| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
-Converting Enzyme1
Departments of
*
Biochemistry and
Anatomy, University of Kiel, Kiel, Germany; and
School of Biological Science, University of East Anglia, Norwich, United Kingdom
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
- converting enzyme
(TACE) and, indeed, mRNA transcripts of the membrane-bound
metalloproteinase-disintegrin TACE could be detected in Karpas 299
cells. The ectodomain of TACE was expressed in bacteria as a GST fusion
protein (GST-TACE) which cleaved CD30 from the surface of Karpas 299
cells and concomitantly increased the level of sCD30 in the cell
supernatants. Hence, TACE does not only control the release of TNF-,
but also that of sCD30. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The ectodomains of many membrane proteins can be released
proteolytically from the cell by receptor stimulation or in response to
protein kinase C activators such as PMA. As demonstrated for the
angiotensin-converting enzyme, the Alzheimer’s amyloid precursor
protein, pro-TNF-, the Fas ligand, CD16, L-selectin, the TNFRs,
CD30, CD43, CD44, and the IL-6R, the endoproteolytic conversion of
membrane-anchored proteins is blocked by broad-spectrum hydroxamate
inhibitors of matrix metalloproteinases (MMP). This indicates that MMPs
or enzymes related to MMPs are responsible (8, 9, 10). The
TNF--converting enzyme (TACE; ADAM 17), responsible for the release
of TNF- by proteolytic cleavage of the membrane-associated precursor
form (pro-TNF-), was recently characterized as a membrane-anchored
metalloproteinase-disintegrin (ADAM, a metalloproteinase and
disintegrin) (11, 12). Metalloproteinase-disintegrins
belong to the metzincin superfamily of metalloproteinases encompassing
the physiologically important families of MMPs, reprolysins and
astacins. Due to their x-ray crystal structure,
metalloproteinase-disintegrins are closely related to snake venom
metalloproteinases (reprolysins) and are therefore regarded as members
of the reprolysin family of metalloproteinases (13). Both
snake venom proteinases and metalloproteinase-disintegrins exhibit
membrane protein sheddase activity through their catalytic domain
(11, 12, 14) and binding to cellular disintegrin receptors
mediated by the disintegrin domain (15, 16, 17). Besides
pro-TNF-, TACE cleaves the amyloid precursor protein
(18) and mediates the shedding of L-selectin, the p75
TNFR, and TGF- (16). Other
metalloproteinase-disintegrins such as the Drosophila ADAM
10 homologue KUZ and ADAM 9 have been found to cleave the Notch
receptor or the membrane-anchored heparin-binding EGF-like growth
factor, respectively (19, 20). Physiologically, the
activity of metalloproteinases is regulated by tissue inhibitors of
metalloproteinases (TIMPs). Although the activity of MMPs is blocked by
TIMP-1, -2, and -3 (21), TACE is only inhibited by TIMP-3
(22). Hence, the shedding of TNF- and L-selectin is
inhibited by TIMP-3 and not by TIMP-1 and -2 (23, 24, 25).
In the present study, we characterized the CD30-cleaving enzyme found to be membrane-associated and inhibited by the TACE inhibitor TIMP-3. Since TACE-specific mRNA was detected in CD30+ Karpas 299 cells, we describe the bacterial expression of the TACE ectodomain. Its potency to cleave CD30 was compared with that of ADAM 10 and the related snake venom metalloproteinase hemorrhargin.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The mAbs Ki-2 (
1,
) and Ki-3 (2b,) were used for
detection of cell-bound and sCD30 (26). The
anti-2-phenyloxazolone (anti-phOx) Ab BH-1 (2b,) served
as an isotype-matched control in flow cytometry (27).
OKT-3 (anti-CD3 mAb) was obtained from American Type Culture
Collection (Manassas, VA). The tissue inhibitors of metalloproteinases
TIMP-1, TIMP-2, and TIMP-3 and the recombinant ADAM 10 were
from G.M. (Norwich, U.K.). BB-2116
(N1-(5-acetylamino-1S-methylcarbamoyl-pentyl)-2S-(2,2-dimethyl-propyl)-N4-hydroxy-3R-(4-hydroxy-phenylsulfanyl-methyl)-succinamide)
was a kind gift from British Biotech Pharmaceuticals (Oxford, U.K.).
Hemorrhargin from Echis pyramidum laekeyi was donated by
Gavin Laing (Liverpool, U.K.). The large cell anaplastic lymphoma cell
line Karpas 299 was a kind gift from Abraham Karpas (Cambridge, U.K.).
The cells were cultured at 37°C and 7% CO2 in
RPMI 1640 medium supplemented with 10% FCS, 2 mM glutamine, 100 U/ml
penicillin, and 100 µg/ml streptomycin.
Stimulation of human lymphocytes
PBLs were isolated from buffy coat preparations of normal donors. The lymphocytes were purified by Ficoll density centrifugation (1.077 g/ml; Seromed, Berlin, Germany) and cultivated for 1 h in complete RPMI 1640 medium/10% FCS. Nonadherent lymphocytes were cultivated in complete RPMI 1640 medium/10% FCS + 100 U/ml IL-2 (106/ml cells) for 72 h in the absence or presence of PHA (0.1% phytohemagglutinin P; Difco, Detroit, MI) and immobilized OKT3 (anti-CD3-mAb), respectively. For the OKT3-induced activation, dishes were coated with 10 µg/ml OKT3 for 1 h at room temperature and washed thoroughly before lymphocyte stimulation.
Membrane extraction
Karpas 299 cells were cultivated with or without PMA (30 ng/ml, 30 min) and lysed by ultrasonication (5 min) on ice. A crude membrane fraction was obtained by centrifugation (50,000 x g, 2 h, 4°C) which was resuspended by ultrasonication (2 min on ice) in 2 ml of 0.14 M NaCl and 20 mM HEPES (pH 7.4). Aliquots were then incubated under shaking with 1% 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS; Sigma, St. Louis, MO) for 2 h at 4°C. The mixture was then centrifuged (50,000 x g, 3 h, 4°C) and supernatants were intensively dialyzed against 140 mM NaCl and 20 mM HEPES (pH 7.4) and then collected as solubilizate.
Cloning of the human TACE ectodomain and its expression as GST-TACE fusion protein
Total RNA from Karpas 299 cells was extracted with Trizol reagent (Life Technologies, Karlsruhe, Germany), digested with RNase-free DNase I (Roche Diagnostics, Mannheim, Germany), and cDNA synthesis was performed using a SuperScript Preamplification System and oligo(dT)12–18 primers (Life Technologies). For an amplification of the cDNA fragment encoding the catalytic, disintegrin, and cysteine-rich domain of TACE, total cDNA was subjected to 30 cycles of PCR using proofreading polymerase (Elongase Enzyme mix; Life Technologies). As specific primers, which were 5' extended to allow restriction enzyme cleavage, we used the BamHI-TACE sense primer (5'-GTGAAAAGGATCCTTGCTGACCCAGATCCCATGAAGAACACG and the EcoRI-TACE antisense primer (5'-AGTGCTAGAATTCTACATCCTGTACTCGTTTCTCACATTTGCC. The sequences were derived from GenBank accession number U69611. The PCR product was purified by UV band elution (28) and restricted by BamHI and EcoRI enzymes (Roche Diagnostics) before the in-frame ligation with T4 DNA ligase (New England Biolabs, Beverly, MA) into the BamHI-EcoRI-restricted multiple cloning site of the pGEX-3X expression vector (Amersham Pharmacia Biotech, Freiburg, Germany). The insert of one clone was subsequently sequenced using an Abi Prism 310 Genetic Analyzer (Applied Biosystems, Weiterstadt, Germany). Then the recombinant expression vector was transformed into competent Escherichia coli cell strain XL1-blue and grown on ampicillin-containing agar plates. PCR-tested colonies were used to inoculate 2-ml cultures of Luria-Bertani medium containing 100 µg/ml ampicillin and 1 ml of this culture was used to inoculate an ampicillin-containing 500-ml culture. When the culture reached an OD (A600) of 0.5, the expression was induced by addition of isopropyl-1-thio-ß-D-galactopyranoside (1.5 mM final concentration) and the cells were incubated for 5 h more at 37°C. GST-TACE was obtained from the inclusion bodies and solubilized in 20 mM Tris-HCl (pH 8) containing 8 M urea and 100 mM 2-ME. The solubilized proteins were refolded by a 1:100 dilution in either 1) standard refolding buffer (20 mM Tris-HCl (pH 7.6) containing 200 mM NaCl, 5 mM CaCl2, 100 µM ZnCl2, 100 mM arginine, and 0.002% NaN3) or 2) in this buffer which was further supplemented with 1 mM DTT and 3 mM oxidized glutathione (GSSG) (oxido-shuffling buffer). After incubation for 3 days at 4°C, the crude extract was diluted with the same volume of ice-cold water and the recombinant proteins were purified on glutathione-Sepharose (Amersham Pharmacia Biotech). The elution of GST-TACE was conducted with 10 mM of reduced glutathione in PBS.
Flow cytometry
Membrane-bound proteins were determined by direct immunofluorescence analysis. Cells (3 x 105) were labeled with saturating amounts of FITC-conjugated Abs Ki-3-FITC (anti-CD30), anti-CD25-FITC (Dako, Hamburg, Germany), or BH1-FITC (anti-phOx) in PBS containing 0.1% BSA and 0.02% sodium azide for 20 min on ice. Cells were analyzed using a FACScan flow cytometer (Becton Dickinson, Heidelberg, Germany).
Determination of sCD30
Flexible 96-well microtiter plates (Integra Bioscience, Fernwald, Germany) were coated with 50 µl of Ki-2 mAb (50 µg/ml) by overnight incubation at 4°C. The plates were washed and subsequently blocked with PBS/10% FCS for 1 h at room temperature. After washing (three times with PBS/0.1% Tween 20), serial dilutions of both the CD30 standard (1–300 U/ml) (29) and the sCD30-containing samples were added and incubated for 1 h at room temperature. After washing,125I-labeled Ki-3 mAb was added and incubated for 1 h and, after washing again, the radioactivity of the single wells was determined and compared with the internal standard.
Gelatin zymography
TACE was analyzed by SDS-polyacrylamide gel zymography. Samples were prepared in conventional nonreducing loading buffer without boiling and run on 10% polyacrylamide gels containing 0.1% gelatin. The gels were then washed twice for 15 min in 2.5% Triton X-100 to remove SDS, followed by a 20-min wash in metalloproteinase buffer (50 mM Tris-HCl (pH 7.6), 5 mM CaCl2, 100 µM ZnCl2, and 0.02% NaN3). After a further incubation period for 20 h at 37°C in this buffer, the gels were stained with Coomassie brilliant blue. A clear zone indicated the presence of a proteinase with gelatinolytic activity.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
CD30 is expressed on CD30+ lymphoma cell
lines, e.g., the Hodgkin’s disease derived cell line L540
and the large cell anaplastic lymphoma cell line Karpas 299 as well as
on normal PBL after stimulation with PHA or anti-CD3 Ab (OKT-3).
Constitutive shedding of CD30 was detected from all cells. This
endoproteolytic release of the CD30 ectodomain (sCD30) was strongly
activated by PMA, resulting in a loss of membrane-bound CD30 detected
by flow cytometry and a corresponding increase of sCD30 in the
supernatant detected by an CD30 Ab-based sandwich RIA (Fig. 1
, A and C). The
FITC-labeled 2-phOx Ab BH1 (BH1-FITC), which served as an isotype
control in flow cytometry, showed no binding to any of the tested cells
(Fig. 1B). PMA-induced shedding of CD30 was effectively
blocked by the hydroxamic acid-based broad-spectrum MMP inhibitor
BB-2116 (20 µM), whereas inhibition of constitutive shedding varied
depending on the cell type. Although BB-2116 blocked the constitutive
sCD30 release from tumor cells, the release from activated normal cells
was hardly affected. These data showed that PMA-induced shedding was
mediated by metalloproteinases; however other proteinases might be
involved in constitutive shedding from normal cells.
|
To decide whether PMA-induced CD30 cleavage was mediated by a
secreted or a membrane-anchored metalloproteinase, the CD30-cleaving
activities of supernatant fluids and membrane extracts of
PMA-stimulated Karpas 299 cells were compared. Although a direct
incubation of Karpas 299 cells with PMA (30 ng/ml, 30 min) induced a
loss of membrane-bound CD30 to 65% of the untreated control, an
incubation of the cells for 1 h with the supernatant of
PMA-activated Karpas cells (30 ng/ml, 30 min) had no influence on the
CD30 expression (Fig. 2). For the
determination of CD30-cleaving activity in cell membranes, membrane
fractions of PMA-activated Karpas 299 cells were extracted with the
solubilizing reagent CHAPS. The extract induced a loss of CD30 to 57%
of the dialysis buffer-incubated control (buffer). Interestingly,
membrane extracts of nonstimulated cells exhibited CD30 sheddase
activity as well. This activity was weaker but still capable to induce
a reduction of CD30 to 77% of the untreated control. As with PMA,
these membrane effects were dependent on metalloproteinases, since
BB-2116 (20 µM) abolished the CD30-cleaving activity. The
CHAPS-extracted membrane preparation of PMA-activated Karpas 299 cells
also induced a loss of CD30 on PHA-activated normal PBLs, but had no
influence on the expression of CD25 on both cells (data not shown).
These data suggest that PMA-stimulated CD30 shedding was mediated by
endogenous membrane-anchored metalloproteinases that could be activated
or up-regulated by PMA. Moreover, membrane anchoring via the
metalloproteinase transmembrane domain is not essential for activity in
this system.
|
For a characterization of the responsible enzyme(s), the
sensitivity of the PMA-induced CD30 shedding for a variety of
metalloproteinase inhibitors was tested: 1) The efficacy of the
broad-spectrum hydroxamate MMP inhibitor BB-2116 (20 µM) to prevent
CD30 cleavage (10) (
Figs. 1–3
) suggested the involvement of MMPs
or related enzymes in the shedding of CD30. 2) In contrast, the natural
inhibitors TIMP-1 (10 µg/ml) and TIMP-2 (10 µg/ml), which inhibit
soluble and membrane-type MMPs (21, 30), could not prevent
the PMA-induced CD30 shedding (Fig. 3A). This does not
support an involvement of MMPs. 3) Phosphoramidon (10 µM) and
captopril (10 µM), which are known inhibitors of thermolysin,
neprilysin, and angiotensin-converting enzyme, respectively, also
failed to influence CD30 cleavage. 4) Like BB-2116, TIMP-3 inhibited
the PMA-induced CD30 shedding from Karpas 299 cells in a dose-dependent
manner (Fig. 3B). The inhibitory potency of TIMP-3
(IC50, 30 nM) was 8-fold higher than that of
BB-2116 (IC50, 230 nM). A similar inhibition by
TIMP-3 was obtained when we analyzed CD30 shedding from
CD30+ normal cells (data not shown). Since the
MMP inhibitor TIMP-3 potently blocks the membrane-anchored
metalloproteinase-disintegrin TACE (22), our data provide
evidence for a role of TACE or a TACE-like proteinase in CD30
shedding.
|
TACE-specific mRNA transcripts were detected by RT-PCR from
PMA-activated Karpas 299 cells and CD30+ PBLs.
Using TACE-specific primers, a 1299-bp cDNA fragment was amplified from
both sources as shown for Karpas 299 (Fig. 4). The purified 1299-bp fragment from
Karpas 299 cells, encoding the catalytic, disintegrin, and
cysteine-rich domain of TACE, was cloned into the pGEX-3X GST gene
fusion vector. Sequencing confirmed that it was identical with the
published mRNA sequence of TACE derived from the GenBank accession
number U69611 (data not shown).
|
The TACE ectodomain was expressed in bacteria as a GST fusion
protein (GST-TACE) (Fig. 5A).
Crude extracts from the insoluble fraction of the transfected bacteria
were either refolded by 1) a standard dilution protocol that allowed
the renaturation of the GST tag, but not of the cysteine-rich TACE
ectodomain (GST-TACE(st)) or 2) dilution into the oxido-shuffling
system which facilitates the formation of proper disulfide bonds after
denaturing extraction (GST-TACE(ox)). After affinity purification on
reduced glutathione-Sepharose, homogeneous GST-TACE was obtained from
both preparations (Fig. 5B). From the oxido-shuffling
buffer, a lower amount of material could be recovered, yielding about
20–30% of that from the standard refolded preparation. This might be
due to the glutathione (GSSG) in the oxido-shuffling buffer which might
interact with the subsequent purification procedure. However, the
proteinase activity of GST-TACE(ox) recovered from the oxido-shuffling
buffer was 100-fold higher, since 10 ng elicited a gelatinolytic
activity equivalent to 1 µg of GST-TACE(st) in gelatin zymography
(Fig. 5C). Hence, the two refolding procedures allowed the
preparation of an active and inactive conformation of the TACE
ectodomain.
|
, A and E). The
CD30 cleavage was detectable at 300 ng/ml GST-TACE, comparable in its
activity with the purified snake venom metalloproteinase-disintegrin
hemorrhargin from Echis pyramidum laekeyi, which also caused
a detectable CD30 cleavage at the same concentration (Fig. 6, B and F). To elucidate the physiological
relevance of TACE, we applied recombinant ADAM 10, another
membrane-anchored metalloproteinase-disintegrin. Although ADAM 10 was
active degrading bovine myelin basic protein (data not shown), its
CD30-cleaving activity was weak in comparison to that of TACE. No loss
of CD30 was visible in flow cytometry. Only the more sensitive sandwich
RIA detected an enhanced sCD30 level in the supernatant of Karpas 299
cells after treatment with 3000 ng/ml ADAM 10 (Fig. 6B).
These findings suggest TACE being the more relevant CD30sheddase. As
a control, GST-TACE-, ADAM 10, and snake venom-mediated CD30 shedding
was blocked by BB-2116 (20 µM), indicating that CD30 cleavage was
only effected by metalloproteinase action.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
), and hence referred to as broad-spectrum MMP
inhibitor. Unlike BB-2116, the physiological MMP inhibitors TIMP-1 and
-2 failed to inhibit PMA-induced CD30 shedding. We concluded that CD30
is released by a MMP-related metalloproteinase but neither by soluble
MMPs nor by any of the hitherto characterized membrane-type MMPs, since
these are all sensitive to TIMP-2 or TIMP-1 (21, 30, 35, 36, 37, 38, 39). In contrast to TIMP-1 and -2, CD30 shedding was
potently inhibited by TIMP-3. This inhibition profile has also been
described for the shedding of other membrane proteins, e.g.,
pro-TNF-, L-selectin, the p75 TNFR, and the IL-6R
(22, 23, 24, 25), suggesting a common releasing mechanism.
Pro-TNF-, L-selectin, and the p75 TNFR are released by TACE which is
a membrane-anchored metalloproteinase-disintegrin (ADAM) and belongs,
along with soluble snake venom metalloproteinases, to the reprolysin
family of metalloproteinases (11, 12, 16). TACE is
strongly inhibited by TIMP-3, but not affected by the MMP inhibitors
TIMP-1 and -2 (22). The strong inhibition of CD30 shedding
from Karpas 299 cells by TIMP-3 and the inability of TIMP-1 and -2
suggested that TACE might be responsible for the cleavage of CD30 as
well. This assumption was further substantiated: 1) It could be
demonstrated that CD30 shedding was mediated by a membrane-associated
metalloproteinase since solubilized membrane extracts of Karpas 299
cells were able to cleave CD30 at the cell surface of intact cells. 2)
TACE-specific mRNA transcripts were detected in Karpas 299 cells by
means of RT-PCR. 3) It could be demonstrated that the recombinant
fusion protein containing GST and the TACE ectodomain (GST-TACE)
elicited CD30 sheddase activity in a dose-dependent manner. These
findings demonstrated that TACE is expressed by Karpas 299 cells and is
able to cleave membrane-bound CD30. The CD30-cleaving activity of the
construct was comparable to that of the snake venom metalloproteinase
hemorrhargin, both belong to the reprolysin family of
metalloproteinases. Since hemorrhargin is a TNF--releasing enzyme
(14), the cleaving of CD30 serves to corroborate the
common releasing mechanism.
Regarding the related shedding of TNF-, it has not been clarified
whether pro-TNF- is exclusively cleaved by TACE on all cell types
since inactivation of the TACE gene in mouse T cells caused a marked
decrease but not complete inhibition of TNF- release
(11). ADAM 10, another membrane-anchored
metalloproteinase-disintegrin closely related to TACE, was also able to
cleave pro-TNF- (40, 41) from the cell surface,
indicating that other metalloproteinases might play a role. Similarly,
sCD30 was not only released by TACE but also by ADAM 10, although less
effectively. Since we detected mRNA of both TACE and ADAM 10 (data not
shown) in CD30+ Karpas 299 cells, the question
arises whether TACE represents the only physiologically relevant
CD30-cleaving enzyme. The data from direct application of the
recombinant ADAMs do not clearly answer this question. The evaluation
of their inhibition profile appears to be more promising. Although
inhibition data on ADAMs are incomplete, TIMPs play a role in
distinguishing different ADAMs. TACE is inhibited by TIMP-3 and not by
TIMP-1 and 2, whereas both TIMP-1 and -3 inhibit ADAM 10 (22, 42). Thus, the inhibition of CD30 shedding by TIMP-3 and not by
TIMP-1 and -2 argues in favor of TACE as the physiologically relevant
CD30-cleaving metalloproteinase. TACE and ADAM 10 are structurally very
similar and differ from other known ADAMs (13, 40, 41).
Nonetheless, catalytic activity has also been described for two other
metalloproteinase-disintegrins, i.e., ADAM 12 and ADAM 9 (MDC 9)
(43, 44). The inhibition profile of ADAM 12 appears to be
completely different from that of TACE since neither the hydroxamate
inhibitor BB-94 nor TIMP-1, -2, and -3 were effective
(45). Inhibition data on MDC 9 are not yet available.
Hence, although inhibition data suggest a role of TACE in CD30
shedding, the involvement of so far uncharacterized TACE-related
enzymes cannot be excluded.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Hinrich Hansen, Department of Biochemistry, University of Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany.
3 Current address: Department of Microbiology, Columbia University, New York, NY.
4 Abbreviations used in this paper: CD30L, CD30 ligand; ADAM, a metalloproteinase and disintegrin; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate; GSSG, oxidized glutathione; MFI, mean fluorescence intensity; MMP, matrix metalloproteinase; phOx, phenyloxazolone; sCD30, soluble CD30; TACE, TNF--converting enzyme; TIMP, tissue inhibitor of metalloproteinases.
Received for publication July 12, 1999. Accepted for publication September 7, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
from cells. Nature 385:729.[Medline]
. Nature 385:733.[Medline]
-converting enzyme. Proc. Natl. Acad. Sci. USA 95:3408. by venom metalloproteinases: a hypothesis explaining local tissue damage following snake bite. Eur. J. Immunol. 26:2000.[Medline]
converting enzyme is involved in regulated -secretase cleavage of the Alzheimer amyloid protein precursor. J. Biol. Chem. 273:27765./ADAM9 and PKC
are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. EMBO J. 17:7260.[Medline]
converting enzyme (TACE) is inhibited by TIMP-3. FEBS Lett. 435:39.[Medline]
receptors on the surface of human colon carcinoma cells. Cytokine 9:770.[Medline]
convertase activity but does not activate pro-MMP2. J. Biol. Chem. 275:14046.-processing enzyme from the ADAM family of zinc metalloproteases. J. Biol. Chem. 272:24588. convertase. FEBS Lett. 400:333.[Medline]
) is an active metalloprotease. J. Biol. Chem. 273:16993.This article has been cited by other articles:
|
|
 |
|
  R.-O. Casasnovas, N. Mounier, P. Brice, M. Divine, F. Morschhauser, J. Gabarre, J.-Y. Blay, L. Voillat, P. Lederlin, A. Stamatoullas, et al. Plasma Cytokine and Soluble Receptor Signature Predicts Outcome of Patients With Classical Hodgkin's Lymphoma: A Study From the Groupe d'Etude des Lymphomes de l'Adulte J. Clin. Oncol., May 1, 2007; 25(13): 1732 - 1740. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Li, K. Boyd, P. J. Dempsey, and D. A. A. Vignali Non-Cell Autonomous Expression of TNF-{alpha}-Converting Enzyme ADAM17 Is Required for Normal Lymphocyte Development J. Immunol., April 1, 2007; 178(7): 4214 - 4221. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Eichenauer, V. L. Simhadri, E. P. von Strandmann, A. Ludwig, V. Matthews, K. S. Reiners, B. von Tresckow, P. Saftig, S. Rose-John, A. Engert, et al. ADAM10 Inhibition of Human CD30 Shedding Increases Specificity of Targeted Immunotherapy In vitro Cancer Res., January 1, 2007; 67(1): 332 - 338. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Garton, P. J. Gough, and E. W. Raines Emerging roles for ectodomain shedding in the regulation of inflammatory responses J. Leukoc. Biol., June 1, 2006; 79(6): 1105 - 1116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. K. Sutherland, R. J. Sanderson, K. A. Gordon, J. Andreyka, C. G. Cerveny, C. Yu, T. S. Lewis, D. L. Meyer, R. F. Zabinski, S. O. Doronina, et al. Lysosomal Trafficking and Cysteine Protease Metabolism Confer Target-specific Cytotoxicity by Peptide-linked Anti-CD30-Auristatin Conjugates J. Biol. Chem., April 14, 2006; 281(15): 10540 - 10547. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Buckley, F. N. Rouhani, M. Kaler, B. Adamik, F. I. Hawari, and S. J. Levine Amino-terminal TACE prodomain attenuates TNFR2 cleavage independently of the cysteine switch Am J Physiol Lung Cell Mol Physiol, June 1, 2005; 288(6): L1132 - L1138. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Nagata, T. Ise, M. Onda, K. Nakamura, M. Ho, A. Raubitschek, and I. H. Pastan Cell membrane-specific epitopes on CD30: Potentially superior targets for immunotherapy PNAS, May 31, 2005; 102(22): 7946 - 7951. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Levine Mechanisms of Soluble Cytokine Receptor Generation J. Immunol., November 1, 2004; 173(9): 5343 - 5348. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Budagian, E. Bulanova, Z. Orinska, A. Ludwig, S. Rose-John, P. Saftig, E. C. Borden, and S. Bulfone-Paus Natural Soluble Interleukin-15R{alpha} Is Generated by Cleavage That Involves the Tumor Necrosis Factor-{alpha}-converting Enzyme (TACE/ADAM17) J. Biol. Chem., September 24, 2004; 279(39): 40368 - 40375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Li and H. Fan Loss of Ectodomain Shedding Due to Mutations in the Metalloprotease and Cysteine-rich/Disintegrin Domains of the Tumor Necrosis Factor-{alpha} Converting Enzyme (TACE) J. Biol. Chem., June 25, 2004; 279(26): 27365 - 27375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. von Tresckow, K.-J. Kallen, E. P. von Strandmann, P. Borchmann, H. Lange, A. Engert, and H. P. Hansen Depletion of Cellular Cholesterol and Lipid Rafts Increases Shedding of CD30 J. Immunol., April 1, 2004; 172(7): 4324 - 4331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Weskamp, J. Schlondorff, L. Lum, J. D. Becherer, T.-W. Kim, P. Saftig, D. Hartmann, G. Murphy, and C. P. Blobel Evidence for a Critical Role of the Tumor Necrosis Factor {alpha} Convertase (TACE) in Ectodomain Shedding of the p75 Neurotrophin Receptor (p75NTR) J. Biol. Chem., February 6, 2004; 279(6): 4241 - 4249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Matthews, B. Schuster, S. Schutze, I. Bussmeyer, A. Ludwig, C. Hundhausen, T. Sadowski, P. Saftig, D. Hartmann, K.-J. Kallen, et al. Cellular Cholesterol Depletion Triggers Shedding of the Human Interleukin-6 Receptor by ADAM10 and ADAM17 (TACE) J. Biol. Chem., October 3, 2003; 278(40): 38829 - 38839. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Contin, V. Pitard, T. Itai, S. Nagata, J.-F. Moreau, and J. Dechanet-Merville Membrane-anchored CD40 Is Processed by the Tumor Necrosis Factor-{alpha}-converting Enzyme: IMPLICATIONS FOR CD40 SIGNALING J. Biol. Chem., August 29, 2003; 278(35): 32801 - 32809. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T Seifert, B C Kieseier, S Ropele, S Strasser-Fuchs, F Quehenberger, F Fazekas, and H-P Hartung TACE mRNA expression in peripheral mononuclear cells precedes new lesions on MRI in multiple sclerosis Multiple Sclerosis, December 1, 2002; 8(6): 447 - 451. [Abstract] [PDF]
|
|
|
|
 |
|
 S J H van Deventer Small therapeutic molecules for the treatment of inflammatory bowel disease Gut, May 1, 2002; 50(90003): iii47 - 53. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Guo, J. R. Eisenman, R. M. Mahimkar, J. J. Peschon, R. J. Paxton, R. A. Black, and R. S. Johnson A Proteomic Approach for the Identification of Cell-surface Proteins Shed by Metalloproteases Mol. Cell. Proteomics, January 1, 2002; 1(1): 30 - 36. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
