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(Received for publication, February 20, 1996)
From the ABSTRACT CD30 is a member of the tumor necrosis factor
(TNF) receptor family of proteins. CD30 can regulate proliferation of
lymphocytes and may also play an important role in human
immunodeficiency virus replication. However, little is known about CD30
signal transduction. We performed a yeast two-hybrid library screen
with the cytoplasmic domain of CD30 and isolated multiple independent
cDNAs encoding human tumor necrosis factor receptor-associated
factor (TRAF) 1, TRAF2, and CRAF1 (TRAF3). The ability of TRAF1, TRAF2,
and CRAF1 to associate with CD30 was confirmed using an in
vitro coprecipitation assay, further demonstrating that the
interaction was specific and direct. The TRAF-binding domain of CD30
was mapped to the COOH-terminal 36 amino acid residues, which contained
two independent binding sites. CRAF1 bound only a single site, which
contained the sequence PEQET, whereas TRAF1 and TRAF2 were capable of
binding to either the PEQET site or an additional downstream domain.
These data indicate that the TRAF protein binding pattern of CD30
differs from other TNF receptor family members and suggest that
signaling specificity through TNF receptor family proteins may be
achieved through differences in their abilities to bind TRAF
proteins.
INTRODUCTION CD30 was originally identified as an antigen expressed on the
surface of Hodgkin's lymphoma cells (1, 2). Subsequently, CD30 was
shown to be expressed by lymphocytes with an activated phenotype
(3, 4, 5, 6, 7), cells on the periphery of germinal centers (2, 7), CD45RO+
(memory) T cells (4), and Epstein-Barr virus- and human T cell
lymphotrophic virus type I and II-transformed cells (3, 5, 7, 8). CD30
is expressed as both membrane bound and soluble forms (9). Increases in
the amount of soluble CD30 have been detected in patients with human
immunodeficiency virus infections, leading to speculation that CD30 may
play a role in the development and progression of AIDS (10, 11, 12). CD30
may also play a role in the development of T helper 2 type cells
(13, 14, 15).
CD30 is a member of the TNF1 receptor
superfamily of receptor proteins (16, 17). The membrane bound form of
CD30 is a 120-kDa 595-amino acid glycoprotein with a 188-amino acid
cytoplasmic domain (7, 16, 17, 18, 19, 20). Cross-linking of CD30 with either
antibodies or with CD30 ligand produces a variety of effects in cells,
including augmenting the proliferation of primary T cells following T
cell receptor engagement (5, 21), induction of the NF- Most of the homology between TNF receptor family members occurs in the
extracellular domain, with little homology in the cytoplasmic domain
(17). This suggested that different members of the TNF receptor family
might utilize distinct signaling pathways. Consistent with this
hypothesis, the TNF receptor type 1 and Fas have been shown to interact
with a set of intracellular signaling molecules through a 65-amino acid
domain termed a death domain (17, 23, 24, 25, 26), whereas the TNF receptor
type 2 and CD40 have been found to associate with members of the tumor
necrosis factor receptor-associated factor (TRAF) family of signal
transducing molecules (27, 28, 29, 30, 31, 32). The T cell activation properties of the
TNF receptor family member 4-1BB have been shown to involve the
specific ability of its cytoplasmic domain to associate with the
tyrosine kinase p56lck (33). The sequence of the cytoplasmic
domain of CD30 shows little sequence similarity to any of these
receptors (17). CD30 lacks an obvious death domain or a
p56lck-binding site. Therefore, the yeast two-hybrid system was
used to screen a cDNA library in order to identify proteins that
interacted with the cytoplasmic domain of CD30. Multiple independent
cDNA isolates of human TRAF2 (TRAP; 27, 31), TRAF1 (EBI6; 27, 32),
and CRAF1 (TRAF3, CAP1, CD40-bp, LAP1; 28-30, 32) were identified.
Each of these proteins was found to associate specifically with CD30 in
yeast and in an in vitro coprecipitation assay using a
glutathione S-transferase (GST)-CD30 fusion protein. This is
the first demonstration of a direct interaction between TRAF1 and a
receptor protein. The region of CD30 required for the interaction with
the TRAF proteins was mapped to the COOH-terminal 36 amino acids. This
region of CD30 was found to contain a single binding site for CRAF1.
However, both TRAF1 and TRAF2 were capable of binding either to the
CRAF1-binding site or a downstream site. These results demonstrate that
CD30, in addition to its extracellular similarities to TNF receptor
type 2 and CD40, shares with these receptors the ability to bind
members of the TRAF family of signal transducing molecules.
Nevertheless, there appear to be different binding specificities of
individual TNF receptor proteins for the TRAF proteins. The
differential ability of these receptors to bind distinct members of the
TRAF family may, at least partially, account for the differences in
their biological activities.
MATERIALS AND METHODS The yeast expression vectors pAS1 and pACT have
been described previously (34). The Matchmaker human B cell library was
purchased from Clontech and is derived from Epstein-Barr
virus-transformed peripheral blood lymphocytes (B cell population).
Polymerase chain reaction (PCR) was used to construct the wild type and
all deleted forms of the CD30 cytoplasmic domain (CD30 cyto). In all
cases described below, Pfu polymerase (Stratagene) was used in order to
minimize the possibility of PCR introduced errors. pAS1-CD30 cyto
contains the coding sequence for the entire cytoplasmic domain of CD30
(amino acid residues 408-595). Arginine 409 was mutated to a
methionine in order to create an NdeI site to facilitate
cloning into pAS1. PCR was used to amplify the cytoplasmic domain of
CD30 out of a Full-length TRAF1, TRAF2, and CRAF1 cDNAs that were isolated in the
yeast two-hybrid screen were subcloned into Bluescript SK(+)
(Stratagene) in order to facilitate in vitro transcription
and translation. pACT plasmids containing the full-length TRAF clones
were digested with XhoI (in the case of human TRAF2 the
digest was partial), and the fragments were ligated into the
XhoI site of Bluescript SK(+).
GST-CD30 cyto was constructed by using PCR to amplify the CD30
cytoplasmic domain coding sequence from pAS1-CD30 cyto. The sense
primer, 5 Yeast two-hybrid library
screening and analysis were performed essentially as described in the
Matchmaker protocol provided by Clontech using the yeast strain Y153.
Briefly, Y153 was transformed with the appropriate pAS1 and pACT
plasmid DNA derivatives (for directed assays, 200 ng of each plasmid;
for library screening, 30 µg of each plasmid) and then plated on
plates lacking leucine, tryptophan, and histidine and containing 25
mM 3-aminotriazole (3-AT) and plates lacking leucine and
tryptophan. After 3 days at 30 °C, colonies from plates lacking
leucine, tryptophan, and histidine and containing 3-AT were transferred
to filters and assayed for GST coprecipitation assays were
performed as described by Lewis et al. (35). GST and GST
fusion proteins were expressed in XL1 Escherichia coli.
35S-Labeled full-length TRAF1, TRAF2, and CRAF1 were
in vitro transcribed/translated from the Bluescript plasmid
templates described above in rabbit reticulocyte lysate using the TNT
T7/T3-coupled reticulocyte lysate system (Promega). Precipitated
proteins were separated by SDS-polyacrylamide gel electrophoresis. Gels
were fluorographed with En3Hance (DuPont NEN) and
visualized by autoradiography.
RESULTS To identify proteins that
associate with the cytoplasmic domain of CD30, we used the yeast
two-hybrid system. The DNA sequence encoding the 188-amino acid
cytoplasmic domain of CD30 was cloned into the pAS1 expression vector
(34) fusing this domain to the DNA-binding domain of GAL4. This vector
was used to screen a cDNA library prepared from Epstein-Barr
virus-transformed B cells cloned into the GAL4 transcriptional
activation domain vector pACT (34). Approximately 700,000 transformants
were screened yielding 25 positive clones as defined by growth on
medium lacking histidine and containing 3-AT and
In addition to full-length clones for each member of the TRAF family,
several NH2-terminal deletions were obtained, indicating
that this domain is not required for interaction with CD30. The
CRAF1 The
possibility existed that the interaction between the TRAF proteins
(TRAF1, TRAF2, and CRAF1) and CD30 in yeast was nonspecific.
Furthermore, TRAF1 has not been previously shown to interact directly
with receptor proteins. TRAF1 has been shown to interact indirectly
with the TNF receptor type 2 by forming heteromers with TRAF2 (27).
Thus, it was formally possible that a TRAF-like protein in yeast might
be facilitating the interaction between TRAF1 and CD30. To confirm the
specificity of the interaction between CD30 and TRAF1, TRAF2, and
CRAF1, the CD30 cyto was fused to glutathione S-transferase.
Affinity purified GST-CD30 cyto was tested for its ability to
precipitate 35S-labeled in vitro translated
full-length TRAF2, TRAF1, and CRAF1. As shown in Fig. 2,
each of these proteins could be precipitated with GST-CD30 cyto. In
contrast, neither GST alone nor a GST fusion protein containing the
cytoplasmic domain of the mouse CD28 protein coprecipitated detectable
amounts of TRAF2, TRAF1, or CRAF1, indicating that the interactions
between CD30 and the TRAF proteins observed in yeast are specific. In
addition, the ability of GST-CD30 cyto to coprecipitate TRAF1 in
vitro argues that these proteins associate directly.
In order to map the domain(s) of CD30 required for
interaction with TRAF1, TRAF2, and CRAF1, COOH-terminal deletion
mutants of the CD30 cytoplasmic domain were constructed (Fig.
3A). These mutants were then tested for their
ability to interact with the TRAF proteins in yeast (Fig.
3B). In these and subsequent experiments shown in this
paper, TRAF1, TRAF2, and CRAF1 clones containing the largest
NH2-terminal truncations were used in order to examine the
minimal CD30 interaction domain. However, in those cases tested,
identical results were obtained with full-length TRAF clones (data not
shown). The yeast were cotransformed with plasmids expressing the
various CD30 COOH-terminal deletion mutants and the TRAF expression
vectors and then assayed for their ability to grow on medium lacking
histidine and containing 3-AT and for
Deletion mutants lacking the NH2-terminal 96, 117, and 146
amino acids ( Computer alignments of the cytoplasmic domain of CD30 with
the cytoplasmic domains of other TNFR family members revealed little
overall homology. The cytoplasmic domain of CD40 was most similar to
the COOH-terminal region of CD30, which contains the putative binding
domain for the TRAF proteins (Fig. 4A). The CD40 cytoplasmic
domain has been shown to associate with both TRAF2 and CRAF1 (37).
There are two regions of particularly high similarity between CD40 and
CD30. The first is a 5-amino acid stretch with the sequence PEQET,
which is almost identical to the sequence PVQET in CD40. The threonine
residue (Thr254) in this sequence is known to be required
for several functions of CD40 (38, 39), including binding of CRAF1
(30). The PEQET sequence was deleted in the To test this possibility, an internal deletion mutant ( As shown in Fig. 4C, neither the
DISCUSSION The TNF receptor (TNFR) type 2 and CD40 are known to regulate
cellular proliferation (40, 41, 42) and induce the NF- The TRAF proteins are most related in the COOH-terminal TRAF domain,
which has been further subdivided into a TRAF-N domain and TRAF-C
domain (28, 36). The TRAF domain is required for the ability of TRAF
proteins to form multimers and, in the case of TRAF1 and TRAF2,
heteromers (27, 28, 37). In addition, experiments using CRAF1 and TRAF2
have demonstrated that the TRAF domain encodes the receptor binding
function (28, 37). Our data confirm that the ability of TRAF1 to bind
to the CD30 receptor is also confined to the carboxyl-terminal TRAF
domain as demonstrated by the smallest TRAF1 clone isolated in the
yeast two-hybrid screen. Overexpression of a truncated CRAF1 protein
containing the CD40-binding domain has been shown to block the ability
of CD40 to induce CD23 in transfected cells (28). Deletion of the
NH2-terminal 87 amino acids of TRAF2 abolishes the ability
of TNFR type 2 and CD40 to induce NF- The data presented here and elsewhere (27, 28, 29, 30, 31, 37) indicate that
members of the TNF receptor family have distinct TRAF binding
properties. We have found that CD30 can associate directly with TRAF1,
TRAF2, and CRAF1. In contrast, TNFR type 2 has been shown to associate
directly only with TRAF2 (27), whereas CD40 has been shown to associate
with both CRAF1 and TRAF2 (37). The differential abilities of the TNF
receptor family to bind to TRAF proteins is reminiscent of cytokine
receptor signaling through the Jak/STAT signal transduction pathway
(48). The ability of cytokine receptors to bind different combinations
of Jaks and STATs allows these receptors to send specific signals.
Thus, by binding different combinations of TRAF proteins, TNF receptor
proteins may be able to achieve signaling specificity while using an
overlapping signal transduction pathway. The analogy to Jak/STAT
pathway is further supported by the identification of a fourth member
of the TRAF family, CART1 (49). CART1 was identified by its
differential expression in breast carcinoma cells and was found to
localize to the nucleus of these cells, suggesting that TRAFs may be
latent cytoplasmic transcription factors (49). TRAF2 and TRAF1 were
recently shown to bind to c-IAP1 and c-IAP2 (36), which belong to the
recently identified family of cellular homologues of the baculovirus
IAP protein (36, 50, 51, 52). It is possible that the cellular IAP proteins
may be transcription factors as well. In addition to the differing
abilities to bind TRAF proteins, our observation that CD30 contains two
nonidentical binding sites for TRAF proteins adds further complexity to
the possible CD30-TRAF protein signaling complexes that assemble in
cells. Because CD30, like other TNF-related receptors, is likely to
trimerize in response to ligand binding and each receptor contains two
binding sites for TRAF proteins, the composition of CD30 signaling
complexes could be quite divergent in different cell types or under
different conditions of stimulation.
It will be important to determine the roles played by the individual
TRAF proteins during CD30 signal transduction. In addition, there may
be other factors involved in CD30 signal transduction. The TRAF-binding
domain was localized to the COOH-terminal 36 amino acids of the CD30
cytoplasmic domain, which is 188 amino acids long (16). Therefore, it
is possible that the remaining 153 amino acids of the CD30 cytoplasmic
domain have been retained during evolution because they also contribute
to the assembly of a CD30 signaling complex. To address these issues,
the signaling properties of a CD30 receptor containing the minimal
TRAF-binding domain will need to be compared with the wild type
receptor tail.
FOOTNOTES Acknowledgments We thank David Wang for technical assistance
and Therese Conway for help in manuscript preparation.
REFERENCES
Volume 271, Number 22,
Issue of May 31, 1996
pp. 12852-12858
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,, and§¶
Gwen Knapp Center for Lupus and Immunology
Research, Department of Medicine, the § Committee on
Immunology, and the ¶ Howard Hughes Medical Institute, Department
of Molecular Genetics and Cell Biology, The University of Chicago,
Chicago, Illinois 60637
B
transcription factor (11, 22), induction of human immunodeficiency
virus gene expression in infected T cells (11, 12), increases in
intracellular calcium (4), and cell death (5). However, little is known
about the mechanisms of CD30 signal transduction.
gt11 cDNA library from the human T cell line HUT78
(Clontech) using the oligonucleotides: sense,
5
-ACGTACGTCATATGAGGGCCTGCAGGAAGCGAATTCGG-3, and antisense,
5-AAGGATCCTCACTTTCCAGAGGCAGCTGTG-3. The PCR products were then
ligated into the NdeI and BamHI sites of pAS1.
The COOH-terminal deletions of CD30 (
124, 71, 36, 19, and
9) were made by PCR using antisense oligonucleotides that introduced
in-frame stop codons in the appropriate positions.
NH2-terminal deletions (N96, N117, and N146) were
also constructed by PCR using 5 primers that inserted an
NdeI site in-frame with pAS1 upstream of the appropriate
codon. The PEQET internal deletion and point mutations of this
sequence were made using the Chameleon mutagenesis system (Stratagene)
according to the manufacturer's protocol. Mutations were verified by
sequencing.
-GTGGATCCCACCCGAGGGCCTGCAGGAAGCGAATT-3, added an in-frame
BamHI site to the 5 end that facilitated subcloning into
pGEX-2TK (Pharmacia Biotech Inc.). GST-CD28 cyto was constructed
similarly by using PCR to amplify the CD28 cytoplasmic domain coding
sequence from a plasmid containing a full-length mouse CD28 cDNA.
The oligonucleotide primers inserted an in-frame BamHI site
at the 5 end and an EcoRI site at the 3 end that
facilitated subcloning into pGEX-2TK.
-galactosidase activity. However, in all
cases tested, colonies from the plates lacking leucine and tryptophan
gave identical results. In general, -galactosidase activity was
apparent within 1 h, but the filters were allowed to incubate for
24 h. In all assays, transformants were tested for both the
ability to grow on medium lacking histidine and containing 3-AT and for
-galactosidase expression. Without exception, protein-protein
interactions were considered to be positive if both growth in the
absence of histidine and -galactosidase expression were
observed.
-galactosidase
expression. These positive clones interacted specifically with the CD30
fusion construct but not with either the GAL4 DNA-binding domain alone
or a GAL4-CD28 fusion (data not shown). Sequence analysis revealed that
13 of the 25 cDNA clones encoded members of the TRAF family of
signal transducing proteins. As shown in Fig. 1, seven
independent isolates of human TRAF2, four independent isolates of human
TRAF1, and two independent isolates of CRAF1 were obtained.
Fig. 1.
Summary of the TRAF proteins identified in
the yeast two-hybrid screen with the CD30 cytoplasmic domain.
Shown are schematics of the structures of wild type (wt)
TRAF2, TRAF1, and CRAF1 (28). Below each are schematics of the
individual TRAF-related clones isolated from the screen.
N125, C6 (Fig. 1), which has a 125-amino acid
NH2-terminal and a 6-amino acid COOH-terminal deletion, was
the only isolate with a COOH-terminal deletion. Thus, all of the TRAF2,
TRAF1, and CRAF1 clones obtained in this screen contain intact TRAF
domains at their COOH termini, consistent with previously published
data indicating that this domain is necessary and sufficient for
association with receptor proteins (28, 36).
Fig. 2.
In vitro association of the TRAF
proteins with the cytoplasmic domain of CD30. Coprecipitation
assays using bacterially expressed GST, GST-CD30 cytoplasmic domain
(GST-CD30 cyto), and GST-CD28 cytoplasmic domain and in
vitro transcribed/translated full-length TRAF2, TRAF1, and CRAF1
were performed as described under ``Materials and Methods.''
Precipitated proteins were separated by SDS-polyacrylamide gel
electrophoresis on 10% gels. Gels were fluorographed and visualized by
autoradiography.
-galactosidase activity. The
mutants 9 and 19, which lack the COOH-terminal 9 and 19 amino
acids, respectively, associated with TRAF2, TRAF1, and CRAF1.
Interestingly, yeast coexpressing the 19 mutant and TRAF1
reproducibly did not grow as well or express as much -galactosidase
as wild type or the 9 mutation (Figs. 3B and
4C and data not shown), suggesting that
although it can interact with TRAF1, the 19 mutant has a lower
affinity for TRAF1. Mutants 36, 71, and 124 did not interact
with either TRAF2, TRAF1, or CRAF1. These data indicate that the domain
of CD30 required for interaction with these proteins lies within the
COOH-terminal 36 amino acids.
Fig. 3.
Effects of carboxyl-terminal and
amino-terminal deletions on the ability of the CD30 cytoplasmic domain
to associate with TRAF proteins. A, schematics depicting the
structures of wild type (wt) and the various COOH-terminal
CD30 deletions. The deletion mutants were constructed as described
under ``Materials and Methods.'' B, -galactosidase
filter assay from the yeast two-hybrid assay using the COOH-terminal
deletion mutants. The yeast were cotransformed with plasmids expressing
the GAL4 DNA-binding domain fused to wild type (wt) or
deleted CD30 cytoplasmic domain and plasmids expressing the GAL4
activation domain fused to TRAF2, TRAF1, or CRAF1 as described under
``Materials and Methods.'' These results are representative of at
least three independent experiments. C, schematics depicting
the structures of the NH2-terminal deletions of the CD30
cytoplasmic domain (left) and the results of the yeast
two-hybrid assays with these constructs (right). These
results are representative of at least three independent experiments.
WT, wild type.
Fig. 4.
Deletion analysis of the carboxyl-terminal 36
amino acids of CD30. A, computer alignment of the
COOH-terminal region of CD30 with the cytoplasmic domain of CD40. The
shaded boxes indicate the two regions of highest homology.
The alignment was performed with the BESTFIT program (Genetics Computer
Group, University of Wisconsin). B, schematics of the
structures of the various internal and COOH-terminal mutants. The
19 and 9 mutants were described in Fig. 3A. The
PEQET mutation deletes the homology to the site in CD40 that
contains the threonine residue (Thr254) previously shown to
be required for binding to CRAF1 (30). Construction of PEQET,
PEQET/19, and PEQET/9 is described under ``Materials
and Methods.'' C, -galactosidase filter assay from the
yeast two-hybrid assay. Identical results for -galactosidase
activity were obtained using plates lacking leucine and tryptophan. The
results shown are representative of three independent experiments.
WT, wild type.
N96, N117, and N146, respectively) of the CD30
cytoplasmic domain were also constructed and tested in the yeast
two-hybrid assay for the ability to interact with the TRAF proteins
(Fig. 3C). Yeast were cotransformed with the vectors
expressing the individual NH2-terminal mutations and
vectors expressing the TRAF proteins and then assayed for growth on
medium lacking histidine and containing 3-AT and for -galactosidase
activity. The empty pACT vector, which expresses only the GAL4
transcriptional activation domain, was also tested to rule out the
possibility that the CD30 NH2-terminal mutations could
activate transcription in the absence of an interaction with the TRAF
proteins. As shown in Fig. 3C, all of the
NH2-terminal mutants, including N146, which encodes only
the COOH-terminal 42 amino acids of CD30, were capable of interacting
with TRAF1, TRAF2, and CRAF1 but not the GAL4 activation domain (pACT)
alone. This correlates with the data obtained from the COOH-terminal
deletion analysis and indicates that the COOH-terminal 42 amino acids
of CD30 are necessary and sufficient for binding to TRAF1, TRAF2, and
CRAF1.
36 mutant (Fig.
4A), which failed to bind TRAF2, TRAF1, and CRAF1. The
second region of homology is a 6-amino acid stretch with the sequence
EEEGKE. This sequence is contained in the 9 mutant but is deleted in
the 19 mutant (Fig. 4, A and B). As noted
above, both the 9 and 19 constructs were capable of interacting
with all of the TRAF proteins in a yeast two-hybrid assay (Fig.
3B). This suggested that the 10-amino acid sequence between
the 9 and 19 mutations, which contains the EEEGKE sequence, is
not required for binding and that the PEQET sequence is most likely the
domain involved in binding to the TRAF proteins.
PEQET)
lacking the amino acid sequence PEQET in the context of the wild type
CD30 cytoplasmic domain was constructed and then analyzed in a yeast
two-hybrid assay for its ability to interact with the TRAF proteins
(Fig. 4C). The PEQET mutant failed to bind CRAF1,
indicating that this sequence is necessary for CRAF1 binding.
Individual alanine substitutions for each of the residues conserved in
CD40 (i.e. Pro, Gln, Glu, and Thr) also abolished the
ability of CD30 to bind to CRAF1 in the yeast two-hybrid assay (not
shown). Surprisingly, the PEQET mutant interacted with both TRAF1
and TRAF2, suggesting that these amino acids were either not involved
or not absolutely required in the binding of either of these proteins.
This result suggested two possibilities. One was that the TRAF1 and
TRAF2 binding site(s) were contained in the remaining sequences between
the 36 and 19 mutations. However, these sequences share no
homology to CD40. Another possibility was that there were two binding
sites for TRAF1 and TRAF2 in the COOH-terminal 36 amino acids of CD30
and that each site alone was capable of binding either TRAF1 or TRAF2
independent of the other. We tested the second possibility by combining
the PEQET mutation with the 9 and the 19 mutations (Fig.
4B) and testing for TRAF binding in yeast.
PEQET nor the 19
mutations alone abolished TRAF1 or TRAF2 binding. However, the
PEQET/19 mutant, which lacks both regions of homology to CD40,
did not bind either TRAF1 or TRAF2. In contrast, the PEQET/9
mutation had no effect on either TRAF1 or TRAF2 binding. These data
indicate that the region between the 9 and 19 mutations, which
contains the EEEGKE sequence, contains a second binding site for TRAF1
and TRAF2 that can function independently from the PEQET sequence. As
seen in Figs. 3B and 4C, TRAF1 does not interact
with the 19 mutant as well as wild type or 9, as judged by the
-galactosidase activities. This suggests that although TRAF1 is
capable of interacting with either the PEQET or the EEEGKE sites in
yeast, it prefers the EEEGKE site. These results are summarized in Fig.
5.
Fig. 5.
Results of the CD30 mutational analysis.
The drawing at the top represents the full-length CD30
cytoplasmic domain. Shown are the two regions of highest homology to
CD40. The black bars represent the regions of CD30 required
for strong binding to TRAF2, TRAF1, and CRAF1. The hatched
bar represents weaker binding.
B transcription
factor (27, 39, 43, 44), and these abilities appear to correlate at
least in part with their ability to bind TRAF proteins (27, 37). The
domain of TNFR type 2 required for induction of NF-B is also
required for its ability to coprecipitate TRAF1 and TRAF2 (27). The
role of TRAF2 in TNFR type 2 signal transduction is further supported
by the observation that the overexpression of TRAF2 can induce NF-B
(37). Threonine 254 in CD40 has been shown to be essential for
signaling (38), and a threonine to alanine substitution in this
position was found to abolish CRAF1 binding (26). In addition, the cell
survival function of CD40 (45) was found to correlate with its ability
to induce Bcl-xL expression (46), and a COOH-terminal
deletion of CD40, which removed the region containing threonine 254,
abolished the induction of Bcl-xL, suggesting that CRAF1
binding is required for this effect (47). Thus, the TRAF proteins
appear to play a role in regulating cell proliferation or survival.
CD30 has also been shown to regulate cellular proliferation and to
induce NF-B (5, 11, 22). Like CD40, CD30 can directly associate with
TRAF2 and CRAF1. Unlike TNFR type 2 and CD40, CD30 was also found to
directly associate with TRAF1. Previously, TRAF1 was only found to
associate indirectly with receptor proteins by forming heteromers with
TRAF2 (27). We also found that CD30 contained two independent binding
sites for the TRAF proteins and that these proteins had different
specificities for each site. CRAF1 binding was the most restricted
because it recognized only the domain containing the sequence PEQET.
TRAF1 was capable of binding to the cytoplasmic tail of CD30 through
either the PEQET domain or through the downstream domain, which
contains the sequence EEEGKE. However, TRAF1 formed a stronger
interaction with the EEEGKE-containing domain as measured by yeast
two-hybrid analysis. TRAF2 was the most promiscuous of the three
proteins, binding well to either site. The ability of CD30 to bind
directly to TRAF1 suggests a mechanism by which CD30 can mediate novel
signaling effects. Furthermore, these data indicate that the TRAF
protein binding pattern of CD30 differs from that of other members of
the TNF receptor family. This suggests that the signaling specificity
of these receptors may be determined by their ability to bind different
combinations of TRAF proteins.
B in cotransfection assays
without affecting its ability to bind TNFR type 2 or CD40 (37). Thus,
the NH2 termini of TRAF proteins appear to be involved in
signal transduction. The NH2 terminus of TRAF1 is the most
divergent in the TRAF family, suggesting that TRAF1 may have signaling
properties that are different than TRAF2 or CRAF1. Furthermore, TRAF1
has a more restricted tissue distribution relative to TRAF2 or CRAF1.
Like CD30, TRAF1 appears to be expressed primarily in lymphoid tissues
(27, 32).
To whom correspondence should be addressed: University of
Chicago, Gwen Knapp Center, 924 E. 57th St., Rm. R413A, Chicago, IL
60637-5420. Tel.: 312-702-4360; Fax: 312-702-1576.
1
The abbreviations used are: TNF, tumor necrosis
factor; TRAF, tumor necrosis factor receptor-associated factor; GST,
glutathione S-transferase; PCR, polymerase chain reaction;
CD30 cyto, cytoplasmic domain of CD30; 3-AT, 3-aminotriazole; TNFR, TNF
receptor.
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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 C. W. Wright, J. M. Rumble, and C. S. Duckett CD30 Activates Both the Canonical and Alternative NF-{kappa}B Pathways in Anaplastic Large Cell Lymphoma Cells J. Biol. Chem., April 6, 2007; 282(14): 10252 - 10262. [Abstract] [Full Text] [PDF]
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 E. M. Esparza and R. H. Arch Glucocorticoid-Induced TNF Receptor, a Costimulatory Receptor on Naive and Activated T Cells, Uses TNF Receptor-Associated Factor 2 in a Novel Fashion as an Inhibitor of NF-{kappa}B Activation J. Immunol., June 15, 2005; 174(12): 7875 - 7882. [Abstract] [Full Text] [PDF]
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J. C. Wilkinson, B. W. M. Richter, A. S. Wilkinson, E. Burstein, J. M. Rumble, B. Balliu, and C. S. Duckett VIAF, a Conserved Inhibitor of Apoptosis (IAP)-interacting Factor That Modulates Caspase Activation J. Biol. Chem., December 3, 2004; 279(49): 51091 - 51099. [Abstract] [Full Text] [PDF]
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 H. M. Toennies, J. M. Green, and R. H. Arch Expression of CD30 and Ox40 on T lymphocyte subsets is controlled by distinct regulatory mechanisms J. Leukoc. Biol., February 1, 2004; 75(2): 350 - 357. [Abstract] [Full Text] [PDF]
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 M. Watanabe, Y. Ogawa, K. Ito, M. Higashihara, M. E. Kadin, L. J. Abraham, T. Watanabe, and R. Horie AP-1 Mediated Relief of Repressive Activity of the CD30 Promoter Microsatellite in Hodgkin and Reed-Sternberg Cells Am. J. Pathol., August 1, 2003; 163(2): 633 - 641. [Abstract] [Full Text] [PDF]
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F. Henkler, B. Baumann, M. Fotin-Mleczek, M. Weingartner, R. Schwenzer, N. Peters, A. Graness, T. Wirth, P. Scheurich, J. A. Schmid, et al. Caspase-mediated Cleavage Converts the Tumor Necrosis Factor (TNF) Receptor-associated Factor (TRAF)-1 from a Selective Modulator of TNF Receptor Signaling to a General Inhibitor of NF-{kappa}B Activation J. Biol. Chem., August 1, 2003; 278(31): 29216 - 29230. [Abstract] [Full Text] [PDF]
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H. Harlin, E. Podack, M. Boothby, and M.-L. Alegre TCR-Independent CD30 Signaling Selectively Induces IL-13 Production Via a TNF Receptor-Associated Factor/p38 Mitogen-Activated Protein Kinase-Dependent Mechanism J. Immunol., September 1, 2002; 169(5): 2451 - 2459. [Abstract] [Full Text] [PDF]
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R. Horie, T. Watanabe, K. Ito, Y. Morisita, M. Watanabe, T. Ishida, M. Higashihara, M. Kadin, and T. Watanabe Cytoplasmic Aggregation of TRAF2 and TRAF5 Proteins in the Hodgkin-Reed-Sternberg Cells Am. J. Pathol., May 1, 2002; 160(5): 1647 - 1654. [Abstract] [Full Text] [PDF]
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N. S. Chandel, P. T. Schumacker, and R. H. Arch Reactive Oxygen Species Are Downstream Products of TRAF-mediated Signal Transduction J. Biol. Chem., November 9, 2001; 276(46): 42728 - 42736. [Abstract] [Full Text] [PDF]
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S. S. Mir, B. W. M. Richter, and C. S. Duckett Differential effects of CD30 activation in anaplastic large cell lymphoma and Hodgkin disease cells Blood, December 15, 2000; 96(13): 4307 - 4312. [Abstract] [Full Text] [PDF]
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A. L. DeYoung, O. Duramad, and A. Winoto The TNF Receptor Family Member CD30 Is Not Essential for Negative Selection J. Immunol., December 1, 2000; 165(11): 6170 - 6173. [Abstract] [Full Text] [PDF]
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J. M. Zapata, M. Krajewska, S. Krajewski, S. Kitada, K. Welsh, A. Monks, N. McCloskey, J. Gordon, T. J. Kipps, R. D. Gascoyne, et al. TNFR-Associated Factor Family Protein Expression in Normal Tissues and Lymphoid Malignancies J. Immunol., November 1, 2000; 165(9): 5084 - 5096. [Abstract] [Full Text] [PDF]
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H. Muta, L. H. Boise, L. Fang, and E. R. Podack CD30 Signals Integrate Expression of Cytotoxic Effector Molecules, Lymphocyte Trafficking Signals, and Signals for Proliferation and Apoptosis J. Immunol., November 1, 2000; 165(9): 5105 - 5111. [Abstract] [Full Text] [PDF]
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 J.-K. Choi, S. Ishido, and J. U. Jung The Collagen Repeat Sequence Is a Determinant of the Degree of Herpesvirus Saimiri STP Transforming Activity J. Virol., September 1, 2000; 74(17): 8102 - 8110. [Abstract] [Full Text]
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A. Hatzoglou, J. Roussel, M.-F. Bourgeade, E. Rogier, C. Madry, J. Inoue, O. Devergne, and A. Tsapis TNF Receptor Family Member BCMA (B Cell Maturation) Associates with TNF Receptor-Associated Factor (TRAF) 1, TRAF2, and TRAF3 and Activates NF-{kappa}B, Elk-1, c-Jun N-Terminal Kinase, and p38 Mitogen-Activated Protein Kinase J. Immunol., August 1, 2000; 165(3): 1322 - 1330. [Abstract] [Full Text] [PDF]
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 H. Ye and H. Wu Thermodynamic characterization of the interaction between TRAF2 and tumor necrosis factor receptor peptides by isothermal titration calorimetry PNAS, July 19, 2000; (2000) 160241997. [Abstract] [Full Text]
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T. Tatsuta, A. Shiraishi, and J. D. Mountz The Prodomain of Caspase-1 Enhances Fas-mediated Apoptosis through Facilitation of Caspase-8 Activation J. Biol. Chem., May 5, 2000; 275(19): 14248 - 14254. [Abstract] [Full Text] [PDF]
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M. E. Kadin Regulation of CD30 Antigen Expression and Its Potential Significance for Human Disease Am. J. Pathol., May 1, 2000; 156(5): 1479 - 1484. [Full Text] [PDF]
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R. Horie, V. Gattei, K. Ito, S. Imajo-Ohmi, T. Tange, J. Miyauchi, A. Pinto, M. Degan, A. De Iuliis, F. Tassan Mazzocco, et al. Frequent Expression of the Variant CD30 in Human Malignant Myeloid and Lymphoid Neoplasms Am. J. Pathol., December 1, 1999; 155(6): 2029 - 2041. [Abstract] [Full Text] [PDF]
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M. Mori, C. Manuelli, N. Pimpinelli, C. Mavilia, E. Maggi, M. Santucci, B. Bianchi, P. Cappugi, B. Giannotti, and M.E. Kadin CD30-CD30 Ligand Interaction in Primary Cutaneous CD30+ T-Cell Lymphomas: A Clue to the Pathophysiology of Clinical Regression Blood, November 1, 1999; 94(9): 3077 - 3083. [Abstract] [Full Text] [PDF]
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Y. Matsumura, T. Hori, S. Kawamata, A. Imura, and T. Uchiyama Intracellular Signaling of gp34, the OX40 Ligand: Induction of c-jun and c-fos mRNA Expression Through gp34 upon Binding of Its Receptor, OX40 J. Immunol., September 15, 1999; 163(6): 3007 - 3011. [Abstract] [Full Text] [PDF]
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E. Leo, K. Welsh, S.-i. Matsuzawa, J. M. Zapata, S. Kitada, R. S. Mitchell, K. R. Ely, and J. C. Reed Differential Requirements for Tumor Necrosis Factor Receptor-associated Factor Family Proteins in CD40-mediated Induction of NF-kappa B and Jun N-terminal Kinase Activation J. Biol. Chem., August 6, 1999; 274(32): 22414 - 22422. [Abstract] [Full Text] [PDF]
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R. Schwenzer, K. Siemienski, S. Liptay, G. Schubert, N. Peters, P. Scheurich, R. M. Schmid, and H. Wajant The Human Tumor Necrosis Factor (TNF) Receptor-associated Factor 1 Gene (TRAF1) Is Up-regulated by Cytokines of the TNF Ligand Family and Modulates TNF-induced Activation of NF-kappa B and c-Jun N-terminal Kinase J. Biol. Chem., July 2, 1999; 274(27): 19368 - 19374. [Abstract] [Full Text] [PDF]
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R. Chiarle, A. Podda, G. Prolla, E. R. Podack, G. J. Thorbecke, and G. Inghirami CD30 Overexpression Enhances Negative Selection in the Thymus and Mediates Programmed Cell Death Via a Bcl-2-Sensitive Pathway J. Immunol., July 1, 1999; 163(1): 194 - 205. [Abstract] [Full Text] [PDF]
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H. Lee, J.-K. Choi, M. Li, K. Kaye, E. Kieff, and J. U. Jung Role of Cellular Tumor Necrosis Factor Receptor-Associated Factors in NF-kappa B Activation and Lymphocyte Transformation by Herpesvirus Saimiri STP J. Virol., May 1, 1999; 73(5): 3913 - 3919. [Abstract] [Full Text]
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N. Tsukamoto, N. Kobayashi, S. Azuma, T. Yamamoto, and J.-i. Inoue Two differently regulated nuclear factor kappa B activation pathways triggered by the cytoplasmic tail of CD40 PNAS, February 16, 1999; 96(4): 1234 - 1239. [Abstract] [Full Text] [PDF]
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 H. WU, Y.C. PARK, H. YE, and L. TONG Structural Studies of Human TRAF2 Cold Spring Harb Symp Quant Biol, January 1, 1999; 64(0): 541 - 550. [Abstract] [PDF]
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L. Galibert, M. E. Tometsko, D. M. Anderson, D. Cosman, and W. C. Dougall The Involvement of Multiple Tumor Necrosis Factor Receptor (TNFR)-associated Factors in the Signaling Mechanisms of Receptor Activator of NF-kappa B, a Member of the TNFR Superfamily J. Biol. Chem., December 18, 1998; 273(51): 34120 - 34127. [Abstract] [Full Text] [PDF]
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H. Yamamoto, T. Kishimoto, and S. Minamoto NF-{kappa}B Activation in CD27 Signaling: Involvement of TNF Receptor-Associated Factors in Its Signaling and Identification of Functional Region of CD27 J. Immunol., November 1, 1998; 161(9): 4753 - 4759. [Abstract] [Full Text] [PDF]
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B. R. Wong, R. Josien, S. Y. Lee, M. Vologodskaia, R. M. Steinman, and Y. Choi The TRAF Family of Signal Transducers Mediates NF-kappa B Activation by the TRANCE Receptor J. Biol. Chem., October 23, 1998; 273(43): 28355 - 28359. [Abstract] [Full Text] [PDF]
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 R. H. Arch, R. W. Gedrich, and C. B. Thompson Tumor necrosis factor receptor-associated factors (TRAFs)---a family of adapter proteins that regulates life and death Genes & Dev., September 15, 1998; 12(18): 2821 - 2830. [Full Text]
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W. Min, J. R. Bradley, J. J. Galbraith, S. J. Jones, E. C. Ledgerwood, and J. S. Pober The N-Terminal Domains Target TNF Receptor-Associated Factor-2 to the Nucleus and Display Transcriptional Regulatory Activity J. Immunol., July 1, 1998; 161(1): 319 - 324. [Abstract] [Full Text] [PDF]
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 K. Saoulli, S. Y. Lee, J. L. Cannons, W. C. Yeh, A. Santana, M. D. Goldstein, N. Bangia, M. A. DeBenedette, T. W. Mak, Y. Choi, et al. CD28-independent, TRAF2-dependent Costimulation of Resting T Cells by 4-1BB Ligand J. Exp. Med., June 1, 1998; 187(11): 1849 - 1862. [Abstract] [Full Text] [PDF]
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H. Akiba, H. Nakano, S. Nishinaka, M. Shindo, T. Kobata, M. Atsuta, C. Morimoto, C. F. Ware, N. L. Malinin, D. Wallach, et al. CD27, a Member of the Tumor Necrosis Factor Receptor Superfamily, Activates NF-kappa B and Stress-activated Protein Kinase/c-Jun N-terminal Kinase via TRAF2, TRAF5, and NF-kappa B-inducing Kinase J. Biol. Chem., May 22, 1998; 273(21): 13353 - 13358. [Abstract] [Full Text] [PDF]
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 W. E. Miller, J. L. Cheshire, and N. Raab-Traub Interaction of Tumor Necrosis Factor Receptor-Associated Factor Signaling Proteins with the Latent Membrane Protein 1 PXQXT Motif Is Essential for Induction of Epidermal Growth Factor Receptor Expression Mol. Cell. Biol., May 1, 1998; 18(5): 2835 - 2844. [Abstract] [Full Text]
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H. Nakano, M. Shindo, S. Sakon, S. Nishinaka, M. Mihara, H. Yagita, and K. Okumura Differential regulation of Ikappa B kinase alpha and beta by two upstream kinases, NF-kappa B-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1 PNAS, March 31, 1998; 95(7): 3537 - 3542. [Abstract] [Full Text] [PDF]
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S. Kawamata, T. Hori, A. Imura, A. Takaori-Kondo, and T. Uchiyama Activation of OX40 Signal Transduction Pathways Leads to Tumor Necrosis Factor Receptor-associated Factor (TRAF) 2- and TRAF5-mediated NF-kappa B Activation J. Biol. Chem., March 6, 1998; 273(10): 5808 - 5814. [Abstract] [Full Text] [PDF]
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M. C. Gilfillan, P. J. Noel, E. R. Podack, S. L. Reiner, and C. B. Thompson Expression of the Costimulatory Receptor CD30 Is Regulated by Both CD28 and Cytokines J. Immunol., March 1, 1998; 160(5): 2180 - 2187. [Abstract] [Full Text] [PDF]
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R. Brink and H. F. Lodish Tumor Necrosis Factor Receptor (TNFR)-associated Factor 2A (TRAF2A), a TRAF2 Splice Variant with an Extended RING Finger Domain That Inhibits TNFR2-mediated NF-kappa B Activation J. Biol. Chem., February 13, 1998; 273(7): 4129 - 4134. [Abstract] [Full Text] [PDF]
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M. Kashiwada, Y. Shirakata, J.-I. Inoue, H. Nakano, K. Okazaki, K. Okumura, T. Yamamoto, H. Nagaoka, and T. Takemori Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) Stimulates Extracellular Signal-regulated Kinase (ERK) Activity in CD40 Signaling Along a Ras-independent Pathway J. Exp. Med., January 19, 1998; 187(2): 237 - 244. [Abstract] [Full Text] [PDF]
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R. H. A. a. C. B. Thompson 4-1BB and Ox40 Are Members of a Tumor Necrosis Factor (TNF)-Nerve Growth Factor Receptor Subfamily That Bind TNF Receptor-Associated Factors and Activate Nuclear Factor kappa B Mol. Cell. Biol., January 1, 1998; 18(1): 558 - 565. [Abstract] [Full Text]
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W. R. Force, T. C. Cheung, and C. F. Ware Dominant Negative Mutants of TRAF3 Reveal an Important Role for the Coiled Coil Domains in Cell Death Signaling by the Lymphotoxin-beta Receptor J. Biol. Chem., December 5, 1997; 272(49): 30835 - 30840. [Abstract] [Full Text] [PDF]
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C. S. Duckett and C. B. Thompson CD30-dependent degradation of TRAF2: implications for negative regulation of TRAF signaling and the control of cell survival Genes & Dev., November 1, 1997; 11(21): 2810 - 2821. [Abstract] [Full Text] [PDF]
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H. Y. Song, C. H. Regnier, C. J. Kirschning, D. V. Goeddel, and M. Rothe Tumor necrosis factor (TNF)-mediated kinase cascades: Bifurcation of Nuclear Factor-kappa B and c-jun N-terminal kinase (JNK/SAPK) pathways at TNF receptor-associated factor 2 PNAS, September 2, 1997; 94(18): 9792 - 9796. [Abstract] [Full Text] [PDF]
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D. E. Speiser, S. Y. Lee, B. Wong, J. Arron, A. Santana, Y.-Y. Kong, P. S. Ohashi, and Y. Choi A Regulatory Role for TRAF1 in Antigen-induced Apoptosis of T Cells J. Exp. Med., May 19, 1997; 185(10): 1777 - 1783. [Abstract] [Full Text] [PDF]
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S. Y. Lee, S. Y. Lee, and Y. Choi TRAF-interacting Protein (TRIP): A Novel Component of the Tumor Necrosis Factor Receptor (TNFR)- and CD30-TRAF Signaling Complexes That Inhibits TRAF2-mediated NF-kappa B Activation J. Exp. Med., April 7, 1997; 185(7): 1275 - 1286. [Abstract] [Full Text] [PDF]
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T. L. VanArsdale, S. L. VanArsdale, W. R. Force, B. N. Walter, G. Mosialos, E. Kieff, J. C. Reed, and C. F. Ware Lymphotoxin-beta receptor signaling complex: Role of tumor necrosis factor receptor-associated factor 3 recruitment in cell death and activation of nuclear factor kappa B PNAS, March 18, 1997; 94(6): 2460 - 2465. [Abstract] [Full Text] [PDF]
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E. N. Tsitsikov, D. A. Wright, and R. S. Geha CD30 induction of human immunodeficiency virus gene transcription is mediated by TRAF2 PNAS, February 18, 1997; 94(4): 1390 - 1395. [Abstract] [Full Text] [PDF]
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K. M. Izumi, K. M. Kaye, and E. D. Kieff The Epstein-Barr virus LMP1 amino acid sequence that engages tumor necrosis factor receptor associated factors is critical for primary B lymphocyte growth transformation PNAS, February 18, 1997; 94(4): 1447 - 1452. [Abstract] [Full Text] [PDF]
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S. Aizawa, H. Nakano, T. Ishida, R. Horie, M. Nagai, K. Ito, H. Yagita, K. Okumura, J. Inoue, and T. Watanabe Tumor Necrosis Factor Receptor-associated Factor (TRAF) 5and TRAF2 Are Involved in CD30-mediated NFkappa B Activation J. Biol. Chem., January 24, 1997; 272(4): 2042 - 2045. [Abstract] [Full Text] [PDF]
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S. Ansieau, I. Scheffrahn, G. Mosialos, H. Brand, J. Duyster, K. Kaye, J. Harada, B. Dougall, G. Hubinger, E. Kieff, et al. Tumor necrosis factor receptor-associated factor (TRAF)-1, TRAF-2, and TRAF-3 interact in vivo with the CD30 cytoplasmic domain; TRAF-2 mediates CD30-induced nuclear factor kappa B activation PNAS, November 26, 1996; 93(24): 14053 - 14058. [Abstract] [Full Text] [PDF]
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S. Pype, W. Declercq, A. Ibrahimi, C. Michiels, J. G. I. Van Rietschoten, N. Dewulf, M. de Boer, P. Vandenabeele, D. Huylebroeck, and J. E. Remacle TTRAP, a Novel Protein That Associates with CD40, Tumor Necrosis Factor (TNF) Receptor-75 and TNF Receptor-associated Factors (TRAFs), and That Inhibits Nuclear Factor-kappa B Activation J. Biol. Chem., June 9, 2000; 275(24): 18586 - 18593. [Abstract] [Full Text] [PDF]
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E. Leo, Q. L. Deveraux, C. Buchholtz, K. Welsh, S.-i. Matsuzawa, H. R. Stennicke, G. S. Salvesen, and J. C. Reed TRAF1 Is a Substrate of Caspases Activated during Tumor Necrosis Factor Receptor-alpha -induced Apoptosis J. Biol. Chem., March 9, 2001; 276(11): 8087 - 8093. [Abstract] [Full Text] [PDF]
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J. M. Zapata, K. Pawlowski, E. Haas, C. F. Ware, A. Godzik, and J. C. Reed A Diverse Family of Proteins Containing Tumor Necrosis Factor Receptor-associated Factor Domains J. Biol. Chem., June 22, 2001; 276(26): 24242 - 24252. [Abstract] [Full Text] [PDF]
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H. Ye and H. Wu Thermodynamic characterization of the interaction between TRAF2 and tumor necrosis factor receptor peptides by isothermal titration calorimetry PNAS, August 1, 2000; 97(16): 8961 - 8966. [Abstract] [Full Text] [PDF]
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