13121-06PID_Poster(4x5ft).indd

Shiva Krupa

, Kira Anthony

, Jeffrey Buchoff

, Matthew Day

, Timo Hannay

, Carl Schaefer

. Web Publishing, Nature Publishing Group, 25 First Street, Suite 104, Cambridge, MA, 02141, USA

. National Cancer Institute Center for Bioinformatics and Information Technology, 2115 E Jefferson Street, Rockville, MD, 20852, USA

. Web Publishing, Nature Publishing Group, The Macmillan Building, 4 Crinan Street, London, N1 9XW, UK

. Nature.com, Nature Publishing Group, The Macmillan Building, 4 Crinan Street, London, N1 9XW, UK

Abstract

The Pathway Interaction Database (PID,

http://pid.nci.nih.gov

) is a freely available

collection of curated and peer-reviewed signaling pathways composed of human
biomolecular interactions and cellular processes. Created in a collaboration between the
U.S. National Cancer Institute and Nature Publishing Group, the database is a research
tool for cell biologists, biochemists, computational biologists and bioinformaticians.
The PID offers a range of tools to facilitate pathway exploration. Users can browse the
pre-defi ned set of pathways and also create interaction network maps centered on
a single molecule of interest or an extensive list of molecules. In addition, users can
download complete data sets in extensible markup language (XML) and Biological
Pathway Exchange (BioPAX) Level 2 formats. The database is updated every month and
supplemented by a concise editorial section that provides synopses of recent noteworthy
papers in cell signaling and specially commissioned articles on the practical uses of
other relevant online tools. Users can sign up for free email alerts or RSS feeds to receive
database updates.

Curation principles

· Human model system: We focus on human data. Interactions in other mammals that

are inferred to occur in humans may be included with appropriate evidence codes.

· Biological relevance: Meaningful networks of undisputed interactions are synthesized

into pathways. Pathways selected for curation are based on suggestions made by our
users, potential drugs targets and other biomolecules we know to be of interest to
researchers.

· Authority: Molecular interactions are identifi ed in primary peer-reviewed literature.

Editors judge whether an interaction is physiologically relevant and assign evidence
codes to each interaction. All pathways are reviewed by experts in the fi eld for
accuracy and completeness.

· Standardized nomenclature: We use HUGO (

http://www.hugo-international.org/

committee_nomen.htm

) gene symbols, Entrez Gene (

http://www.ncbi.nlm.nih.

gov/sites/entrez?db=gene

) aliases or UniProt (

http://www.pir.uniprot.org

) names

or aliases for molecules. We use Gene Ontology (

GO, http://www.geneontology.

org

) and NCI Thesaurus (

http://nciterms.nci.nih.gov/NCIBrowser/Dictionary.

) controlled vocabulary terms as gene and gene product labels for molecules and

pathway processes.

Data representation

A pathway is a set of interactions modeled as a directed graph with
labeled nodes and edges.

Pathway building blocks
Biomolecules (nodes)

in PID may be proteins, mRNA, small molecules and

complexes

. Proteins are annotated with UniProt and Entrez Gene identifi ers; mRNA

is annotated with the Entrez Gene identifi er; small molecules are annotated with CAS
Registry Numbers; and complexes may be annotated with the GO cellular component
identifi er for the complex, if available.

Additional biomolecular nomenclature

may include activity states, post-translational

modifi cations

, and GO terms for location and molecular function.

Intra-pathway assembly
Role of biomolecule (edge)

: Each biomolecule can be an input, output, positive

regulator

or negative regulator. Inputs are transformed into outputs, and regulators

act either directly or indirectly on the input. An output biomolecule can form the input,
positive regulator or negative regulator biomolecule in subsequent interactions.

Generic process types (nodes)

: Four process types describe the general nature of each

interaction. These process types are: Modifi cation (binding) including post-translational
modifi cations, translocation, transcription and reaction. Each process may also
possess a condition, which is a requirement for the interaction to take place. A condition
may be defi ned by a GO Biological Process term, a GO Molecular Function term or the
NCI Thesaurus if a cell type-specifi c condition is necessary.

Descriptive process types (node)

: Macroprocesses are multi-step events that are often

defi ned by a GO Biological process term (e.g. activated T cell apoptosis) or by the NCI
Thesaurus if a cancer-related term is necessary.

Evidence

Interactions are supported by references, annotated with PubMed identifi ers. Evidence
codes are also included in the interaction, and are partially derived from GO Evidence
codes. PID evidence codes are as follows:

Acronym Expansion

Description

IAE

Inferred from Array Experiments

ChIP on chip

Protein microarrays/protein chips

Chemical compound arrays

Inferred by Curator

An experimentally-determined interaction, not falling under any of the other
evidence codes, but still deemed to occur by the curator. (Not commonly applied.)

IDA

Inferred from Direct Assay

Enzyme assays

In vitro reconstitution

Functional and activity assays

IFC

Inferred from Functional Complementation

A gene from one organism complements a mutation in another species.

IGI

Inferred from Genetic Interaction

Genetic interactions such as suppressors, synthetic lethals, and rescue experiments

Inference about one gene drawn from the phenotype of a mutation in a different gene

IMP

Inferred from Mutant Phenotype

Any gene mutation/knockout

Overexpression/ectopic expression of wild-type or mutant genes

Anti-sense

experiments

RNAi

experiments

Polymorphism or allelic variation

IOS

Inferred from Other Species

An interaction that is inferred from another species due to a lack of evidence in human.

IPI

Inferred from Physical Interaction

Any physical interaction detection method, common ones are: 2-hybrid interactions

co-purifi cation, co-immunoprecipitation, and ion/protein binding experiments.

RCA

Inferred from Reviewed Computational Analysis Predictions based on large-scale experiments (e.g. genome-wide

two-hybrid, genome-wide synthetic interactions)

Predictions based on integration of large-scale datasets of several types

Text-based computation (e.g. text mining)

RGE

Inferred from Reporter Gene Expression

Reporter gene expression studies

TAS

Traceable Author Statement

Anything found in secondary literature (such as a review article or textbook) where
the original experiments are traceable through that piece of literature.

Inter-pathway assembly

To facilitate additional connectivity, curated pathways may be linked to from one another.
In addition, to arrange the cascade of events, pathways may be divided into smaller,
biologically meaningful subnetworks.

http://pid.nci.nih.gov

PID homepage

Curation process

Interactive network map

Predefi ned pathways and dynamically generated network maps based on web queries
are generated by the freely available GraphViz (

http://www.graphviz.org

) program

and can be visualized in either Scalable Vector Graphics (SVG) or Graphics Interchange
(GIF) Formats. The SVG format requires that a plugin be downloaded from

http://www.

adobe.com/SVG/viewer/install/main.html

. The network maps are interactive; users

can click on a biomolecule or interaction icon for more information. The search term,
TAB1, is shown in blue.

A CELL SIGNALING RESOURCE

PID NCI-Nature Curated

Pathway Data

response to stress

TRAF6+

<p38 alpha/TAB1>[cy]

p38 alpha+

TAB1

<PKG I alpha/cGMP/

p38 alpha>

PKG I alpha

p38 alpha

cGMP

apoptosis

<TAK1/TAB family>+

TAK1+

TAB family

p38alpha-beta+

TAK1

TAB family

Nemo like kinase+

Nemo like kinase

TAB1

TAK1+

MKK3+

MKK3

TRAF6

TAB2

p38 alpha

<PKG I alpha/cGMP>+

PKG I alpha

cGMP

MKK6+

MKK6

family:

TAB family

family:

MKK3-MKK6

Browsing & searching

Users can browse complete, predefi ned pathways, and perform simple or advanced
molecule or process searches. Searches can also be limited by evidence code.

Batch query
The Batch query allows users to upload long lists of molecules and analyze their
relationships in pathways. Two lists can be uploaded simultaneously in order to compare
data sets (e.g. gene expression results). Using the list from Stratton and colleagues
(2007) of 120 protein kinases found to contain at least one cancer-predisposing
mutation and selecting the NCI-Nature curated data source, users can view the network
connectivity of the uploaded molecules. The output is a set of 19 distinct network maps
(the one with the most interactions is shown below). Query molecules are shown in blue
in the network map:

Editorial content

Research highlights
Relevant cell signaling and bioinformatics research highlights written by the Nature
Reviews team are featured in the PID monthly updates.

Bioinformatics primers
Bioinformatics primers provide practical advice on how to make the most of important
online resources. Previously published Bioinformatics primers include:

We are currently commissioning Bioinformatics primers for the second half of 2008.

Data download options

Users can download data in either XML (Extensible Markup Language) or BioPAX
(

http://www.biopax.org/

) formats by visiting the Download data page at

http://pid.

nci.nih.gov/PID/download.shtml

. The PID supports BioPAX Level 2 format for pathway

data exchange, which includes metabolic pathways, molecular interactions and protein
post-translational modifi cations.

Community

BioPAX
The PID is participating in the development of future levels of BioPAX, which will increase
support for signaling pathways, gene regulatory networks and genetic interactions.

Pathway Commons
PID pathways are also featured in Pathway Commons (

http://www.pathwaycommons.

org

), which is a biological pathways portal allowing for pathway visualization and analysis

via Cytoscape (

http://www.cytoscape.org

References

An Introduction to the NCI-Nature Pathway Interaction Database
Carl F. Schaefer

Pathway Interaction Database (09 November 2006) DOI: 10.1038/PID.2006.001

Patterns of somatic mutation in human cancer genomes.
Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague
J, Butler A, Stevens C, Edkins S, O'Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe
S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K,
Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T,
Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S,
Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga
L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E,
Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster
R, Futreal PA, Stratton MR

Nature. 2007;446;153-8. PMID: 17344846 DOI: 10.1038/nature05610

PID NCI-Nature Curated

Pathway Data

epidermal growth

factor receptor

activity

p38alpha-beta+

response to UV

RAR alpha

response to oxidative

stress

<NF kappa B1 p50/

RelA>+[cy]

NF kappa B1 p50

RelA

I kappa B alpha[cy]

CD8-positive alpha-beta
T cell lineage commitment

<STAT3>+

STAT3

calcium-dependent

protein kinase C

activity

ITK+

mitosis

<Aurora B/TACC1>[spindle midzone]

Aurora B

TACC1

G2/M transition

checkpoint

CDC25B[centrosome]

activation of NF-kappaB

transcription factor

ELAM1

mitotic prometaphase

hSgo1

Survivin

Aurora B

cytokinesis

<Aurora B/Septin1>[midbody]

Aurora B

Septin1

oligodendrocyte

cell fate commitment

JNK family+

response to nutrient

p70S6K+

<STAT1 (dimer)>+

STAT1

senescence

Cortactin

Src+

beta Arrestin2

meiosis

Aurora A

CPEB

response to stress

<p38 alpha/TAB1>[cy]

p38 alpha+

TAB1

<PKG I alpha/cGMP/

p38 alpha>

PKG I alpha

p38 alpha

cGMP

response to insulin

stimulus

<Aurora C/Aurora B/
INCENP>[chromosome]

Aurora C+

INCENP

Aurora B+

metaphase

<Aurora C/Aurora B/
INCENP>[chromosome]

Aurora C+

INCENP

Aurora B

MLCK

VCAM1

tumor necrosis factor

receptor activity

<IKK complex/ELKS>+1

ELKS

IKK alpha

NEMO

IKK beta

I kappa B alpha-[cy]

prophase

<NDEL1/TACC3>[centrosome]

NDEL1

TACC3

Desmin[cleavage furrow]

<Condensin I complex>[chromosome]

Condensin complex

subunit 3

SMC2

Condensin complex

subunit 1

SMC4

Condensin complex

subunit 2

RXR alpha

IRS1-

Aurora A

BRCA1

Aurora B[inner kinetochore of condensed chromosome]

ICAM1

anaphase

Vimentin[cleavage furrow]

NPM1

NSUN2-

Nucleolin

natural killer cell

activation

<AKT1/mTOR/p70S6K/

Hsp90/TERT>+

Hsp90

AKT1+

p70S6K+

mTOR+

TERT+

G2/M transition
of mitotic cell

cycle

<Aurora A/RasGAP/

Survivin>

Aurora A-

Survivin

RasGAP

Histone H3

G2 phase of mitotic

cell cycle

Ajuba

Aurora A+

circulation

<Tie2/SHP2>+[m]

Tie2+

SHP2

Tie2+

muscle cell differentiation

MAPKKK cascade

mitotic anaphase

proteasomal ubiquitin-dependent

protein catabolic

process

JNK cascade

cell survival

actin cytoskeleton

reorganization

<PDGF/PDGFRA/SHB>+

PDGFRA[plasma membrane]

PDGFA-B-C[ex]

PDGFRA[plasma membrane]

SHB

regulation of mast
cell degranulation

PLA2 Group 4A+

PKC beta+

actin cytoskeleton
organization and

biogenesis

PKC zeta+

T cell proliferation

alpha-beta T cell

proliferation

JNK2+

platelet activating
factor biosynthesis

p38 beta+

cell proliferation

<alphaV beta3 Integrin/

TGFBR2>

alphaV Integrin

TGFBR2

beta3 Integrin

JNK1+

JNK1+[n]

p38 alpha+

Role of Calcineurin-dependent

NFAT signaling in

lymphocytes

<PDGF/PDGFRA/Shf>+

PDGFRA[plasma membrane]

PDGFA-B-C[ex]

PDGFRA[plasma membrane]

Shf

chemotaxis

Typical PKCs+[plasma membrane]

muscle contraction

positive regulation
of innate immune

response

platelet activation

Signaling mediated
by p38alpha-beta

<RhoA/GTP/ROCK1>+

RhoA

ROCK1+

GTP

centrosome duplication

<PAK1/Aurora A>[centrosome]

PAK1+

Aurora A+

protein catabolic

process

<Aurora A/PP2A>-[centrosome]

Aurora A

PP2A

Aurora A

Antizyme1

PKA+

PI3K Class IA+[plasma membrane]

macrophage chemotaxis

<Interferon-gamma receptor/

IFN gamma>+

Interferon-gamma

receptor

IFN gamma

<PDGF/PDGFRA>+

PDGFRA[plasma membrane]

PDGFA-B-C[ex]

PDGFRA[plasma membrane]

Aurora A

neuron differentiation

<RELN/LRP8/DAB1/FYN/

MAPK8IP1/MKK7/MAP3K11/

JNK1>

...

endothelial cell

proliferation

PKC alpha+

mRNA polyadenylation

regulation of mRNA

stability

<p38alpha-beta/MAPKAPK2>+

p38alpha-beta+

MAPKAPK2

p38 signaling mediated

by MAPKAP kinases

neuron migration

<RELN/VLDLR/DAB1/

FYN>

DAB1+

RELN[ex]

FYN

VLDLR[plasma membrane]

protein ubiquitination

DAB1+

RELN[ex]

FYN

LRP8[plasma membrane]

cell migration

MATK+[cy]

<Tie2/Ang1/Integrin>+[m]

...

LYN

<PI3K>+[plasma membrane]

PI3K catalytic alpha

polypeptide 1

PI3K regulatory

subunit polypeptide

spindle checkpoint

Aurora B

Aurora B Signaling

Bub1

ubiquitin-dependent
protein catabolism

<VEGFR1 homodimer/

VEGFA homodimer/

CBL/CD2AP>+[plasma membrane]

...

long-term memory

<GRIN2B/RELN/LRP8/

DAB1/FYN>

FYN

GRIN2B+

RELN[ex]

LRP8

DAB1

<GRIN2A/RELN/LRP8/

DAB1/FYN>

FYN

GRIN2A+

RELN[ex]

LRP8

DAB1

apoptosis

JNK1+[n]

MKK4+[cy]

<NF-kappa-B/RelA/

I kappa B alpha/

ubiquitin>

NF-kappa-B

I kappa B alpha

RelA

CBL[cy]

<NF-kappa-B/RelA/

I kappa B alpha>

NF kappa B1

I kappa B alpha

RelA

IKK alpha+

PKC beta+

PKC epsilon+[cy]

spindle assembly

<Aurora A/TACC1/TRAP/

chTOG>[centrosome]

chTOG

Aurora A

TRAP

TACC1

<Aurora A/TPX2>[spindle pole]

Aurora A+

TPX2

HURP

negative regulation

of apoptosis

<FGFR2b/FGF1/PAK4/

Grb2>

GRB2

FGFR2b

PAK4

FGF1

tube development

FYN+[cy]

VEGFR1 specific

signals

<VEGFR1 homodimer>[plasma membrane]

VEGFR1

Na CD8+ T cell

downstream signals

PKC theta+[plasma membrane]

MAPK events mediated

by Trk Receptor

signaling

PKC delta+[plasma membrane]

Aurora A signaling

Aurora A

Aurora C Signaling

Aurora C

Canonical NF kappa

B Pathway

<IKK complex>+1[cy]

IKK alpha

NEMO

IKK beta

<p38alpha-beta/MAPKAPK3>+

p38alpha-beta+

MAPKAPK3

Alternative NF kappa

B Pathway

IKK alpha[cy]

<VEGFR1 homodimer/

VEGFA homodimer/

SHP2>+[plasma membrane]

VEGFA

VEGFR1

VEGFA

SHP2[cy]

<VEGFR1 homodimer/

VEGFA homodimer>+[plasma membrane]

VEGFR1

VEGFA

<PDGF/PDGFRA/Caveolin-3>+

PDGFRA[plasma membrane]

PDGFA-B-C[ex]

PDGFRA[plasma membrane]

Caveolin-3

LYN+[plasma membrane]

LYN[cy]

LPA

LPA1-2-3[plasma membrane]

Aurora A-

RasGAP

AURKAIP1

Antizyme1

MKK4 fragments-[cy]

MKK4[cy]

Lethal factor[cy]

metalloendopeptidase activity

TH+

Src Family Kinases

Src Family Kinases+

<p62DOK/Csk>[plasma membrane]

p62DOK+

CSK

AKT1-

AKT1+[plasma membrane]

<RhoA/GDP>+

RhoA

GTP

PKC zeta+[plasma membrane]

MKK4+

MEKK1 (cleaved)

MEKK1+

ATF2+

ATF2

VEGFR1[plasma membrane]

VEGFR2[plasma membrane]

AKT1+[plasma membrane]

AKT1[cy]

<NF kappa B1 p50/

RelA>+[n]

NF kappa B1 p50

RelA

mTOR+

p38alpha-beta

<RAL/GTP>+

RAL

GTP

NEMO[cy]

IKK beta[cy]

ER81-

ER81

NCK1

Dok-R

<Tie2/Ang1>+[m]

Ang1

Tie2+

NCK1[cy]

Fes+[cy]

Fes[cy]

<Tie2/Ang2>[m]

Ang2

Tie2-

<IL2/IL2R alpha/beta/
gamma/JAK1/LCK/JAK3/

SHC>+[integral to membrane]

...

<EGF/EGFR>+

EGF[ex]

EGFR[m]

EGF[ex]

EGFR[m]

FYN+

FYN-

CD45[integral to membrane]

protein tyrosine phosphatase activity

VEGFA

Aurora A-

GADD45A

LYN+

<EPO/EPOR (dimer)/

LYN>

EPO[ex]

LYN+

EPOR+[plasma membrane]

EPOR+[plasma membrane]

EPO[ex]

EPOR+[plasma membrane]

JNK family

<proNGF (dimer)/p75(NTR)/

Sortilin/TRAF6/NRIF>+[integral to membrane]

...

<Aurora A/NDEL1/TACC3>[centrosome]

NDEL1

Aurora A+

TACC3

<LAT/GRAP2/SLP76/

VAV1/ITK/PLCgamma1>+[integral to membrane]

...

PLCgamma1-[cy]

<LAT/GRAP2/SLP76/

VAV1/ITK>+[integral to membrane]

VAV1

LAT

SLP76

GRAP2

ITK

FER+

FER

<Antigen/IgE/Fc epsilon R1/

LYN/SYK>

...

FASLG[ex]

JNK1+

JNK1

MKK7+[cy]

MEKK2+

MEKK2

<RAP1/GTP>+[endosome]

RAP1

GTP

RAR alpha

<RET51/GFRalpha1/
GDNF/PKC alpha>[m]

...

<RET51/GFRalpha1/

GDNF>[m]

...

PKC alpha

<NF kappa B1 p50/

RelA/I kappa B alpha>[cy]

NF kappa B1 p50-

RelA

I kappa B alpha

LCK+

RAF1+[cy]

RAF1[cy]

HRAS+[plasma membrane]

Yes+

Yes

<Noncanonical Wnts/

FZD>

Noncanonical Wnts

Noncanonical FZD

3_6[m]

<TCR/CD3/MHC II/CD4/

FYN>+[integral to membrane]

...

<TCR/CD3/MHC II/CD4>+[integral to membrane]

...

PKC epsilon[cy]

DAG

PKC theta[cy]

<LAT/GRAP2/SLP76/
VAV1/PI3K Class IA>+

VAV1

LAT

SLP76

GRAP2

PI3K Class IA

<TCR/CD3/MHC I/CD8/

LCK/ZAP-70>+[integral to membrane]

...

Src+[plasma membrane]

<IKK complex/PKC

alpha>+

PKC alpha

IKK alpha

NEMO

IKK beta

<IKK complex>[cy]

IKK alpha

NEMO

IKK beta

ERK1-2+[cy]

ERK1-2-[cy]

<IL2/IL2R>+[integral to membrane]

IL2

IL2R alpha

IL2R gamma

IL2R beta

STAT3

<IL12/IL12R/TYK2/

JAK2>+[integral to membrane]

...

Caveolin-1+

Caveolin-1

Src+

MKK3-MKK6+

MKK3-MKK6

BRAF+[cy]

<NF kappa B/RelA>-[cy]

NF kappa B

RelA

<NF kappa B/RelA>+[cy]

NF kappa B

RelA

<Tie2/Ang1/ABIN2>+[m]

Ang1

Tie2+

ABIN2

<Tie2/Ang1/Grb7>+[m]

Ang1

Tie2+

GRB7

Src

<alpha4 beta1 Integrin/

VCAM1>

alpha4 Integrin

VCAM1

beta1 Integrin

JUN+[n]

JUN[n]

USF1+

USF1

BCL2-

BCL2

MAPKA C-alphaP2-3+

MAPKA C-alphaP2-3

<VEGFR1 homodimer/

VEGFB homodimer>+[plasma membrane]

VEGFB

VEGFR1

VEGFB

VEGFB

ITK

PKC

Tie2[m]

Ang2[ex]

<PDGFB-D/PDGFRB/CBL>+

PDGFB-D[ex]

CBL

PDGFB-D[ex]

PDGFRB[plasma membrane]

<PDGFB-D/PDGFRB>+

PDGFRB[plasma membrane]

PDGFB-D[ex]

PDGFRB[plasma membrane]

CBL

eIF4E+

eIF4E

<p38alpha-beta/MNK1>+

p38alpha-beta+

MNK1

<TCR/CD3/MHC I/CD8/

LCK>+[integral to membrane]

...

<TCR/CD3/MHC I/CD8>+[integral to membrane]

...

<B7 family/CD28>+[integral to membrane]

CD28

B7 family

LCK+

PTP1B+

PTP1B

TACC1

CHOP+

CHOP

PKC alpha+[plasma membrane]

PKC alpha[cy]

p38 beta

MKK3+

NFAT1+[n]

JNK1+[n]

<RAC1/OSM/MEKK3/MKK3>+[plasma membrane]

MKK3

OSM

Rac1

MEKK3

NHE1+

NHE1

SHIP

PKC beta

Ca ++[cy]

Plasmin[ex]

Plasmin[cy]

alphaV Integrin

beta3 Integrin

TGFBR2

MEK1+[cy]

MEK1[cy]

<p38alpha-beta/MKP7>-

p38alpha-beta-

MKP7+

<Tie2/Ang1/Shc>+[m]

Ang1

Tie2+

SHC

SHC[cy]

<PI3K>[cy]

PI3K catalytic alpha

polypeptide 1

PI3K regulatory

subunit polypeptide

<VEGFR1 homodimer/

PLGF homodimer>+[plasma membrane]

PLGF

VEGFR1

PLGF

MEF2C+[n]

MEF2C[n]

NERF2

JNK1

RAR alpha

GIT1

beta-PIX

<GIT1/beta-PIX/PAK1>[centrosome]

GIT1

PAK1+

beta-PIX

KRT8+

KRT8

<TXA2/TXA2-R family>[integral to membrane]

TXA2

TXA2-R family-

<TXA2/TXA2-R family>+[integral to membrane]

TXA2

TXA2-R family

CRK[cy]

Dok-R

CRK[cy]

Dok-R

CRK[cy]

Ku70

BARD1

KU80

DNA-PKcs

BARD1

<DNA-PK>

DNA-PKcs

KU80

Ku70

RAB7

BRAF[cy]

<RIT1/GTP>+

RIT1

GTP

<NGF (dimer)/p75(NTR)/

TRAF6/RIP2/IRAK/

p62/Atypical PKCs>+[integral to membrane]

...

<NGF (dimer)/p75(NTR)/

TRAF6/RIP2/IRAK>+[integral to membrane]

...

Atypical PKCs

p62

TSC2+

TSC2

JNK1[cy]

<AP1>+[n]

FOS

JUN

<AP1>[n]

FOS

JUN

BTK+[plasma membrane]

5-LO+

5-LO

<mTOR/RHEB/Raptor/

eIF4E>

eIF4E+

Raptor

mTOR

RHEB

4E-BP1-

eIF4E-

4E-BP1

TSC1

TSC2

Raptor

mTOR

RHEB

p38 alpha+

p38 alpha

LCK-

LCK

<CSK/PAG1>+

CSK

PAG1

<GNAI2/GTP>+

GNAI2

GTP

ASK1+[cy]

FYN[cy]

MKK4+

VAV2+

VAV2

PP2A

Aurora A

ERK1-2+

ERK1-2

<IGF-1R/IRS1>

IGF-1R

IRS1

p130Cas+

p130Cas

RAF1+

RAF1

<Fc epsilon R1/FcgammaRIIB/

SHIP/RasGAP/p62DOK>

...

HRAS+

CREB1+[n]

CREB1[n]

<PI3K>[plasma membrane]

PI3K catalytic alpha

polypeptide 1

PI3K regulatory

subunit polypeptide

<IKK complex>[cy]

IKK alpha

NEMO

IKK beta

PKC epsilon+[plasma membrane]

CDC25B

<TCR/CD3/MHC I/CD8/

FYN>+[integral to membrane]

...

<RAS family/GTP>+[plasma membrane]

RAS family

GTP

PLCgamma1+[cy]

PLCgamma1[cy]

RAF1+[cy]

MAPKAPK2+

MAPKAPK2

MAPKAPK3

MKK4+[cy]

PKC theta[plasma membrane]

FLNA

PKC theta+[plasma membrane]

FLNA

p70S6K+

p70S6K

cAMP

TNF alpha[ex]

<NFAT1-c-4 (dimer)/

EGR4>

NFAT1-c-4+[n]

EGR4[n]

<Tie2/Ang1>+

Ang1

Tie2+

Elf1

ASK1-

PP5C

Rapamycin

ASK1+

mTOR+

PP5C

<RAR gamma2/9cRA>+

Rar gamma2

9cRA

Rar gamma2

<TFIIH>

Cyclin H

MAT1

Cdk7

9cRA

PRL-1

CEBPB+

CEBPB

ceramide

JAK1+

JAK1

<PDGF/PDGFRA/CRK>+

PDGFRA[plasma membrane]

PDGFA-B-C[ex]

PDGFRA[plasma membrane]

CRK[cy]

MKK6+

<LAT/GRAP2/SLP76/

VAV1>+[integral to membrane]

VAV1

LAT

SLP76

GRAP2

ITK+[plasma membrane]

MEK1+[cy]

MEK2+[cy]

MEK2[cy]

PKC beta+[plasma membrane]

MMP2[ex]

MMP2[cy]

RasGAP+[cy]

RasGAP[cy]

CD45[m]

protein tyrosine phosphatase activity

mTOR

AKT1+[plasma membrane]

hSgo1

Survivin

<p75(NTR)/beta APP>+

p75(NTR)

beta APP

TRPV1+[cy]

TRPV1[cy]

Src+

<RAS family/GTP/PI3K>+[plasma membrane]

GTP

PI3K catalytic alpha

polypeptide 1

RAS family

PI3K regulatory

subunit polypeptide

Septin1[midbody]

Aurora B[midbody]

ITK[cy]

<TCR/CD3/MHC II/CD4/

LCK>+[integral to membrane]

...

PLGF

PKC beta[cy]

TPX2[microtubule]

<TRAF6/MEKK3>+

TRAF6

MEKK3

TRIP6

LPA

LPA2[plasma membrane]

PP2A-

<RAC1/GTP>+

Rac1

GTP

<NFATc/p38 alpha>-[cy]

NFATc

p38 alpha

NFATc[cy]

Src[plasma membrane]

<HGF/MET/Paxillin/

FAK1/FAK12/RasGAP>+[plasma membrane]

...

CDC42+

CDC42

I kappa B alpha-[cy]

<NF kappa B1 p50/

RelA/I kappa B alpha>+1[cy]

NF kappa B1 p50-

RelA

I kappa B alpha

<IKK alpha homodimer>+[cy]

IKK alpha

<NF kappa B2 p100/

RelB>-[cy]

NF kappa B2 p100

RelB

<NF kappa B2 p100/

RelB>-[cy]

NF kappa B2 p100

RelB

NIK+[cy]

MEKK1+

<STAT5A (dimer)>+[n]

STAT5A

PLCgamma1+[cy]

MKK6

<ASK1/ASK2>+

ASK1

ASK2

MITF+

MITF

RasGAP

Dok-R

FYN

MEK1+

MEK2+

MEK1

MEK2

RAF1+

KSR+

PLD2+

PLD2

<Antigen/IgE/Fc epsilon R1/

FYN>

...

<APC/C>+

CENP-A+1

CENP-A

MEK5+

MEK5

KRT19+

KRT19

<p38alpha-beta/MAPKAPK2/

TCF3>-

p38alpha-beta+

TCF3

MAPKAPK2

TCF3

BIM+

BIM

JNK1+

PKC zeta+

ceramide

<Antigen/IgE/Fc epsilon

R1>

Fc epsilon RI gamma-chain[m]

IgE

Fc epsilon RI beta-chain[m]

Antigen

Fc epsilon RI alpha-chain[m]

IgE

SYK

Fc epsilon RI beta-chain[m]

Fc epsilon RI gamma-chain[m]

Fc epsilon RI alpha-chain[m]

LYN[plasma membrane]

Antigen

SRF+[n]

SRF[n]

NOS2

Hec1[kinetochore]

<SHC/Grb2/SOS1>+

SOS1[cy]

SHC

GRB2[cy]

SOS1[cy]

SHC

GRB2[cy]

MKK7[cy]

<FAS/FADD/DAXX/Ask1/

Caspase 8/Caspase 8/

FASLG>

...

<TNFR1A/Caspase 2/

TNF alpha/FADD/TRADD/

RIP1/cIAP2/TRAF1/
TRAF2/Ask1/RAIDD>

...

RELN[ex]

DAB1+

VLDLR[plasma membrane]

RELN[ex]

DAB1+

LRP8[plasma membrane]

RELN[ex]

FYN

LRP8[plasma membrane]

RELN[ex]

FYN

VLDLR[plasma membrane]

DAB1

Src family inhibitors PP1 and PP2

<IKK complex/A20>[cy]

NEMO

IKK beta

TNF alpha[ex]

TNFR1A

A20

<IKK complex/ELKS>[cy]

ELKS

IKK alpha

NEMO

IKK beta

ELKS[cy]

SYK+

LAT+[m]

LAT[m]

<TCR/CD3/MHC II/CD4/

LCK/ZAP-70>+[integral to membrane]

...

PLCgamma1+[plasma membrane]

PLCgamma1[plasma membrane]

Aurora B-

PP1-gamma

Aurora B-

PP2A

PP1-gamma[chromatin]

<PDK1/PKC theta>+

PDK1

PKC theta

PKC delta+

PKC delta

<SHH Np/Cholesterol>[ex]

SHH Np

Cholesterol

Gab1+[cy]

Gab1[cy]

HGF[ex]

MET+[m]

<VEGFR3/VEGFC-D/CRK>+[plasma membrane]

VEGFR3

VEGFC-D

CRK

<p38alpha-beta/MKP1>-

p38alpha-beta-

MKP1+

p70S6K+[cy]

p70S6K[cy]

STAT3+[cy]

STAT3[cy]

ATM+[n]

<NEMO/ATM>[n]

NEMO

ATM

ADAP+

ADAP

SHP2

<TAK1/TAB family>+

TAK1+

TAB family

TAK1

TRAF6+

TAB family

IKK alpha

NF kappa B1+

<TSC1/TSC2>+

TSC1

TSC2

<LAT/GRAP2/SLP76/

VAV1/ITK/PLCgamma1/

CBL>-[integral to membrane]

...

CBL+[cy]

<IGF-1R/IRS1/SHP2>

IGF-1R

SHP2+

IRS1

SHP2+[cy]

Stathmin

<PKC theta/SPAK>+

PKC theta

SPAK

PKC theta[plasma membrane]

IP3

PI-4-5-P2[plasma membrane]

Ang1

<PDK1/PKC theta>+[plasma membrane]

PDK1

PKC theta

MEK1-2+[cy]

MEK1-2[cy]

Src-

STAT1

Cortactin

MKK4

<B-cell antigen/BCR complex/

LYN>

Ig-beta[m]

B-cell antigen[ex]

BCR[m]

LYN+

Ig-alpha[m]

PAG1

CSK+

<B-cell antigen/BCR

complex>

Ig-alpha[m]

B-cell antigen

Ig-beta[m]

BCR[m]

CD45+

beta Arrestin2

<CK2>

<CaM/Ca2+/Calcineurin

A alpha-beta B1>+

CaM

Calcineurin A alpha-beta

Ca2+

<CaM/Ca2+/Calcineurin

A alpha-beta B1>

CaM

Calcineurin A alpha-beta

Ca2+

protein tyrosine phosphatase activity

<NFATc/JNK1>-[cy]

NFATc

JNK1+

<NF kappa B1 p105/

p50>+[cy]

NF kappa B1 p50

<NF kappa B1 p105/

p50>-[cy]

NF kappa B1 p50

ATF6+

ATF6

CPEB

<IKK complex/ELKS>+

ELKS

IKK alpha

NEMO

IKK beta

CENP-A

LSP1+

LSP1

PDGFA-B-C[ex]

PDGFRA[plasma membrane]

NEMO[cy]

c-Abl+

c-Abl

PLCgamma1+[plasma membrane]

NEMO[n]

BAD[cy]

Alpha-Synuclein+[cy]

PKC delta

Alpha-Synuclein+[cy]

BAD[cy]

HURP

PDK1+[plasma membrane]

<PKG I alpha/cGMP>+

PKG I alpha

cGMP

TAB1

Adenylyl Cyclase+

Adenylyl Cyclase

PGC1+

PGC1

<VEGFR2 homodimer/

VEGFA homodimer/

Src>+[plasma membrane]

VEGFR2

VEGFA

Src

<VEGFR2 homodimer/

VEGFA homodimer>+[plasma membrane]

VEGFR2

VEGFA

<Aurora B/RasGAP>-

Aurora B

RasGAP

PRAK+

PRAK

BAD+

BAD

RHEB

ERK1+[cy]

PKC delta

ERK1+[cy]

IGF1+

IKK beta+

NEMO-

Hsp27+

Hsp27

<MAPK8IP1/MKK7/MAP3K11/

JNK1>

JNK1

MAPK8IP1

MAP3K11

MKK7

ARHGEF2

<RET51/GFRalpha1/

GDNF/Dok6>[m]

...

Dok6

<JNK2/NFAT4>-[cy]

JNK2

NFAT4

NFAT4[cy]

JNK2+[cy]

<IKK alpha homodimer>[cy]

IKK alpha

ABIN2

INCENP

VAV1+[plasma membrane]

VAV1[cy]

<VEGFR1 homodimer/

NRP2/VEGFR121>[plasma membrane]

VEGFR121

VEGFR1

NRP2

VEGFR1

<VEGFR1 homodimer/

NRP2>[plasma membrane]

VEGFR1

NRP2

VEGFR1

VEGFA121

PYK2+

TRAF6

<CARD11/BCL10/MALT1/

TAK1>+

TAK1+

CARD11

MALT1

BCL10

<PDGF/PDGFRA/CRK/

C3G>+

...

C3G

<Chromosomal passenger
complex>+[chromosome]

Borealin

Aurora B

Survivin

INCENP

Borealin

<GAB2/PI3K/SHP2>+

PI3K regulatory

subunit polypeptide

GAB2+

PI3K catalytic alpha

polypeptide 1

SHP2

GAB2

JNK1+[cy]

<Telomerase/AKT1/

mTOR/p70S6K>+

...

...

IL2[ex]

JNK1+[cy]

TSC2+

FKBP12

Rapamycin

MLCK

<Tie2/Ang1/Grb2>+[m]

Ang1

Tie2+

GRB2

GRB2[cy]

MATK[cy]

<SCF/KIT>+[m]

SCF

KIT

FGFR2b

FGF1

PAK4

ER alpha+[n]

ER alpha[n]

PKC epsilon

<Tie2/Ang1/Grb14>+[m]

Ang1

Tie2+

GRB14

<RAC1-CDC42/GTP/PAK

family>+[plasma membrane]

RAC-CDC42

PAK family+

GTP

Shf

<LYN/TEC/p62DOK>[plasma membrane]

LYN

p62DOK

TEC

p62DOK

TEC

<NGF (dimer)/TRKA/
MATK>+[endosome]

NGF

TRKA

NGF

TRKA

MATK

<NGF (dimer)/TRKA>+[endosome]

NGF

TRKA

NGF

TRKA

MATK

BCL2[mi]

NRP2

<S1P1/Sphingosine-1-phosphate/

PDGFB-D/PDGFRB>+[plasma membrane]

...

<STAT4 (dimer)>+[n]

STAT4

<STAT3/STAT4>+[n]

STAT4

YWHAZ+

YWHAZ

<NGF (dimer)/TRKA>+[integral to membrane]

NGF

TRKA

NGF

TRKA

Alpha-Synuclein+[cy]

Alpha-Synuclein[cy]

<AP-1/NFAT1-c-4>+[n]

FOS

NFAT1-c-4+[n]

JUN

p53

p53-

p53

AKT1+

<VEGFR2 homodimer/

VEGFA homodimer/

Yes>+[plasma membrane]

VEGFR2

VEGFA

Yes

CaT1+[plasma membrane]

CaT1[plasma membrane]

PLD+

PLD

COT

<RET51/GFRalpha1/
GDNF/DOK/RasGAP/

NCK>[m]

...

PKC delta[cy]

MSK1-2+

MSK1-2

p38alpha-beta-

DUSP8

<TXA2/TP alpha>-[integral to membrane]

TXA2

TP alpha

<TXA2/TP alpha>+[integral to membrane]

TXA2

TP alpha

<PGK/cGMP>+

PGK

cGMP

p53+

MEK1+

RAF1[plasma membrane]

NDEL1

TACC3

CDC25B-

TRAP

chTOG

<proBDNF (dimer)/
p75(NTR)/Sortilin/

TRAF6/NRIF>+[integral to membrane]

...

MEF2A+

MEF2A

GDI1+

GDI1

Desmin

TAK1+

RELN[ex]

VLDLR[plasma membrane]

RELN[ex]

LRP8[plasma membrane]

MKK7 fragments-[cy]

Gab1+[plasma membrane]

Gab1[plasma membrane]

I kappa B alpha-

I kappa B alpha

MAP3Ks+

PKC zeta

<IL2/IL2R alpha/beta/
gamma/JAK1/LCK/JAK3/
SHC/Grb2/SOS1/GAB2/

SHP2/PI3K>+[integral to membrane]

...

COX-2

Raptor

<Condensin I complex>[chromosome]

Condensin complex

subunit 3

SMC2

Condensin complex

subunit 1

SMC4

Condensin complex

subunit 2

<AP1>+[n]

FOS[n]

JUN[n]

<AP1>[n]

FOS[n]

JUN[n]

p21CIP1

I kappa B alpha-[cy]

NFAT1-c-4+[cy]

NFAT1-c-4-[cy]

<NF-kappa-B/RelA>+[cy]

NF-kappa-B

RelA

I kappa B alpha-

<NF-kappa-B/RelA/
I kappa B alpha>-[cy]

NF-kappa-B

I kappa B alpha+

RelA

SAP1+

SAP1

LCK-

SHP1+

protein tyrosine phosphatase activity

STAT5A+[cy]

STAT5A[cy]

FER+[cy]

JAK2+[cy]

CK-II[n]

ERK1+[n]

cPLA2-alpha+

cPLA2-alpha

RXR alpha

<AP-1/NFAT1-c-4>+[n]

FOS

NFAT1-c-4+[n]

JUN

GLI2A+[n]

GLI2[cy]

DLK

RASGRP1+[plasma membrane]

RASGRP1[cy]

<p38alpha-beta/CK2>+

p38alpha-beta+

<CK2>+

ERK1-2+

TRPV1

IRS1+

LY294002

<RIP1/MEKK3>+

RIP1[cy]

MEKK3

JNK1+[cy]

<GAB1/CRKL/SHP2/PI3K>+[cy]

PI3K catalytic alpha

polypeptide 1

Gab1[cy]

SHP2

CRKL

PI3K regulatory

subunit polypeptide

TAK1+

<PDGF/PDGFRA/alphaV

Integrin>+

PDGFRA[plasma membrane]

PDGFA-B-C[ex]

PDGFRA[plasma membrane]

alphaV Integrin

SHB

CD2AP

Aurora A-

Gsk3beta[cy]

NEMO[cy]

<NGF (dimer)/p75(NTR)/

TRAF6/RIP2>+[integral to membrane]

...

MYD88

IRAK

Fibronectin

IRS1

IGF-1R

NEMO[cy]

CDC42+[cy]

MKK7

IL6

MEK1+[cy]

<IL2/IL2R beta/gamma/

JAK1/LCK/JAK3>+[integral to membrane]

...

STAT5

JNK1-2+

JNK1-2

<IL18/IL18R>+

IL18

IL18Rbeta

IL18R1

<RIN/GTP>+

RIN

GTP

<PDGF/PDGFRA/Caveolin-1>+

PDGFRA[plasma membrane]

PDGFA-B-C[ex]

PDGFRA[plasma membrane]

Caveolin-1

MSK1+

MSK1

FER[cy]

<VEGFR2 homodimer>[plasma membrane]

VEGFR2

PKC delta+[plasma membrane]

RXRs

RAR alpha

RAR alpha

RXRs

<RARs/RAC3/Cbp/p300/

PCAF/9cRA>

...

<RARs/RAC3/Cbp/p300/

PCAF/9cRA>+

...

BMX+[cy]

BMX[cy]

NF kappa B1 p105-

NF kappa B1 p105

BRCA1

Sck (SHC2)

<p38alpha-beta/HBP1>+

p38alpha-beta+

HBP1

<IKK complex/ELKS>-

ELKS

IKK alpha

NEMO

IKK beta

ASK1[cy]

<NFAT1-c-4 (dimer)/

EGR1>

NFAT1-c-4+[n]

EGR1[n]

<proNGF (dimer)/p75(NTR)/

Sortilin/NRAGE>+[integral to membrane]

Sortilin

proNGF

p75(NTR)

proNGF

NRAGE

<VEGFR2 homodimer/

VEGFA homodimer/

FYN>+[plasma membrane]

VEGFR2

VEGFA

FYN

NFAT1[n]

Ca2+[cy]

Gsk3beta

PKA

CK1 alpha

<IL2/IL2R alpha/beta/

gamma/JAK1/LCK/JAK3>+[integral to membrane]

...

RAF1+[cy]

<NF-kappa-B/RelA>[cy]

NF-kappa-B

RelA

KU80

p53

DNA-PKcs

BARD1

Ku70

<PDGF/PDGFRA/CRKL>+

PDGFRA[plasma membrane]

PDGFA-B-C[ex]

PDGFRA[plasma membrane]

CRKL

CRKL[cy]

Vimentin

<FASLG/FAS/FADD/FAF1/

Caspase 10>

FAF1

FASLG

FADD

FAS[m]

Caspase 10+

<VEGFR1 homodimer/

NRP1/VEGFR 121>[plasma membrane]

VEGFR121

VEGFR1

NRP1

VEGFR1

<VEGFR1 homodimer/

NRP1>[plasma membrane]

VEGFR1

NRP1

VEGFR1

alpha5 Integrin

beta1 Integrin

NRP1

IFN gamma[ex]

NFATc+[n]

Typical PKCs[cy]

PKC zeta[cy]

NSUN2

Nucleolin

NPM1

VEGFR3[m]

ATF2+

Hsp90[cy]

TERT

NIK+

I kappa B beta-

<NF-kappa-B/RelA/
I kappa B beta>-[cy]

NF-kappa-B

I kappa B beta+

RelA

Histone H3

Ajuba

PKC zeta-

PAR4

<VEGFR1 homodimer/

VEGFA homodimer/

NCK1>+[plasma membrane]

VEGFA

VEGFR1

VEGFA

NCK1[cy]

GRIN2A

GRIN2B

<LYN/PLCgamma2>+

LYN+

PLCgamma2

c-Jun+[n]

c-Jun[n]

FYN-

<p38alpha-beta/MKP5>-

p38alpha-beta-

MKP5+

MNK1

family:

Src Family Kinases

family:

p38alpha-beta

family:

Typical PKCs

family:

VEGFR Family

family:
JNK1-2

family:
NFAT1-2

family:
STAT1-3

family:
MEK1-2

family:

PKC (LPA responsive)

family:

MKK3-MKK6

family:

Angiogenic Integrins

family:

CRK family

family:

Dok Family

family:
Integrin

family:

Aurora Kinases

family:

RAF family

family:

GLI family

family:

I kappa B Family

family:

Fibronectin Binding Integrin

family:

NFAT1-c-4

family:

STAT1-3-5

family:

JNK family

13121-06PID_Poster(4x5ft).indd 1

8/11/07 17:05:24

Nature Precedings : doi:10.1038/npre.2007.1311.1 : Posted 12 Nov 2007