this cell-surface TACE by the of this Another is that a protein by TACE metalloprotease) in response to PMA a that TACE Both of that the amount of TACE activity on the surface of cells is the down-regulation of shedding may be a of their The observation that the of TACE is down-regulated in response to PMA that active of TACE are to down-regulation that cell-surface TACE is not the down-regulation of TACE and the of are with a for TACE The of TACE down-regulation may be a in the of shedding, the of the of surface proteins. of this in studies of cells the a cell-surface to be by TACE, J. D. C. R. J. and R. A. J. Biol. Chem. cell-surface decreased shedding in response to PMA from its of C. Y. H. Wallach D. J. PubMed Scopus Google Scholar). the release of soluble TNF-α from cells with proTNF-α in response to PMA the cells be of R. P. and R. A. are with the that the induced down-regulation of TACE in decreased shedding It is not other are down-regulated by down-regulation of other the that the shedding response is the of metalloprotease on the cell surface. a of are down-regulated in response to the and of the shedding response may change of It also be of to other that shedding also the down-regulation of shedding as a It has recently that the of TACE can be by mechanism cell in the of metalloprotease J. and C. P. J. of TACE with the extracellular is the of TACE in and not and in metalloprotease were is decreased as a of this are to and for on the and to for and for of TACE and TACE also the Immunex and for their and Slack for

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