KPP: KEGG Pathway Painter
The motivation for the development of KPP came up from the idea to build a user-friendly,
platform-independent and simple tool to visualize the placement of genes in their
associated pathways. The simplicity of KPP is due to the acceptance of gene identifiers
without reference to respective microarray platform. This isolation enhances its utility
for the studies of the data from RealTime-PCR or medium-throughput platforms or even
for validation of the various hypotheses concerning an involvement of the groups of
genes in one or another biological process.
This utility of KPP was demonstrated by highlighting of cell cycle related events
using the publicly available prostate carcinoma dataset (GDS1439) 17] from the NCBI GEO database (see Figure 1), by aiding the selection of the mutations and epigenetic events to be tested as
a companion diagnostics of treatment susceptibility and resistance in non-small lung
carcinoma patients (not shown) and an analysis of the host-associated risk factors
associated with lack of sustained virological response (SVR) in various cohorts of
HCV patients 18,19].
Figure 1. Image of the MAPK signaling pathway painted by KPP according to the imported list
of genes differentially expressed in the prostatic carcinoma as compared to normal
prostate. Red and blue boxes represent up- and down- regulated genes, respectively. The genes
in green background represent the species specific genes (Homo sapiens, in this case).
In one of these examples, KPP-aided visual parsing the pathways encompassing molecular
components relevant to HCV pathogenesis allowed to pinpoint the Janus kinase-signal
transducers and activators of transcription signaling cascade as the major pathogenetic
component responsible for not achieving SVR 18], a conclusion that was later confirmed in in vitro experiments with blocking antibodies, a pharmacological inhibitor, and siRNAs 20].
In another example, KPP allowed to visualize a sustained pattern of treatment-induced
gene expression in patients carrying interferon/ribavirin-responding IL28B genotype
C/C, while in patients with therapy-resistant IL28B T* genotype, the background pre-activation
of interferon-dependent genes precluded further therapeutic boost 19]. Thus, KPP provided a critical insight into the lower rate of SVR observed in these
patients. Furthermore, KPP analysis revealed LI28B genotype independent role of SOCS1
in therapeutic response 19]. This KPP-aided hypothesis was later investigated both in vitro experiments showing
that SOCS1 acts as a suppressor of type I IFN function against HCV 21] and in serum samples interferon/ribavirin-treated Hepatitis C patients who demonstrated
that methylation-based silencing of SOCS-1 is associated with better therapeutic response
22]. Thus, KPP was indispensable in acquiring mechanistic insights into the differential
therapeutic response in Hepatitis C infected patients.
The major fetching point of the KPP tool lies in its tight connection with the KEGG
database, as this will allow for the pathway visualization of every sequenced organism.
However this flexibility comes at the cost of possible KEGG-attributed delay of the
data transfer, the resultant tool is substantially more convenient for the user than
the tools embed into existing pathway analysis environment, for example, Cytoskape
(http://www.cytoscape.org/). Another commonly used pathway parsing tool, Reactome Skypainter (http://www.reactome.org/), is restricted to underlying knowledge base and, therefore, limits the potential
set of insights to be extracted.
It is important to note that the painting of individual pathways can be performed
through by the KEGG website itself (http://www.genome.jp/kegg/), however, the practicality of KPP is in its comprehensive visual representation
of up- and downregulated genes in the KEGG dataset as a whole. In other words, KPP
allows one to extract immediate and visual insights about cumulative change in each
pathway under scrutiny. Users can browse through high-resolution pathway images and
download an archive of the painted pathways that may be used as figures for upcoming
manuscripts.