B RIEFINGS IN BIOINF ORMATICS . VOL 12. NO 6.

702^713
Advance Access published on 17 September 2010

doi:10.1093/bib/bbq064

Protein^protein interaction and

pathway databases, a graphical review
Tomas Klingstrom and Dariusz Plewczynski
Submitted: 13th July 2010; Received (in revised form) : 14th August 2010

Abstract
The amount of information regarding protein ^ protein interactions (PPI) at a proteomic scale is constantly
increasing. This is paralleled with an increase of databases making information available. Consequently there are
diverse ways of delivering information about not only PPIs but also regarding the databases themselves. This creates
a time consuming obstacle for many researchers working in the field. Our survey provides a valuable tool for
researchers to reduce the time necessary to gain a broad overview of PPI-databases and is supported by a graphical
representation of data exchange. The graphical representation is made available in cooperation with the team
maintaining www.pathguide.org and can be accessed at http://www.pathguide.org/interactions.php in a new
Cytoscape web implementation. The local copy of Cytoscape cys file can be downloaded from http://bio.icm.edu
.pl/darman/ppi web page.
Keywords: proteins; interactome; pathways; signalling; metamining; literature curation; protein^protein interaction;
binary-interactions

INTRODUCTION
Understanding the organization of genetic networks
and protein pathways to establish how they contribute to cellular and organism phenotypes is one of the
major challenges in the post-genomic era [1]. The
proteinprotein interaction (PPI) community has
been characterized by a wide and open distribution
of proteomic data [2] through the collection of PPI
and pathway databases. The ability to distribute and
share data between various research groups has resulted in a large number of different source databases.
However, the general overlap between those databases is very limited [3, 4], which means that a
common procedure for researchers is to unify these
diverse data sets to support their own work [58].
Several metamining databases have been created that
perform such unification. This has lead to the

spontaneous development of a network of data

exchange between literature curated databases, metamining databases and databases generating predicted
PPIs. The exchange of information is supported by
three major data exchange formats: BioPAX [9],
PSI-MI [10] and SBML [11]. An extensive review
of these data formats has already been published by
others [12], and a more detailed description has
therefore been omitted from this article. Previous
reviews regarding PPI and pathway databases have
largely focused on the potential of using databases
to support drug development [13, 14] or cover the
early development of literature curated and pathway
databases [15, 16].
A single illustration containing all databases would
create an extremely complicated image clouded by a
large amount of superfluous information. We have

Corresponding author. Dariusz Plewczynski, Interdisciplinary Centre for Mathematical and Computational Modelling, University of
Warsaw, Pawinskiego 5a Street, 02-106 Warsaw, Poland. Tel: 4 822 554 0838 and 4 850 472 6203; Fax: 4 822 554 0801; E-mail:
darman@icm.edu.pl
Tomas S. Klingstrom is studying at the Master of Science programme in Molecular Biotechnology Engineering at Uppsala
University (estimated to finish in January 2011) and recipient of the Anders Wall scholarship to young researchers 2010. His main
area of interest is large-scale studies of proteinprotein interactions on a proteomic level for usage in systems biology and the
pharmaceutical industry.
Dariusz Plewczynski is a Research Professor at University of Warsaw in Interdyscyplinary Centre for Mathematical and
Computational Modelling, Poland. His main expertise covers protein interactions (including both proteinligand and proteinprotein)
especially in the context of docking and high-throughput studies. He applies machine learning algorithms and clustering techniques for
functional annotation of protein sequences and structures.
The Author 2010. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com

Protein^protein interaction and pathway databases

therefore created a set of separate visual networks
defined by our own classification scheme. PPI
source databases are databases that conduct in-house
curation of data, this class includes both pure source
databases and databases combining in-house curation
with metamining of other databases. Pathway source
databases are databases creating networks, or pathways, giving information not only regarding the
PPI but also its biological context. Metamining
databases are databases exclusively relying on source
databases and high-throughput experiments
published as finished data sets. In our classification
we have decided to combine both PPI metamining
databases and metamining pathway databases in order
to allow readers to easily compare their coverage
of available source databases. A separate category is
predictive databases that use interaction data to
computationally predict previously unknown interactions. In this class, we have also decided to incorporate databases (HAPPI and STITCH) that mainly
rely on predicted data but do not make predictions
on their own. Furthermore a visualization of support
for BioPAX, PSI-MI and SBML is included
in the online visualization available at http://
pathguide.org. A complete list of databases covered
in this article and their classification can be found in
Supplementary Data 1. A brief summary of each
database can be found in Supplementary Data 2.

CREATION OF THE NETWORK

Selection of data and databases
The initial selection of investigated databases was
made from the index of databases kept at
Pathguide (http://www.pathguide.org/) and based
on their popularity ranking. Most databases have at
least one article describing them in the annual database issue of Nucleic Acids Research (NAR) journal.
Articles published in this annual issue are obligated
to contain a section comparing it to other similar
databases. Relevant databases mentioned in those
articles have also been added to complement the
initial selection from Pathguide.

Visualization of network
Visualization of databases interactions was carried out
by the open source visualization program Cytoscape
[17]. Each database is represented as a node and
interactions with other nodes are visualized as an
edge. Nodes are also connected to Pathguide IDs
which provide linkage to a Pathguide summary of

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the functionality of the database and a direct link to

the database. Collected data is included in a single
CYS file (the file format used by Cytoscape) that is
freely available upon request from authors for further
development. Databases with the default (beige)
colour have not been specifically investigated, blue
nodes are interaction databases, yellow nodes are
predictive interaction databases, green nodes are
pathway databases, red nodes represent metamining
databases and grey nodes are databases or standards,
allowing the user to access several different databases
through a standardized entrance point.
We have three different shapes for edges. An
arrow means that the database pointed to is mining
data from the node connected by the edge. A diamond means that the database pointed to is being
mapped from the other database, i.e. a database entry
in the database pointed to can be found by searches
in the database pointed from. A straight line shows
that there is an exchange agreement between the
databases, meaning that data can go between the
databases in both directions.

Future development
All data is stored in a single CYS library. By using a
controlled vocabulary, we are able to easily incorporate new data to the already existing maps. A web
implementation of Cytoscape network is available
Pathguide (http://www.pathguide.org/interactions).
A simple html submission system will allow users to
submit updates to the network.

Interaction databases
The topical databases such as DroID (PPIs in
Drosophila melanogaster), MatrixDB (extracellular
PPIs), InnateDB (PPIs in the immune system) and
MPIDB (PPIs in microbes) combine datamining
from other source databases with their own curation
efforts (Figure 1). The combination of extensive
datamining and in house curation make interaction
databases an appealing choice for researchers
interested in the topical area of the database.
BioGRID imported the HPRD and Flybase databases in 2006 [18], but have not added any more data
from other databases since then. BIND, DIP,
HPRD, IntAct and MINT do not incorporate data
from other databases. Overlap between most source
databases is currently small [3, 4]. Each literature
curating database extracts its data from a set of
selected scientific journals, meaning that shared
interactions can only occur if two databases curate

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Klingstrom and Plewczynski

Interaction Type
Source

Mining source data

Source

Maps to source
Bidirectional exchange agreement

Resource Type
Interactions
Pathways
Predictive interactions
Metamining
Exchange format language
Unifying efforts
Not categorized

Figure 1: Interaction databases. Among PPI source databases we see three distinct patterns of data exchange.
Stand alone database who are not actively sharing data (BIND, HPRD and to a certain extent BioGRID), generalist
databases participating in the IMEx agreement (DIP, IntAct and MINT) and topical databases who combine their
own in-house curation with metamining of other databases (DroID, InnateDB, MatrixDB and MPIDB). The combination of in-house curation and extensive metamining make the topical databases an attractive one stop choice for
researchers focused on D. melanogaster (DroID), the immune system (InnateDB), extracellular proteins (MatrixDB)
or physical microbial interactions (MPIDB). IMEx databases only share data curated in accordance with the IMEx
curation rules. This mean that both non-sharing and IMEx databases are likely to contain a large proportion of
entries unique to the database unless the IMEx exchange is combined with a metamining process (like in the case
with the topical databases). Researchers unwilling to spend a significant amount of time on querying generalist
source databases may therefore find it convenient to use metamining databases despite the issues described in the
metamining databases section.

the same journal or the same PPI is mentioned in

two different journals. Searches in several databases
are therefore complementary in the sense that each
new search provides access to a large set of interactions that were not previously searched.
All the major literature curation databases except
HPRD are affiliated with the IMEx consortium
(http://imex.sourceforge.net/). The first step of this
cooperation is the joint effort of literature curation,
leading to continuous increase of shared data in the
databases. Literature sources for curation are divided
among the IMEx members and curated in an IMEx
standardized format, curated data is then made available to all IMEx members.

Metamining databases
APID, MiMI and UniHI are metamining databases
with the mission to unify source databases into a

single
comprehensive
source
meta-database
(Figure 2). APID is dedicated completely to experimental data from interaction databases, and incorporates data from BioGRID, BIND, DIP, HPRD,
IntAct and MINT.
UniHI incorporates experimental and computationally predicted human PPI data. Apart from the
literature curated databases BioGRID, BIND, DIP,
HPRD and IntAct they also include data from
Reactome, high-throughput Y2H experiments
(MDC-Y2H [19] and CCSB [20]), searches for
proteins mentioned together in Medline abstracts
(COCIT [21]), and predictions of orthologous
proteins in model animals predicted in humans
(OPHID [22], HomoMint [23] and ORTHO [24]).
MiMI integrates data from BioGRID, BIND,
DIP, HPRD, IntAct and MINT, and it also adds
interactions from KEGG and Reactome pathway

Figure 2: Metamining databases. The view of metamining databases is obscured by the fact metamining databases in several cases not only extract data from PPI
databases but also extract data from other kinds of databases to provide supporting information. The view does however clearly show three distinctive approaches
to metamining. APID, MIMI, PINE and UniHI are traditional PPI metamining databases in the sense that they periodically download data from source PPI databases
to create a centralized repository. ConsensusPathDB and Pathways Commons provide a similar service aimed at integrating different pathway databases.
ConsensusPathDB here provide access to a far larger number of source databases and also makes use of PPI databases to create its own PPI based pathways.
DASMI is unique in that it maps to several databases rather than datamining them. This mean that DASMI makes it own queries to the databases mapped to each
time a user enters a query into DASMI. Therefore DASMI is always up to date with the most recent version of the source databases being mapped. But also less
suited for large queries where bandwidth limitations may be an issue.

Not categorized

Unifying efforts

Exchange format language

Metamining

Predictive interactions

Pathways

Interactions

Resource Type

Bidirectional exchange agreement

Mining source data

Maps to source

Source
Source

Interaction Type

Protein^protein interaction and pathway databases

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Klingstrom and Plewczynski

that each meta-database has its own scope and therefore often only contain parts of the source databases.
A search in for example APID is not equal to querying BIND, BioGRID, DIP, IntAct and MINT
directly. This can cause serious issues with reproducibility, if the usage of metamining resources is not
clearly mentioned in the report. Researchers
conducting experiments similar to the original
experiments might find themselves with different
sets of data compared to the original author, thereby
causing serious doubts about the integrity of the
results presented by the original author.
Each metamining database contains its own
unique algorithm for unification, with some
strengths and weaknesses. The most easily measured
factor is the coverage of the different source databases. Only APID and ConsensusPathDB provide a
web sites access to the number of interactions which
are taken from their sources. MiMI and UniHI provide similar data, but in their most recent publication
[34, 35]. PathwayCommons does not provide public
access to this kind of data and is therefore omitted
from Table 1.
Table 1 shows the current coverage of the
metamining databases. The coverage of a database

databases together with published databases from

Max Delbruck Center [19] and the WSU
Campylobacter Interactome [25]. In order to
enrich the information regarding each protein
MiMI also adds supplementary protein information
from Gene Onthology (Gene Onthology consortium [26]), InterPro [27], IPI [28], miBLAST [29]
NCBI (NCBI Gene, PubMed and PubMed NLP
Mining), OrganelleDB [30], OrthoMCL [31], Pfam
[32] and ProtoNet [33].
Another way of metamining interaction databases
is to integrate the interaction networks into reaction
pathways. ConsensusPath and PathwayCommons
use this technique to describe their interaction networks. In order to create the complex pathway,
these databases combine data from pathway databases
with the information available from the interaction
databases. Database coverage of the interaction databases is almost equal. Both ConsensusPath and
PathwayCommons mine the majority of the interaction databases, but do not incorporate as many
interactions as the dedicated interaction databases.
The ability to query several interaction databases
in a single search makes meta-databases an appealing
source of interaction data. It is important to realize

Table 1: Number of interactions extracted from each source database by the metamining databases (coverage in
percent)
BIND
APID
MiMI
UniHI
ConsensusPathDB

45 276
233 201
7394
0

28.6%
147.5%
4.7%
0%

BioGRID
94197
167 330
24 624
27 044

89.2%
159%
23.3%
22.8%

DIP
34 235
49 677
1397
1459

HPRD
59.5%
86.1%
2.42%
2.53%

29 803
116 333
40 883
39 939

76.8%
299.8%
105.4%
103%

IntAct
155 746
77 780
19 404
22 230

77.2%
38.6%
9.6%
11.0%

MINTa
131 311
125 672
0
12 943

117.8%
112.7%
0%b
15.5%

Each source database is divided into two columns.The first column show how many protein ^ protein interactions the metamining database has extracted.The second column describes the coverage of the database, i.e. the number of interactions extracted divided by the number of interactions
reported on the source database webpage (03 August 2009).Values >100% where initially thought to be caused by the expansion of complex interactions according to either the matrix model or the spoke model [32]. According to the spoke model a bait-protein interacting with a complex consisting of three proteins is expanded into three interactions, one interaction with each one of the proteins in the complex. Expansion by the
matrix model is similar to the spoke model, but also adds interactions between the proteins participating in the protein complex. Communication
with developers of the metamining databases have, however, shown this theory to be incorrect since MiMI. UniHI and ConsensusPathDB does not
expand protein complexes imported from other databases (Glenn Tarcea, Matthias Futschik and Atanas Kamburov, personal communication).
APID uses the spoke model to expand protein complexes from source databases when applicable (Carlos Prieto, personal communication). But
entries in MINT are already expanded according to the matrix model which mean that any expansion would be redundant and add 0
interactions.Further investigation by Glenn Tarcea at MiMI solved the issues with the MiMI statistics but could not provide further insight in the
issues among the other databases. In the case of MiMI, it turns out that the raw identifier counter providing data for their article [31] was faulty
and will in the future be replaced by agene ^ gene interaction counter (Tarcea,G. personal communication). Please note that this table is not a quality
assessment of databases, most meta-databases only extract data fulfilling certain criteria and are therefore expected to have <100%
coverage.aMINT previously expanded interactions according to the matrix model. On 01August 2009 MINT contained111518 interactions. All databases use data downloads from before this time. We therefore use this older number in the table.bDoes not use MINT, but does use HomoMINT.
A databases of human PPIs predicted from orthology with proteins in other species. UniHI includes 10 174 interactions from this database and thus
a coverage of 41.63%.The number of non-redundant protein ^ protein interactions in each database is (webpages accessed 18 November 2009):
BIND158 149, BioGRID105 593, DIP 57 683, HPRD 38 806, IntAct 201652, MINT 83 323 (please see footnote a) and HomoMINT 24 439 interactions
(only used by UniHI). BioGRID also contain genetic interactions. MiMI is the only database in the table that also incorporates this kind of data
which mean that the total number of interactions in BioGrid (169 723) is a more fitting comparasion.

Protein^protein interaction and pathway databases

is calculated as the proportion of PPIs in a source
database that have been imported into the metamining database. We would like to stress that coverage is
not a quality estimation of databases since each
meta-databases has its own scope which does not
always correspond to the scope of the source databases. Of the meta-databases, MiMI is the most
non-discriminatory database, aiming to include all
interaction data in one single comprehensive database and therefore incorporating all interactions they
can find. APID is focused on experimentally verified
proteins and relies on a unifying algorithm that uses
a protein sequence as an identifier, meaning that
interactions not supported by an experiment or containing a protein with an unknown sequence are
omitted. UniHI focuses on human PPIs extracted
from databases, thereby giving it a low coverage
of databases hosting data from other species.
ConsensusPathDB is a pathway database requiring
more contextual biological information surrounding
an interaction, thus greatly limiting the number of
interactions it can integrate from each source
database.
More worrying is that there are several instances of
meta-databases reporting that they have extracted
>100% of the source interactions. Of the databases
in the table only APID expands imported complexes
(Carlos Prieto, Glenn Tarcea, Matthias Futschik and
Atanas Kamburov, personal communication) and we
have so far been unable to find other satisfactory
explanations.
PINA [36] is a network analysis platform with a
built in data set of data from MINT, IntAct, DIP,
BioGRID, HPRD and MIPS/MPACT. PINA also
allow users to upload their own private PPI data sets
to create custom meta-databases. This combined
with the advanced query and analysis tools make
PINA suitable for researchers who wish to perform
PPI network analysis on specific pathways or to
create novel pathways based on known PPIs.
DASMI [37] is an alternative approach to the integration of protein and domain interaction data.
Rather than collecting all data into a single database,
this extension of the Distributed Annotation System
(DAS) [38] accesses all included databases and then
collects the data upon request from the user.
Decentralized approaches are therefore less suited
than metamining databases for large-scale analysis,
such as genome-wide interaction studies, as huge
amounts of data have to be transferred for each
query. This approach heavily depends on the

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participation of the interaction database providers

and thus far has been only partially successful.
Several databases have been integrated in this way,
yet in other cases the DASMI developers have been
forced to perform static integration of data and host
those resources on a central server. Temporary
caches are updated when the databases are updated
(like HPRD and DIP), or final data sets of finished
projects (like Sanger and CCSB-HI1) are used.
DASMI data sources are programmatically accessible,
which has led to the development of different user
clients that present the interactions in different ways
[37, 39]. It remains to be seen, whether a growing
support from client developers will convince more
database providers to offer a DAS-based interface to
their data, as this would increase their visibility.

Predictive interactions databases

There are four major predictive PPI databases:
HAPPI, STRING, STITCH and Scansite. Both
HAPPI and STITCH are directly reliant on
STRING meta-database to find their predicted
interactions (Figure 3). STITCH novel features
come from the fact that it also provides predictions
regarding proteinchemical interactions.
STRING combines known interaction data from
interaction databases BIND, BioGRID, DIP, IntAct
MINT and HPRD with interactions from the pathway databases PID, Reactome, KEGG and EcoCyc.
To further supplement this database it also includes
interactions predicted by algorithms specifically made
for STRING [40, 41].
HAPPI extracts the human interactions from
STRING and makes a comparison with data found
among main sources: BIND, HPRD, KEGG,
MINT and OPHID. Each source has its own confidence value and the reporting of an interaction
in several databases increases the confidence score.
This yields a database of more than 138 000
non-redundant high-quality PPIs, in HAPPI terminology referred to as 3, 4 or 5 star-quality interactions.
A comparative study with existing gold-standards
suggests that such a unified data set is of higher quality than any of the source data sets [42]. Lower quality predictions are also kept in the database marked as
1 or 2 star interactions bringing the total number to
>1.2-million predicted interactions.
The Scansite database is based on a 1D sequence
comparison with known motifs. Scansite was created
to identify short protein sequences likely to be
recognized by modular signaling domains,

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Klingstrom and Plewczynski

Figure 3: Predictive interaction databases. STRING integrates PPI data from a diverse set of sources not only restricted to pure PPI data. This create a huge data set of both experimentally verified and bioinformatically predicted
PPIs. STITCH is a closely related database which relies on a combination of STRING and chemical data to create a
data set of known and predicted interaction between proteins and chemicals. HAPPI database uses a subset of
STRING source databases and combine it with other experimental evidence that serve as a quality estimator for
the extracted PPIs. Low-quality interactions are then removed in order to create a data set of higher quality than
the source databases providing the PPIs. Scansite is a special case and have very little in common with the other
databases since rely on sequence similarity to predict certain types of interactions.

phosphorylated by protein Ser/Thr- or Tyr-kinases

or mediate specific interactions with protein or
phospholipid ligands [43].

Pathway databases
Pathway databases put protein interactions into a
biological context by creating pathways to describe
biological processes (Figure 4). Some databases
such as KEGG track a direct relationship of
protein interactions while others such as Reactome
base their pathways on biochemical transition and
transportation rather than the protein interactions.
Integration of PPI data from PPI databases is uncommon, of the investigated databases only SPIKE
reports such integration into their database to create
their pathways [44]. But ConsusPathDB and recent
work by Wu et al. [45] prove that despite the differences it is possible to combine data sets of both kinds
to increase proteome coverage but still maintain the
quality of functional PPIs. It should however be noted
that much useful information, such as semantic

relationships between proteins, is lost during the

merging (Guanming Wu, personal communications).
Exchange of data has been hindered by the diverse
ways of defining pathway data but is increasing. There
are currently two major data standards for pathway
data exchange: BioPAX [9] and SBML [11]. Each
one having its own distinct advantages, SBML provides support for modelling and simulations while
BioPAX create a rich hierarchy with a strong degree
of flexibility [12]. Many databases therefore support
both formats with BioPAX being the dominant one
regarding data exchange due to its capability of
exchanging many semantic contents.
The BioPAX data exchange format is currently
used by several databases for data exchange among
pathway databases. NCI-PID mines BioCarta and
Reactome through BioPAX level 2 transfers.
Reactome have extracted data through BioPAX
level 2 from NCI-PID, the Cancer Cell Map and
is working on integrating RiceCyc [46] (Guanming
Wu, personal communication). KEGG data has

Protein^protein interaction and pathway databases

709

Figure 4: Pathway databases. The figure shows that very few pathway databases use available PPI databases
to create their pathways. The figure also show that data exchange between the various pathway databases is less
extensive between PPI databases. SPIKE and Reactome are notable exceptions to this and combine their own
curation efforts with metamining of other Pathway databases. SPIKE is also together with SGMP unusual in the
way that they make use of literature curated data when creating their pathways.

instead been imported in KEGGs own format,

KGML and NCI-PID have been integrated through
SBML
with
Cell-Designer
additions
for
PANTHER. These efforts show that the ability to
exchange data between pathway databases have been
greatly enhanced through the introduction of the
BioPAX and SBML formats.

Unifying efforts
Apart from DASMI (covered in metamining databases) there are two other services that can provide
a single point of access to a wide variety of databases,
InterPro and BioMart (Figure 5). InterPro has recently launched their own BioMart service enabling
users to access InterPro through the BioMart program. BioMart is similar to DASMI, in that both aim
to provide a single portal that allows access to all
decentralized source databases. BioMart is aimed at
general description of proteins rather than PPIs, but
Reactome includes its own BioMart service.
Therefore using BioMart one can access InterPro
and further get access to PANTHER and mapping

to IntAct, as a part of the services offered by

InterPro.

DISCUSSION
The lack of a commonly agreed upon definition of
binary interactions is a source of major confusion in
research regarding PPIs [47, 48]. Cusick et al. [47]
attribute these issues to a lack of transparency on
the behalf of the source databases who do not clearly
enough describe the nature of their source data. We
believe that the problem rather is caused by each
database having its own unique way of delivering
this information. Some databases put all the necessary
information in an article submitted to Nucleic Acids
Research (NAR) database issue, some present their information online and others require the inquirer to
E-mail the database team for answers. The result is
that each individual database is easy to understand in
purpose and content. But gaining an overview of
several databases is almost impossible to do within a
reasonable time frame.

Figure 5: Unifying efforts. Both BioMart and DASMI aim to create a single point of access to a multitude of databases. The systems rely on mapping methods as the
client send queries to multiple servers and assemble the returned information into a comprehensible view. The BioMart system does not support exceptions to
this method while DASMI often download databases of interest and makes the data available from servers maintained by the DASMI team. InterPro provide a one
stop shop for protein classification by creating protein sequence signatures from its member databases and store them in its own database. This protein classification
scheme is also available through BioMart since InterPro now support queries made from BioMart clients.

Not categorized

Unifying efforts

Exchange format language

Metamining

Predictive interactions

Pathways

Interactions

Resource Type

Bidirectional exchange agreement

Mining source data

Maps to source

Source
Source

Interaction Type

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Protein^protein interaction and pathway databases

The effect of these inconsistencies can also be seen
in the confusion regarding the size of the human
interactome [4951]. Venkatesan et al. [51] estimates
the size to 130 000 binary interactions, Hart et al.
[49] to 154 000369 000 interactions and Stumpf
et al. [50] to 650 000 interactions. Closer inspection
reveals that each team has defined its own search
space as the human interactome, Venkatesan et al.
[51] use the most restrictive definition and only include binary physical interactions. Hart et al. [49] use
in-house experimental data obtained by TAP-MS to
create its source networks which means that proteins
belonging to the same protein complex are also considered to be interacting, thus increasing the size of
their defined interactome. Stumpf et al. [50] rely on a
combination of yeast two hybrid (Y2H) derivated
data sets and literature curated data from DIP [52]
and IntAct [53]. Data obtained by Y2H experiments
will, due to experimental constraints, follow the
definition used by Rual et al. [20] while literature
curated databases uses a more flexible definition of
interaction [48] that also considers non-physical
functional interactions to be a form of interaction.
This situation is not likely to improve unless a
conscious effort is made to solve these issues. One
of our initial theories was that it is likely that the PPI
community would undergo a consolidation similar
to how almost all protein information now can be
accessed through Uniprot.org. A quick glance at the
IMEx consortium also supports this idea but
non-IMEx compliant legacy records mean that
each database will contain a mixture of unique and
shared entries (Arnaud Ceol, Lukasz Salwinski and
Sandra Orchard, personal communication). The
PSIQUIC standard will make it possible to make
a single search query to access each database
(Aranda et al., manuscript in preparation) but each
database will still host its own unique legacy records.
These legacy records combined with the slightly different scope of each database mean that it is unlikely
that we will see a quick reduction of the number of
available databases. Among pathway databases this
consolidation is even further away since each single
database has a unique way of creating and defining its
pathways. Therefore it is unlikely that transparency
is going to increase by a reduction of the number
of sources. This means that we should focus on
increasing transparency by presenting the available
information in a more uniform way.
At the moment there are two major sources of
database information, the annual NAR database

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issue and the webpage of each database. NAR articles are indispensable as a tool when assessing a database but the lack of article standardization makes it
highly time consuming to carefully read articles and
still need to contact the authors with further questions. Therefore it would greatly increase the perceived transparency of databases if a more consistent
article layout is required in the database issue.
Likewise a voluntary effort by database teams to present a webpage which clearly describes the scope and
content of the database would make it easier for users
to properly assess the database. A more clear presentation of database methodology may also provide a
major advantage in attracting other research groups
to conduct experimental or bioinformatical research
based on the database data. By clearly presenting data
the database becomes a more attractive source for
information to use in projects like the prediction of
new protein interactions [54], cross-validation to improve the quality of currently available data sets [42]
or the creation of predictor models used to increase
the economics of high throughput experiments [55].
Making the presentation of different databases more
uniform is likely to prove a cheap and efficient way
to make PPI databases more attractive partners for
researchers active in other fields.

SUPPLEMENTARY DATA
Supplementary data are available online at http://
bib.oxfordjournals.org/.

Key points
 The Cytoweb visualization of PPI databases is a convenient to
identify independent PPI resources (available at: http://www
.pathguide.org/interactions.php).
 Querying metamining databases is not equivalent to independently querying the source databases independently.
 The termprotein ^ protein interaction is ambigous and can refer
to direct physical interactions, membership of the same protein
complex or functional (indirect) interactions.

Acknowledgements
We would like to thank all the researchers who have taken the
time to personally answer our questions. We would also like to
thank Hagen Blankenburg for taking the time to extensively
explain DAS to us and Jonas Klingstrom for his linguistic advice.

FUNDING
Linneska stipendiestiftelsen, EC OxyGreen (KBBE2007-212281) 6FP projects as well as the Polish

712

Klingstrom and Plewczynski

Ministry of Education and Science (N301 159735,

N518 409238 and others).

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