Hindawi Publishing Corporation
Journal of Signal Transduction
Volume 2012, Article ID 376470, 10 pages
doi:10.1155/2012/376470
Research Article
A Bioinformatics Resource for TWEAK-Fn14 Signaling Pathway
Mitali Bhattacharjee,1, 2 Rajesh Raju,1, 3 Aneesha Radhakrishnan,1, 4 Vishalakshi Nanjappa,1, 2
Babylakshmi Muthusamy,1, 5 Kamlendra Singh,5 Dheebika Kuppusamy,5
Bhavya Teja Lingala,5 Archana Pan,5 Premendu Prakash Mathur,4, 5 H. C. Harsha,1
T. S. Keshava Prasad,1, 2, 5 Gerald J. Atkins,6 Akhilesh Pandey,7, 8, 9, 10 and Aditi Chatterjee1
1
Institute of Bioinformatics, International Tech Park, Bangalore 560066, India
Amrita School of Biotechnology, Amrita University, Kollam 690525, India
3 Department of Biotechnology, Kuvempu University, Shankaraghatta 577451, India
4 Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry 605014, India
5 Centre of Excellence in Bioinformatics, School of Life Sciences, Pondicherry University, Puducherry 605014, India
6 Bone Cell Biology Group, Discipline of Orthopaedics and Trauma, University of Adelaide and The Hanson Institute,
Adelaide, 5002 SA, Australia
7 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
8 Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
9 Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
10 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2
Correspondence should be addressed to Aditi Chatterjee, aditi@ibioinformatics.org
Received 22 December 2011; Accepted 3 February 2012
Academic Editor: A. Yoshimura
Copyright © 2012 Mitali Bhattacharjee et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
TNF-related weak inducer of apoptosis (TWEAK) is a new member of the TNF superfamily. It signals through TNFRSF12A,
commonly known as Fn14. The TWEAK-Fn14 interaction regulates cellular activities including proliferation, migration,
differentiation, apoptosis, angiogenesis, tissue remodeling and inflammation. Although TWEAK has been reported to be associated
with autoimmune diseases, cancers, stroke, and kidney-related disorders, the downstream molecular events of TWEAK-Fn14
signaling are yet not available in any signaling pathway repository. In this paper, we manually compiled from the literature, in
particular those reported in human systems, the downstream reactions stimulated by TWEAK-Fn14 interactions. Our manual
amassment of the TWEAK-Fn14 pathway has resulted in cataloging of 46 proteins involved in various biochemical reactions and
TWEAK-Fn14 induced expression of 28 genes. We have enabled the availability of data in various standard exchange formats
from NetPath, a repository for signaling pathways. We believe that this composite molecular interaction pathway will enable
identification of new signaling components in TWEAK signaling pathway. This in turn may lead to the identification of potential
therapeutic targets in TWEAK-associated disorders.
1. Introduction
TWEAK (TNFSF12) is a cell surface-associated type II transmembrane protein (249 amino acids) belonging to the
Tumor Necrosis Factor (TNF) superfamily [1]. Transmembrane TWEAK is processed into a secreted 156-aminoacid form, which adopts a homotrimeric conformation. The
human TWEAK gene is located at chromosome 17p13.1 [1].
TWEAK mRNA has been reported to be expressed in
several tissue types, such as heart [2], brain [3, 4], kidney
[5, 6], and also in mononuclear blood cells [7]. Its protein
product has multiple biological activities, including stimulation of cell growth and angiogenesis [8], induction of
inflammatory cytokines [9, 10] and stimulation of apoptosis
[11, 12]. It has been shown to be involved in the induction
of cellular proliferation in liver cells [13], osteoblasts [14],
2
astrocytes [15], synoviocytes [16], kidney cells [17, 18], and
skeletal muscle [19]. TWEAK may also play a role in the cellular differentiation of osteoclasts; however it remains controversial whether this effect is direct [20] or indirect, via
effects on the osteoblastic stromal cell expression of RANKL
(TNFSF11) [21]. TWEAK also plays a role in inducing
glioma cell survival via imparting resistance to cytotoxic
agents [3, 22]. TWEAK serves a dual role in angiogenic regulation. It induces the endothelial cell survival and can be
a potential proangiogenic or antiangiogenic agent based
upon the presence of angiogenic promoting cytokines [8,
23]. Additionally, an apoptotic effect of TWEAK has been
observed in endometrial cancers [24] and peripheral blood
monocytes [25, 26]. The apoptotic function of TWEAK appears to be mediated via the induced secretion of TNFα,
with the TNFα-TNFα receptor complex, thereafter inducing
autocrine cellular apoptosis by activating the RIPK1-FADDCaspase-8 complex [11, 27]. TWEAK was first described as
an apoptotic factor by interacting with DR3 (TNFRSF25).
However, there were conflicting reports to the TWEAK-DR3
interaction [28, 29]. Hence, we chose to exclude TWEAKDR3 pathway analysis from our study. In addition, TWEAK
has been reported to interact with CD163 [30]; however, the
downstream effect of this interaction remains to be explored.
TNFRSF12A (tumor necrosis factor receptor superfamily, member 12A), also known as FGF-inducible 14 (Fibroblast Growth Factor-Inducible-14/Fn14), has been established to date to be the major, if not sole, receptor for
TWEAK [12, 31, 32]. Fn14 is the smallest member of the
TNFR superfamily described so far, and it appears to signal
via recruitment of several different TNFR-associated factors
[33]. This molecule has been reported to be expressed in
variety of organs including the heart [34, 35], kidney [6, 36],
and lung [37]. The cytoplasmic domain of Fn14, like other
members of the TNFR superfamily, does not contain consensus amino acid sequences characteristic of domains with
enzymatic activity. TWEAK binds with high affinity to
Fn14 [12, 31]. This interaction can stimulate a variety of
biological responses, depending on the cell type analyzed.
Winkles et al. (2008) hypothesized two modes of TWEAKFn14 (ligand-receptor) interaction: (i) the ligand-dependent
interaction, which involves the higher concentration of
homotrimeric TWEAK, that binds to low concentration of
Fn14 in a heterohexameric complex [38, 39], and (ii) ligandindependent interaction when the ligand concentration
is lower than the receptor concentration. Here, the free
receptors homotrimerize to activate the downstream events
[38]. Three notable signaling cascades have been reported
under TWEAK-Fn14 interactions. They are the canonical
and noncanonical NF-κB pathways [21, 33, 34, 40] and
the MAPK pathway [41–43] with possible binding to TRAF
proteins.
The differential effects of TWEAK on disease pathogenesis have been proposed by various groups. These diseases
include autoimmune disorders [16, 21, 44, 45], neurological
disorders [46, 47], periodontal disease [7], and cancers [3,
22, 24, 48–50]. Because of its multifunctional properties,
TWEAK is also being considered for use in therapeutics [51].
Journal of Signal Transduction
It is also being considered as a potential early and prognostic
biomarker for conditions such as kidney injury [52, 53], SLE
[54], atherosclerosis [55, 56], cardiovascular disorders [57–
59], immune preconception marker [60], and abdominal
aortic aneurysms [61]. Although the results obtained to
date are captivating, it is clear that additional studies are
required to determine whether TWEAK, and/or Fn14 could
be novel molecular targets for developing anticancer and
antiautoimmune therapeutic agents in humans.
Thus, given its importance in the field of biomedical
research, we carried out an extensive and iterative compilation of TWEAK-Fn14 signaling pathway by literature
mining. Information gathered on protein-protein interactions, posttranslational modifications, protein transportation events, and regulation of gene expression, which are
stimulated by TWEAK were compiled into a signaling pathway using a visualization tool, PathVisio [62]. Our compiled
data will be useful for the scientific community to explore,
further, the role of TWEAK in differential disease pathogenesis, in biomarker development. Using similar approach,
we have also developed signaling pathways on leptin [63]
receptor activator for nuclear factor κB ligand (RANKL) [64]
and follicle stimulating hormone (FSH) [65]. In the current
study, we have generated a reaction map of TWEAK signaling
pathway, which is available for visualization at NetSlim [66]
(http://www.netpath.org/netslim/), an accessory resource for
visualization of NetPath pathways [67].
2. Methods
PubMed searches were performed using TWEAK or Fn14
and their alternate names as keywords to retrieve relevant
articles pertaining to TWEAK signaling. The articles were
screened to capture molecular reactions stimulated by
TWEAK in mammalian cells as compared to the corresponding unstimulated state. Thereafter, with the use of an inhouse developed software, PathBuilder [68] that enables conversion of pathway data into standard community formats,
namely, PSI-MI, BioPAX, and SBML formats, we annotated
biological information and reactions pertaining to TWEAK
signaling. These included protein-protein interactions,
enzyme-substrate reactions, gene regulation events, and also
various activation/inhibition reactions under a TWEAK
stimulus. These data after manual revision were exported to
the NetPath database, (http://www.netpath.org/), a manually
assembled resource for signaling pathways generated by our
group [67] which provides the criteria for data compilation.
The entire workflow is briefly summarized in Figure 1.
2.1. Protein-Protein Interactions. The protein-protein interactions gathered from several experimental platforms were
cataloged from literature into either binary or complex interactions. A binary interaction represents the interaction of
two proteins either in homomeric or heteromeric form.
A complex protein interaction comprises reactions involving more than two proteins, which again can be either
homomeric or in heteromeric. For every protein-protein
Journal of Signal Transduction
3
Screening research
articles on
TWEAK signaling
Proteinprotein
interactions
in mammalian
system
Enzyme
catalysis
in
mammalian
system
Activation/
inhibition
reactions in
mammalian
system
Protein
transport
in
mammalian
system
Genes
regulated
by TWEAK in
human
system
Data entry into PathBuilder
Internal review of pathway data
Filtered by NetSlim criteria
TWEAK
signaling
map
drawn using
PathVisio
Review of pathway data
by pathway authority
Conversion of pathway
data into PSI-MI, BioPAX,
and SBML file formats
Data uploaded to NetPath and NetSlim
Figure 1: Workflow of the study. Articles were screened based on TWEAK stimulus and the molecular events were added to PathBuilder.
Data were then transferred to NetPath repository. With the help of PathVisio tool, the reactions were used to generate the TWEAK signaling
map (http://www.netpath.org/netslim/tweak pathway.html).
interaction, we documented information on subcellular
localization, the experimental method used, the name and
species of cell models, and finally, the hyperlinked PubMed
identifier for the corresponding publication.
2.2. Catalytic Reactions. We compiled the posttranslational
modifications under TWEAK stimulus and mapped them
to their corresponding protein sequences in the RefSeq
database. Further, activation or inhibition of the substrate
4
in response to the stimulus was also compiled. The notable modifications chosen were phosphorylation, acetylation, ubiquitination, sumoylation, protein degradation, and
methylation. The mode of amassment was of two types,
direct and indirect. Direct included those reactions where the
enzyme has been reported for the specific type of protein
(substrate) modification. Indirect reactions include those
where the type of modification is experimentally proved;
however no information exists about its immediate upstream
enzyme. The features added for the enzyme-substrate reactions include the type of posttranslational modification, the
site and residue of each modification, the source of protein,
the species used, and cellular localizations of the respective
reaction. Additionally, we have incorporated a PubMed
identifier as a hyperlink pertaining to the reaction.
2.3. Activation-Inhibition Reactions. Several molecules, including the Caspases-3, -7, and -8 (CASP3, CASP7 and
CASP8) [24], JUN [20, 29, 69, 70], and NIK (MAP3K14)
[52, 71], were activated, whereas STAT1 was inhibited under
TWEAK stimulus [72]. These molecules do not abide by the
enzyme-substrate reactions and protein-protein interaction
parameters as described previously and thus cannot be connected directly to the main frame of the TWEAK pathway
and are referred to as orphan molecules. We have provided
the source of protein, subcellular localization, species, and
cell line in which the activation or inhibition event was
reported. The PubMed identifier hyperlinked for every event
was also provided.
2.4. Protein Translocation Events. Subcellular transportation
events of proteins under the influence of TWEAK reported
to date, with appropriate Gene Ontology terms, were added
into the PathBuilder tool. These events were selected on the
basis of the posttranslational modifications, physical interaction or regulatory events. A TWEAK stimulus resulting
in subcellular relocalization of proteins was evidenced by
fluorescent microscopy and immunohistochemical studies.
In addition to a particular protein’s altered localization, we
have also documented the source of protein and cell lines
used. The criteria followed were same as mentioned in the
earlier section.
2.5. Gene Expression Data. We have documented genes
whose expressions are regulated by the TWEAK-Fn14 signaling in humans. Such genes that have been identified by various groups at the mRNA level were catalogued from DNA
microarray and nonarray-based experiments such as Northern blotting, quantitative RT-PCR, or SAGE.
Further, we have included transcription regulators (transcription factors, or their coactivators/corepressors) downstream of TWEAK-Fn14 stimulus. Some of these transcription regulators are involved in the regulation of the genes
(mentioned above) upon TWEAK signaling. This too has
been documented and depicted in the pathway diagram.
Such transcriptional regulators have been identified by approaches such as chromatin immunoprecipitation assays,
Journal of Signal Transduction
electrophoretic mobility shift assays, gene silencing, and
promoter activity assays in TWEAK-Fn14 signaling.
2.6. Selection of Sample and Species Types. Data for proteinprotein interactions, catalytic reactions, and transportation
events were collected from diseased or normal mammalian
sources that include humans and their orthologs. However,
for the gene regulatory reactions, we considered normal
human cells only.
2.7. Generation of the TWEAK-Fn14 Pathway Map. The
manually assembled data in PathBuilder were compiled
and imported into NetPath (explained under methodology)
[67]. A composite map of pathway reactions pertaining
to TWEAK signaling were generated using PathVisio [62] by
following the NetSlim parameters as have been employed
earlier by our group [66]. NetSlim (http://www.netpath.org/
netslim/) is a tributary of NetPath, which projects or summarizes only stringent reactions pertaining to the specific
receptor-ligand complex compiled in a particular study,
for example, TWEAK in this case. The criteria for selecting
high confidence reactions for TWEAK pathway are provided in the NetSlim database (http://www.netpath.org/
netslim/criteria.html).
3. Results and Discussion
We show here for the first time in any scientific repository
a pathway illustration under TWEAK stimulus. Given the
multifunctional properties of TWEAK, we carried out a
comprehensive literature search under TWEAK stimulus
followed by manual amassment, thereafter reviewing and
adding the data into NetPath database [67].
3.1. TWEAK-Stimulated Data in NetPath. Fifty-eight articles were found relevant to our amassment criteria from
amongst 357 articles published between 1997 and 2011. This
study led to the documentation of 46 unique proteins amid
which 17 were associated with protein-protein interactions,
20 involved in enzyme-substrate reactions, 13 involved in
activation-inhibition reactions, and 8 were identified to be
translocated from cytoplasm to nucleus. There were 28 genes
identified to be differentially regulated under TWEAK stimulus in human systems. An overview of the TWEAK
pathway in “NetPath” is summarized in Figure 2, which
can be accessed from http://www.netpath.org/pathways?
path id=NetPath 26.
3.2. TWEAK-Stimulated Signaling Pathway under NetSlim.
The data for visualization of TWEAK signaling pathways
were obtained after filtering NetPath data using NetSlim
parameters. A total of 36 molecules involved in 42 reactions are visually depicted in the TWEAK pathway in
NetSlim. The map generated is provided in Figure 3 and
can be downloaded from http://www.netpath.org/netslim/
tweak pathway.html. The pathway illustration is also accessible at wikipathways from http://www.wikipathways.org/
index.php/Pathway:WP2036.
Journal of Signal Transduction
5
Link to NetSlim
Link to pathway authority details
Link to curator details
Link to feeback
Access
to data
Download pathway in
three standard
forms
Figure 2: Illustration of the TWEAK page in NetPath. The image provides an outline of the TWEAK pathway as visualized in the NetPath
webpage. The figure shows the statistical details of TWEAK pathway-based reactions (right upper corner). Under, “Molecules involved in
TWEAK signaling pathway”, each molecule has been linked to its respective NetPath page. Tabs have been provided which leads to the details
of the “pathway authority,” “curators,” and “comments” tab—where the users can provide their feedback and the reaction tabs. “Access to
data” indicates links to the events regulated by TWEAK. The pathway can be downloaded from the three standard formats provided at the
bottom of the page.
3.3. Data Availability and Reactions. The TWEAK data in
NetPath are available freely and can be used by the scientific
community. The data are represented in various standard
exchange formats that include Biological PAthway eXchange
(BioPAX) [73], Systems Biology Markup Language (SBML)
[74] and Proteomics Standards Initiative Molecular Interaction (PSI-MI) [75] language formats. The PSI-MI is a
community standard language for molecular interaction data
used for data comparison and exchange. However, SBML is
a machine readable format for representing biological
models. BioPAX is another standard language that has
features compatible with SBML and PSI-MI formats. The
TWEAK signaling representation can be downloaded from
the NetSlim database in various formats, such as “gpml”,
“GenMAPP”, “png”, and “pdf ”. The gene regulation data are
made available in tab-limited and Microsoft Excel formats.
3.4. Summary of the TWEAK Pathway Reactions. A pathway
module is defined as an established cascade of events that
takes place inside a cell that has no defined boundaries and is
part of a generic network. Some well-known modules are the
NF-κB, MAPK, the JNK pathways and the PI3K/AKT pathway modules. A schematic model of the TWEAK pathway
with identified pathway modules is represented in Figure 3.
6
Journal of Signal Transduction
TNFSF12
TNFSF12
TNF
TNFSF12
Ligand
Protein
Receptor
TNFRSF12A
TRAF3
P
Ubiquitin
proteosome
pathway
TRAF5
P
TRAF2
TRAF2 TRAF1
BIRC3
AKT2
FADD
RIPK1
BIRC2
EC
AKT1
RAC1
MAP3K7
Lysosomal
degradation
P
CY
Atrophy
CASP8
MAPK14
GSK3B
Stabilization
of MAP3K14
P
P
P
P
MAPK1
P
MAPK14
MAPK3
P
CTNNB1
DeP
P
CHUK
CHUK
CASP8
P
IKBKB
P
P
MAPK8
CASP3
NFκ-BIA
CASP7
NFκ-BIB
MAPK9
Enzyme complex
Protein-protein interaction
Protein-protein dissociation
Leads to through unknown mechanism
Positive regulation of gene expression
Negative regulationof gene expression
Auto catalysis
Acetylation
Deacetylation
Phosphorylation
Dephosphorylation
Sumoylation
Desumoylation
Ubiquitination
Deubiquitination
Methylation
Demethylation
Palmitoylation
Proteolytic cleavage
Inhibition
Transport
TNFRSF1
Inhibited in
skeletal
muscle cells
TRIM63
mRNA
Protein
Induced activation
Protein
Induced catalysis
Degradation
P
RELA NFκ-B1
RELB
Translocation
NFκ-B2
JUN
CY
CY
CY
CY
NU
NU
NU
NU
TNF
PM Plasma membrane
CY
CY Cytoplasm
NU
CTNNB1
HDAC1
P
RELA NFκ-B1
RELB
EC Extracellular
NFκ-B2
EN Endosome
ER Endoplasmic reticulum
GO Golgi apparatus
CCL2
IL6
CCL5 MMP9
CCL5
MT Mitochondrion
TNF
NU Nucleus
Proliferation
(osteoblasts)
Proliferation
(endothelial cells)
Proliferation
(endothelial cells)
Proliferation
(myotubes)
(renal tubular cells)
Apoptosis
(tumor cells)
Figure 3: TWEAK signaling pathway: illustration of the TWEAK signaling pathway as visualized in NetSlim web page. Each molecule
is linked to its corresponding page in NetPath. Each reaction is linked to its respective PubMed citation. Dashed arrows represent the
downstream reactions leading to the corresponding events while the solid arrows indicate the direct association between the indicated
molecules. Gene symbol(s) has been used to denote proteins in the pathway map (refer to Synonymous for common names).
The TWEAK-Fn14 complex binds to the TRAF molecules,
TRAF 1, 2, 3, and 5. However, the downstream signaling
cascade(s) that proceeds upon the association of TWEAKFn14 complex and TRAF 1/3/5 (TRAF1, TRAF3, TRAF5) is
unavailable due to the lack of published studies to date. It
was possible to decipher the downstream events following
the formation of the TRAF2-cIAP1 (BIRC2) complex. This
complex possibly undergoes Cathepsin B mediated degradation. The degradation of the TRAF2-cIAP1 complex leads to
the stabilization of NIK and activation of the noncanonical
NF-κB pathway as represented in the model. The degradation
of the TRAF2-cIAP1 complex also leads to the activation
of the caspase pathway resulting in the apoptosis of tumor
cells [11, 27]. Ikner and Ashkenazi [11] have shown that
TWEAK activates apoptosis through the formation of a
RIP1-FADD-caspase8 complex by TNFα mediated signaling,
wherein cIAP1 plays a crucial role. A possible role of
TWEAK has been reported in bone and cartilage damage.
In fibroblast-like synoviocytes, TWEAK activates TRAF2 and
cIAP2 proteins which in turn activate the MMP9 expression
[76]. Experimental evidence indicates that TWEAK-Fn14
complex formation leads to the activation of p38 (MAPK14),
Journal of Signal Transduction
ERK1/2 (MAPK3/MAPK1), JNK1/2 (MAPK8/MAPK9), and
TAK1 (MAP3K7). No evidence has been obtained from
existing literature for further direct downstream targets of
p38 and ERK1/2. However, the activation of TAK1 leads
further to the downstream activation of the NF-κB/p65/p50
pathway. Also, RAC1 has been reported to interact directly
with the TWEAK-Fn14 complex leading to activation of the
NF-κB pathway. Activation of AKT via phosphorylation has
been observed under TWEAK stimulus with an exception in
the case of skeletal muscle [41]. AKT phosphorylation leads
further to the inactivation of GSK3β resulting in an increase
in levels of phospho-GSK3β and active (dephosphorylated)
β-catenin1 (CTNNB1). The cytoplasmic accumulation of
active β-catenin1 results in its nuclear translocation [14].
In addition to binding of TWEAK with Fn14, we have
also documented the binding of CD163 [30] and DR3 [28]
with TWEAK. Since the interaction between TWEAK and
DR3 remains controversial [28, 29] and the downstream
consequences of a possible TWEAK-CD163 interaction
remain to be explored, the pathway illustration does not
elaborate on the downstream events for these interactions.
4. Conclusions
The ever increasing experimental data on the various molecular events taking place following ligand-receptor interactions, in this case between TWEAK and Fn14, make it
essential to have a repository for the data and also to create
a signaling pathway summary. Our current work, which
incorporates the TWEAK-signaling pathway data into “NetPath”, would open avenues for further studies of TWEAKassociated proteins and related disorders, such as cancers
and autoimmune diseases. To our understanding, this study
compiles for the first time TWEAK induced signaling events;
these include (i) the inactivation of GSK3β followed by
dissociation of β-catenin1 [14], (ii) the proapoptotic nature
of TWEAK mediated through the expression of TNFα, which
further leads to the activation of caspase8 [11], and (iii) the
association between TWEAK and cIAP proteins (1 and 2)
[11, 76]. We believe that our data will be informative in
therapeutic studies, in selecting/pathological events and the
simultaneous production of blocking agents. Importantly,
the “NetPath” repository is dynamic and will allow a progressive update of relevant data, as more published literature
is introduced. In addition to the direct usage of the data
stored in the “NetPath” database, data can also be exported to
other databases, enabling comparison and sharing amongst
multiple databases, especially those which have compatible
language formats, such as BioPAX [73]. Despite the minimal
amount of data, ours can also be used in the overlay of
various high-throughput data enabling pathway analysis
and can be accessed by any pathway resource to generate
a customized pathway. We are currently working on the
features in “NetPath”, which are incompatible with BioPAX,
especially the ontology hierarchy that has been proposed by
the BioPAX group [73]. To our knowledge, our compilation
of data in “NetPath” will allow, for the first time for any
available scientific repository, a comprehensive study of the
TWEAK pathway and its potential biomedical applications.
7
Abbreviations
BioPAX: Biological PAthway eXchange
PSI-MI: Proteomics Standards Initiative for Molecular
Interaction
SBML: Systems Biology Markup Language
TNFα:
Tumor necrosis factor
IFN-γ:
Interferon gamma
STAT-1: Signal transducer and activator of transcription
1, 91 kDa
HDAC-1: Histone deacetylase 1
GSK3β: Glycogen synthase kinase 3 beta
FOXO1a: Forkhead box O1
MTOR: Mechanistic target of rapamycin
(serine/threonine kinase)
RAC1:
Ras-related C3 botulinum toxin substrate 1
p38:
Mitogen-activated protein kinase 14
AKT1:
v-akt murine thymoma viral oncogene
homolog 1
AKT2:
v-akt murine thymoma viral oncogene
homolog 2
TRAF1: TNF receptor-associated factor 1
TRAF2: TNF receptor-associated factor 2
TRAF3: TNF receptor-associated factor 3
TRAF5: TNF receptor-associated factor 5
TNF:
Tumor necrosis factor
RIPK1: Receptor (TNFRSF)-interacting
serine-threonine kinase 1
RELA:
v-rel reticuloendotheliosis viral oncogene
homolog A
RELB:
v-rel reticuloendotheliosis viral oncogene
homolog B
CASP3: Caspase3
CASP7: Caspase 7
CASP8: Caspase 8
IKBKB: Inhibitor of kappa light polypeptide gene
enhancer in B-cells, kinase beta.
Synonymous Names (Gene Symbol :
Common Name )
(1) Tumor necrosis factor superfamily, member 12
(TNFSF12): TNF-related Weak inducer apoptosis
(TWEAK).
(2) Tumor necrosis factor receptor superfamily, member
12A (TNFRSF12A): FGF-inducible 14 (Fn14).
(3) Tumor necrosis factor receptor superfamily, member
25 (TNFRSF25): Death receptor 3 (DR3).
(4) Baculoviral IAP repeat containing 2 (BIRC2): Cellular Inhibitors of Apoptosis 1 (cIAP1).
(5) Mitogen-activated protein kinase kinase kinase 14
(MAP3K14): NF-kappa-beta-inducing kinase (NIK).
(6) Conserved helix-loop-helix ubiquitous
(CHUK): IKappa Kinase alpha (IKKα).
kinase
(7) Nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 (p49/p100) (NFKB2): Nuclear
factor kappa/p52 (p52).
8
Journal of Signal Transduction
(8) Mitogen-activated protein kinase 9 (MAPK9): Mitogen-activated protein kinase 9 (JNK2).
(9) Mitogen-activated protein kinase 8 (MAPK8): JUN
N-terminal kinase (JNK).
[8]
(10) Mitogen-activated protein kinase 7 (MAP3K7): TGF
beta activated kinase 1 (TAK1).
(11) Extracellular regulated kinase 1 (ERK1): Mitogenactivated protein kinase 3 (MAPK3).
Conflict of Interests
[9]
[10]
The authors have no conflict of interests.
Acknowledgments
The authors thank the Department of Biotechnology (DBT),
Government of India, for research support to the Institute
of Bioinformatics, Bangalore. P. P. Mathur thanks the
Department of Biotechnology (DBT), Government of India
and Department of Information Technology (DIT), Government of India, for financial support (Project nos.
BT/BI/03/015/2002 and DIT/R&D/BIO/15(9)/2007). R. Raju
and B. Muthusamy are recipients of the Senior Research
Fellowship from the Council of Scientific and Industrial
Research (CSIR), India. A. Radhakrishnan is supported by
a Junior Research Fellowship from CSIR. T. S. K. Prasad is
the recipient of a Young Investigator Award from DBT. H. C.
Harsha is a Wellcome Trust/DBT India Alliance Early Career
Fellow.
References
[1] Y. Chicheportiche, P. R. Bourdon, H. Xu et al., “TWEAK, a
new secreted ligand in the tumor necrosis factor family that
weakly induces apoptosis,” JournalofBiologicalChemistry, vol.
272, no. 51, pp. 32401–32410, 1997.
[2] T. Novoyatleva, F. Diehl, M. J. Van Amerongen et al., “TWEAK
is a positive regulator of cardiomyocyte proliferation,” Cardiovascular Research, vol. 85, no. 4, pp. 681–690, 2010.
[3] S. P. Fortin, M. J. Ennis, B. A. Savitch et al., “Tumor necrosis
factor-like weak inducer of apoptosis stimulation of glioma
cell survival is dependent on Akt2 function,” Molecular Cancer
Research, vol. 7, no. 11, pp. 1871–1881, 2009.
[4] N. L. Tran, W. S. McDonough, P. J. Donohue et al., “The
human Fn14 receptor gene is up-regulated in migrating
glioma cells in vitro and overexpressed in advanced glial
tumors,” American Journal of Pathology, vol. 162, no. 4, pp.
1313–1321, 2003.
[5] A. Ortiz, M. D. Sanchez-Nino, M. C. Izquierdo et al., “TWEAK
and the kidney: the dual role of a multifunctional cytokine,”
Advances in Experimental Medicine and Biology, vol. 691, pp.
323–335, 2011.
[6] V. Pelekanou, G. Notas, K. Theodoropoulou et al., “Detection
of the TNFSF members BAFF, APRIL, TWEAK and their
receptors in normal kidney and renal cell carcinomas,”
Analytical Cellular Pathology, vol. 34, no. 1-2, pp. 49–60, 2011.
[7] N. G. Kataria, M. M. Bartold, A. A. S. K. Dharmapatni,
G. J. Atkins, C. A. Holding, and D. R. Haynes, “Expression
of tumor necrosis factor-like weak inducer of apoptosis
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
(TWEAK) and its receptor, fibroblast growth factor-inducible
14 protein (Fn14), in healthy tissues and in tissues affected by
periodontitis,” Journal of Periodontal Research, vol. 45, no. 4,
pp. 564–573, 2010.
C. N. Lynch, Y. C. Wang, J. K. Lund, Y. W. Chen, J. A. Leal, and
S. R. Wiley, “TWEAK induces angiogenesis and proliferation
of endothelial cells,” Journal of Biological Chemistry, vol. 274,
no. 13, pp. 8455–8459, 1999.
R. Kawashima, Y. I. Kawamura, T. Oshio et al., “Interleukin13 damages intestinal mucosa via TWEAK and Fn14 in micea pathway associated with ulcerative colitis,” Gastroenterology,
vol. 141, no. 6, pp. 2119–2129, 2011.
M. Petitbarat, M. Rahmati, V. Sérazin et al., “Tweak appears
as a modulator of endometrial il-18 related cytotoxic activity
of uterine natural killers,” PLoS ONE, vol. 6, no. 1, Article ID
e14497, 2011.
A. Ikner and A. Ashkenazi, “TWEAK induces apoptosis
through a death-signaling complex comprising receptorinteracting protein 1 (RIP1), Fas-associated Death Domain
(FADD), and caspase-8,” Journal of Biological Chemistry, vol.
286, no. 24, pp. 21546–21554, 2011.
S. R. Wiley and J. A. Winkles, “TWEAK, a member of the
TNF superfamily, is a multifunctional cytokine that binds the
TweakR/Fn14 receptor,” Cytokine and Growth Factor Reviews,
vol. 14, no. 3-4, pp. 241–249, 2003.
A. Jakubowski, C. Ambrose, M. Parr et al., “TWEAK induces
liver progenitor cell proliferation,” Journal of Clinical Investigation, vol. 115, no. 9, pp. 2330–2340, 2005.
C. Vincent, D. M. Findlay, K. J. Welldon et al., “Proinflammatory cytokines TNF-related weak inducer of apoptosis (TWEAK) and TNFα induce the mitogen-activated protein
kinase (MAPK)-dependent expression of sclerostin in human
osteoblasts,” Journal of Bone and Mineral Research, vol. 24, no.
8, pp. 1434–1449, 2009.
S. Desplat-Jego, S. Varriale, R. Creidy et al., “TWEAK is
expressed by glial cells, induces astrocyte proliferation and
increases EAE severity,” Journal of Neuroimmunology, vol. 133,
no. 1-2, pp. 116–123, 2002.
S. Kamijo, A. Nakajima, K. Kamata, H. Kurosawa, H. Yagita,
and K. Okumura, “Involvement of TWEAK/Fn14 interaction
in the synovial inflammation of RA,” Rheumatology, vol. 47,
no. 4, pp. 442–450, 2008.
H. X. Gao, S. R. Campbell, L. C. Burkly et al., “TNF-like
weak inducer of apoptosis (TWEAK) induces inflammatory
and proliferative effects in human kidney cells,” Cytokine, vol.
46, no. 1, pp. 24–35, 2009.
A. B. Sanz, M. D. Sanchez-Niño, M. C. Izquierdo et al.,
“TWEAK activates the non-canonical NFkappaB pathway in
murine renal tubular cells: modulation of CCL21,” PloS one,
vol. 5, no. 1, p. e8955, 2010.
M. Girgenrath, S. Weng, C. A. Kostek et al., “TWEAK, via its
receptor Fn14, is a novel regulator of mesenchymal progenitor
cells and skeletal muscle regeneration,” EMBO Journal, vol. 25,
no. 24, pp. 5826–5839, 2006.
T. C. Polek, M. Talpaz, B. G. Darnay, and T. Spivak-Kroizman,
“TWEAK mediates signal transduction and differentiation of
RAW264.7 cells in the absence of Fn14/TweakR. Evidence for a
second TWEAK receptor,” Journal of Biological Chemistry, vol.
278, no. 34, pp. 32317–32323, 2003.
A. A.S.S.K. Dharmapatni, M. D. Smith, T. N. Crotti et al.,
“TWEAK and Fn14 expression in the pathogenesis of joint
inflammation and bone erosion in rheumatoid arthritis,”
Arthritis Research and Therapy, vol. 13, no. 2, p. R51, 2011.
Journal of Signal Transduction
[22] N. L. Tran, W. S. McDonough, B. A. Savitch, T. F. Sawyer, J.
A. Winkles, and M. E. Berens, “The tumor necrosis factorlike weak inducer of apoptosis (TWEAK)-fibroblast growth
factor-inducible 14 (Fn14) signaling system regulates glioma
cell survival via NFκB pathway activation and BCL-XL/BCLW expression,” Journal of Biological Chemistry, vol. 280, no. 5,
pp. 3483–3492, 2005.
[23] A. Jakubowski, B. Browning, M. Lukashev et al., “Dual role for
TWEAK in angiogenic regulation,” Journal of Cell Science, vol.
115, no. 2, pp. 267–274, 2002.
[24] D. Wang, J. N. T. Fung, Y. Tuo, L. Hu, and C. Chen,
“TWEAK/Fn14 promotes apoptosis of human endometrial
cancer cells via caspase pathway,” Cancer Letters, vol. 294, no.
1, pp. 91–100, 2010.
[25] M. J. Kaplan, E. E. Lewis, E. A. Shelden et al., “The
apoptotic ligands TRAIL, TWEAK, and fas ligand mediate
monocyte death induced by autologous lupus T cells,” Journal
of Immunology, vol. 169, no. 10, pp. 6020–6029, 2002.
[26] M. Nakayama, N. Kayagaki, N. Yamaguchi, K. Okumura, and
H. Yagita, “Involvement of TWEAK in interferon γ-stimulated
monocyte cytotoxicity,” Journal of Experimental Medicine, vol.
192, no. 9, pp. 1373–1379, 2000.
[27] J. E. Vince, D. Chau, B. Callus et al., “TWEAK-FN14 signaling
induces lysosomal degradation of a cIAP1-TRAF2 complex to
sensitize tumor cells to TNFα,” Journal of Cell Biology, vol. 182,
no. 1, pp. 171–184, 2008.
[28] A. Kaptein, M. Jansen, G. Dilaver et al., “Studies on the
interaction between TWEAK and the death receptor WSL1/TRAMP (DR3),” FEBS Letters, vol. 485, no. 2-3, pp. 135–141,
2000.
[29] P. Schneider, R. Schwenzer, E. Haas et al., “TWEAK can induce
cell death via endogenous TNF and TNF receptor 1,” European
Journal of Immunology, vol. 29, no. 6, pp. 1785–1792, 1999.
[30] J. A. Moreno, B. Munoz-Garcia, J. L. Martı́n-Ventura et al.,
“The CD163-expressing macrophages recognize and internalize TWEAK. Potential consequences in atherosclerosis,”
Atherosclerosis, vol. 207, no. 1, pp. 103–110, 2009.
[31] S. A. N. Brown, H. N. Hanscom, H. Vu, S. A. Brew, and J. A.
Winkles, “TWEAK binding to the Fn14 cysteine-rich domain
depends on charged residues located in both the A1 and D2
modules,” Biochemical Journal, vol. 397, no. 2, pp. 297–304,
2006.
[32] R. L. Meighan-Mantha, D. K. W. Hsu, Y. Guo et al., “The
mitogen-inducible Fn14 gene encodes a type I transmembrane
protein that modulates fibroblast adhesion and migration,”
Journal of Biological Chemistry, vol. 274, no. 46, pp. 33166–
33176, 1999.
[33] S. A. N. Brown, C. M. Richards, H. N. Hanscom, S. L. Y. Feng,
and J. A. Winkles, “The Fn14 cytoplasmic tail binds tumournecrosis-factor-receptor-associated factors 1, 2, 3 and 5 and
mediates nuclear factor-κB activation,” Biochemical Journal,
vol. 371, no. 2, pp. 395–403, 2003.
[34] E. Chorianopoulos, T. Heger, M. Lutz et al., “FGF-inducible
14-kDa protein (Fn14) is regulated via the RhoA/ROCK
kinase pathway in cardiomyocytes and mediates nuclear
factor-kappaB activation by TWEAK,” Basic Research in
Cardiology, vol. 105, no. 2, pp. 301–313, 2010.
[35] E. Mustonen, H. Säkkinen, H. Tokola et al., “Tumour necrosis
factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 during cardiac remodelling in rats,” Acta Physiologica,
vol. 199, no. 1, pp. 11–22, 2010.
[36] J. M. Weinberg, “TWEAK-Fn14 as a mediator of acute kidney
injury,” Kidney International, vol. 79, no. 2, pp. 151–153, 2011.
9
[37] H. Xu, A. Okamoto, J. Ichikawa et al., “TWEAK/Fn14 interaction stimulates human bronchial epithelial cells to produce
IL-8 and GM-CSF,” Biochemical and Biophysical Research
Communications, vol. 318, no. 2, pp. 422–427, 2004.
[38] J. A. Winkles, “The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting,” Nature Reviews
Drug Discovery, vol. 7, no. 5, pp. 411–425, 2008.
[39] J. A. Winkles, N. L. Tran, S. A. Brown, N. Stains, H. E. Cunliffe,
and M. E. Berens, “Role of TWEAK and Fn14 in tumor
biology,” Frontiers in Bioscience, vol. 12, pp. 2761–2771, 2007.
[40] S. A. N. Brown, A. Ghosh, and J. A. Winkles, “Full-length,
membrane-anchored TWEAK can function as a juxtacrine
signaling molecule and activate the NF-κB pathway,” Journal of
Biological Chemistry, vol. 285, no. 23, pp. 17432–17441, 2010.
[41] M. Kumar, D. Y. Makonchuk, H. Li, A. Mittal, and A. Kumar,
“TNF-like weak inducer of apoptosis (TWEAK) activates
proinflammatory signaling pathways and gene expression
through the activation of TGF-β-activated kinase 1,” Journal
of Immunology, vol. 182, no. 4, pp. 2439–2448, 2009.
[42] H. Li, A. Mittal, P. K. Paul et al., “Tumor necrosis factor-related
weak inducer of apoptosis augments matrix metalloproteinase
9 (MMP-9) production in skeletal muscle through the activation of nuclear factor-κB-inducing kinase and p38 mitogenactivated protein kinase: a potential role MMP-9 in myopathy,”
Journal of Biological Chemistry, vol. 284, no. 7, pp. 4439–4450,
2009.
[43] A. Mittal, S. Bhatnagar, A. Kumar, P. K. Paul, S. Kuang, and A.
Kumar, “Genetic ablation of TWEAK augments regeneration
and post-injury growth of skeletal muscle in mice,” American
Journal of Pathology, vol. 177, no. 4, pp. 1732–1742, 2010.
[44] D. J. Ahern and F. M. Brennan, “The role of Natural Killer
cells in the pathogenesis of rheumatoid arthritis: major contributors or essential homeostatic modulators?” Immunology
Letters, vol. 136, no. 2, pp. 115–121, 2010.
[45] N. Schwartz, T. Rubinstein, L. C. Burkly et al., “Urinary
TWEAK as a biomarker of lupus nephritis: a multicenter
cohort study,” Arthritis Research & Therapy, vol. 11, no. 5, p.
R143, 2009.
[46] B. Serafini, R. Magliozzi, B. Rosicarelli, R. Reynolds, T. S.
Zheng, and F. Aloisi, “Expression of TWEAK and its receptor Fn14 in the multiple sclerosis brain: implications for
inflammatory tissue injury,” Journal of Neuropathology and
Experimental Neurology, vol. 67, no. 12, pp. 1137–1148, 2008.
[47] N. L. Tran, W. S. McDonough, B. A. Savitch et al., “Increased
fibroblast growth factor-inducible 14 expression levels promote glioma cell invasion via Rac1 and nuclear factor-κB and
correlate with poor patient outcome,” Cancer Research, vol. 66,
no. 19, pp. 9535–9542, 2006.
[48] S. L. Y. Feng, Y. Guo, V. M. Factor et al., “The Fn14 immediateearly response gene is induced during liver regeneration and
highly expressed in both human and murine hepatocellular
carcinomas,” American Journal of Pathology, vol. 156, no. 4, pp.
1253–1261, 2000.
[49] S. A. Williams, S. K. Martin, C. Vincent et al., “Circulating
levels of TWEAK correlate with bone erosion in multiple myeloma patients,” British Journal of Haematology, vol. 150, no.
3, pp. 373–376, 2010.
[50] A. L. Willis, N. L. Tran, J. M. Chatigny et al., “The fibroblast
growth factor-inducible 14 receptor is highly expressed in
HER2-positive breast tumors and regulates breast cancer cell
invasive capacity,” Molecular Cancer Research, vol. 6, no. 5, pp.
725–734, 2008.
[51] J. S. Michaelson and L. C. Burkly, “Therapeutic targeting of
TWEAK/Fn14 in cancer: exploiting the intrinsic tumor cell
10
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
Journal of Signal Transduction
killing capacity of the pathway,” Results and Problems in Cell
Differentiation, vol. 49, pp. 145–160, 2009.
M. D. Sanchez-Nio, A. Benito-Martin, S. Gonalves et al., “TNF
superfamily: a growing saga of kidney injury modulators,”
Mediators of Inflammation, vol. 2010, Article ID 182958, 2010.
M. I. Yilmaz, J. J. Carrero, A. Ortiz et al., “Soluble TWEAK
plasma levels as a novel biomarker of endothelial function in
patients with chronic kidney disease,” Clinical Journal of the
American Society of Nephrology, vol. 4, no. 11, pp. 1716–1723,
2009.
Z. C. Liu, Q. L. Zhou, X. Z. Li et al., “Elevation of human
tumor necrosis factor-like weak inducer of apoptosis in peripheral blood mononuclear cells is correlated with disease
activity and lupus nephritis in patients with systemic lupus
erythematosus,” Cytokine, vol. 53, no. 3, pp. 295–300, 2011.
S. Kralisch, M. Ziegelmeier, A. Bachmann et al., “Serum levels
of the atherosclerosis biomarker sTWEAK are decreased in
type 2 diabetes and end-stage renal disease,” Atherosclerosis,
vol. 199, no. 2, pp. 440–444, 2008.
B. Munoz-Garcı́a, J. L. Martı́n-Ventura, E. Martı́nez et al.,
“Fn14 is upregulated in cytokine-stimulated vascular smooth
muscle cells and is expressed in human carotid atherosclerotic
plaques: modulation by atorvastatin,” Stroke, vol. 37, no. 8, pp.
2044–2053, 2006.
L. M. Blanco-Colio, J. L. Martin-Ventura, J. J. Carrero et al.,
“Vascular proteomics and the discovery process of clinical
biomarkers: the case of TWEAK,” Proteomics-Clinical Applications, vol. 5, no. 5-6, pp. 281–288, 2011.
E. Chorianopoulos, M. Rosenberg, C. Zugck, J. Wolf, H. A.
Katus, and N. Frey, “Decreased soluble TWEAK levels predict
an adverse prognosis in patients with chronic stable heart
failure,” European Journal of Heart Failure, vol. 11, no. 11, pp.
1050–1056, 2009.
A. Filusch, T. Zelniker, C. Baumgartner et al., “Soluble
TWEAK predicts hemodynamic impairment and functional
capacity in patients with pulmonary arterial hypertension,”
Clinical Research in Cardiology, vol. 100, no. 10, pp. 879–885,
2011.
N. Ledee, M. Petitbarat, M. Rahmati et al., “New pre-conception immune biomarkers for clinical practice: interleukin18, interleukin-15 and TWEAK on the endometrial side, GCSF on the follicular side,” Journal of Reproductive Immunology, vol. 88, no. 2, pp. 118–123, 2011.
J. L. Martin-Ventura, J. S. Lindholt, J. A. Moreno et al.,
“Soluble TWEAK plasma levels predict expansion of human
abdominal aortic aneurysms,” Atherosclerosis, vol. 214, no. 2,
pp. 486–489, 2011.
M. P. van Iersel, T. Kelder, A. R. Pico et al., “Presenting and
exploring biological pathways with PathVisio,” BMC Bioinformatics, vol. 9, article no. 399, 2008.
V. Nanjappa, R. Raju, B. Murthusamy, J. Sharma et al.,
“A comprehensive curated reaction map of leptin signaling
pathway,” Journal of Proteomics & Bioinformatics, vol. 4, pp.
184–189, 2011.
R. Raju, L. Balakrishnan, V. Nanjappa et al., “A comprehensive
manually curated reaction map of rankl/rank-signaling pathway,” Database (Oxford), vol. 2011, Article ID bar021, 2011.
D. Telikicherla, A. Ambekar, S. Palapetta et al., “A comprehensive curated resource for follicle stimulating hormone
signaling,” BMC Research Notes, vol. 4, p. 408, 2011.
R. Raju, V. Nanjappa, L. Balakrishnan et al., “NetSlim: highconfidence curated signaling maps,” Database, vol. 2011,
Article ID bar032, 2011.
[67] K. Kandasamy, S. Sujatha Mohan, R. Raju et al., “NetPath:
a public resource of curated signal transduction pathways,”
Genome Biology, vol. 11, no. 1, p. r3, 2010.
[68] K. Kandasamy, S. Keerthikumar, R. Raju et al., “PathBuilderopen source software for annotating and developing pathway
resources,” Bioinformatics, vol. 25, no. 21, pp. 2860–2862,
2009.
[69] Y. Hosokawa, I. Hosokawa, K. Ozaki, H. Nakae, and T.
Matsuo, “Proinflammatory effects of tumour necrosis factorlike weak inducer of apoptosis (TWEAK) on human gingival
fibroblasts,” Clinical and Experimental Immunology, vol. 146,
no. 3, pp. 540–549, 2006.
[70] M. Wako, T. Ohba, T. Ando et al., “Mechanism of signal
transduction in tumor necrosis factor-like weak inducer of
apoptosis-induced matrix degradation by MMP-3 upregulation in disc tissues,” Spine, vol. 33, no. 23, pp. 2489–2494, 2008.
[71] R. Feltham, M. Moulin, J. E. Vince et al., “Tumor necrosis factor (TNF) signaling, but not TWEAK (TNF-like weak inducer
of apoptosis)-triggered cIAP1 (cellular inhibitor of apoptosis
protein 1) degradation, requires cIAP1 RING dimerization
and E2 binding,” Journal of Biological Chemistry, vol. 285, no.
23, pp. 17525–17536, 2010.
[72] H. Maecker, E. Varfolomeev, F. Kischkel et al., “TWEAK
attenuates the transition from innate to adaptive immunity,”
Cell, vol. 123, no. 5, pp. 931–944, 2005.
[73] E. Demir, S. Paley, K. Fukuda et al., “Erratum: the BioPAX
community standard for pathway data sharing (Nat. Biotechnol. (2010) 28 (935-942),” Nature Biotechnology, vol. 28, no.
12, p. 1308, 2010.
[74] M. Hucka, A. Finney, H. M. Sauro et al., “The systems biology
markup language (SBML): a medium for representation and
exchange of biochemical network models,” Bioinformatics, vol.
19, no. 4, pp. 524–531, 2003.
[75] S. Kerrien, S. Orchard, L. Montecchi-Palazzi et al., “Broadening the horizon-level 2.5 of the HUPO-PSI format for
molecular interactions,” BMC Biology, vol. 5, article no. 44,
2007.
[76] L. Xia, H. Shen, J. Lu, and W. Xiao, “TRAF2 and cIAP2
involve in TWEAK-induced MMP-9 production in fibroblastlike synoviocytes,” Rheumatology International, vol. 32, no. 1,
pp. 281–282, 2012.