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Signalin<br />
Signalin<br />
Wnt1<br />
Wnt5A<br />
LRP5/6<br />
mut<br />
BMPRI<br />
BMPs<br />
BMPRII<br />
mut<br />
exp<br />
mut<br />
ligand<br />
GPCR<br />
GPCR<br />
GPCR [IP 3 ]<br />
[DAG]<br />
PLCβ<br />
PLCβ<br />
PAR-1<br />
p120<br />
Ras<br />
CKI<br />
CKI<br />
Dsh<br />
PAR-1<br />
SARA<br />
TGFβ RI<br />
TGFβ<br />
mut<br />
GPCR<br />
mut, trans, amp, exp<br />
mut<br />
Ras<br />
mut<br />
mut<br />
mut<br />
mut<br />
mut<br />
mut<br />
Src<br />
mut<br />
α-catenin<br />
ERK<br />
VEGF<br />
EPO<br />
PDGF<br />
AC<br />
PI3Kγ<br />
Ubiquitin<br />
mut<br />
mut<br />
14-3-3<br />
KIBRA<br />
[Ca 2+ ]<br />
PI3K<br />
Smad7<br />
Smad7<br />
Crk<br />
C3G<br />
[cAMP]<br />
EPAC<br />
CAMKII<br />
PKC<br />
PP2A<br />
GSK-3β<br />
APC<br />
WTX<br />
Axin<br />
mut<br />
ALK<br />
ROS1<br />
mut<br />
mut<br />
mut<br />
Smad4<br />
amp, mut, exp<br />
14-3-3<br />
YAP<br />
SOS<br />
GRB2<br />
[PIP 3 ]<br />
Ubiquitin<br />
Mst1/2 LATS1/2<br />
SAV1 MOB1<br />
TAB1<br />
TAB2<br />
mut<br />
TAB1<br />
TAB2<br />
mut<br />
mut<br />
Rap<br />
PKA<br />
RasGRF<br />
Ras<br />
NF1<br />
Raf-1<br />
B-Raf<br />
14-3-3<br />
HPH<br />
Ras c-Raf<br />
MEK1/2<br />
ERK1/2<br />
MP1<br />
RasGEF<br />
Smad4<br />
Smurf<br />
NLK<br />
Smad4<br />
mut<br />
MKK3/6<br />
mut<br />
Akt<br />
RAR<br />
mut<br />
mut<br />
SOX<br />
mut<br />
E2F<br />
amp<br />
mut, del<br />
mut<br />
amp, mut, exp<br />
amp, exp<br />
CBP<br />
TCF/LEF<br />
Integrin<br />
Src<br />
FAK<br />
GRB2<br />
GRAF<br />
SOS<br />
Rap<br />
RalGEF<br />
TEAD<br />
Smad<br />
mut<br />
mut<br />
KSR<br />
14-3-3 c-Raf<br />
VHL<br />
HIF-1β<br />
mut<br />
del<br />
ERK1/2<br />
Smad4<br />
p107<br />
E2F<br />
mut<br />
mut<br />
mut<br />
CDK7<br />
RalA<br />
RalB<br />
Cdc2<br />
Wee1A<br />
exp<br />
Miz-1<br />
Smad4<br />
RalBP1<br />
Cdc42 Actin<br />
Rac<br />
MEK1/2<br />
MP1<br />
ERK1/2<br />
exp<br />
ERK1/2<br />
p90 RSK<br />
HIF-1β<br />
PAK1<br />
Cdc25<br />
B/C<br />
Myc<br />
Miz-1<br />
mut, amp<br />
mut, amp<br />
Cytoskeleton<br />
CREB<br />
Rho<br />
JNK<br />
HPV-E7<br />
HDAC<br />
Rb<br />
DP E2F<br />
Rad52<br />
Rad51<br />
FANC<br />
D2<br />
mut<br />
mut, del<br />
mut<br />
vir<br />
exp<br />
Abl<br />
PI3K<br />
class I<br />
ULK1<br />
Beclin<br />
FIP200<br />
Atg14<br />
Atg13<br />
mut<br />
p90 RSK<br />
mut<br />
amp, trans<br />
trans<br />
Elk-1<br />
NBS1<br />
BRCA1<br />
Chk1<br />
Chk2<br />
mut<br />
mut, amp<br />
mut<br />
CDK4/6<br />
Cdc25A<br />
mut<br />
mut mut<br />
mut<br />
mut,del<br />
Cdc2<br />
Cyclin A<br />
LC3-II<br />
Atg7/3<br />
Atg4<br />
LC3-I<br />
mut,del<br />
4E-BP<br />
S6K<br />
DP E2F<br />
MDM2<br />
p21<br />
Rb<br />
amp<br />
GSK-3<br />
mut<br />
mut<br />
mut<br />
SHP1<br />
HIPK2<br />
ARF<br />
MDM2<br />
CDK7<br />
trans, mut<br />
(amino acids<br />
& glucose)<br />
TSC2<br />
TSC1<br />
mTOR<br />
Raptor<br />
p21 p27<br />
FKHR/<br />
FOXO<br />
JAK<br />
JAK<br />
STAT<br />
SHP2<br />
GRB2<br />
STAT<br />
SOS<br />
Shc<br />
Ras<br />
LKB1<br />
PI3K<br />
AMPK<br />
1011010100110101101100101<br />
Rheb<br />
Cdc25A<br />
cyclin E, A<br />
myc, cdc2<br />
p107, E2F<br />
0 10 1 0101<br />
0<br />
0 10 1 0101<br />
0 10 10 10 1<br />
101010110110110<br />
HPV-E6<br />
mut<br />
amp<br />
1011010100110101101010101<br />
trans<br />
vir<br />
mut<br />
amp, exp<br />
CDK2<br />
Cyclin A<br />
mut<br />
mTOR<br />
Rictor<br />
CDK2<br />
Cyclin E<br />
Akt<br />
BRD4<br />
TET<br />
SirT1<br />
DNMT3<br />
XIAP<br />
Lamins<br />
PDK1<br />
Bax<br />
Bcl-2<br />
Casp-2<br />
p21<br />
p27<br />
amp<br />
mut,del<br />
amp,exp<br />
amp, mut, exp<br />
mut<br />
amp, trans<br />
trans<br />
NOXA<br />
PUMA<br />
Smac<br />
AIF<br />
PARP<br />
CAD<br />
mut<br />
mut<br />
cIAP<br />
RelA<br />
NFκB2<br />
RelB<br />
PP2A<br />
c-Raf<br />
HDAC<br />
Sin3<br />
PKM2<br />
pyruvate<br />
LDHA<br />
14-3-3 Bim<br />
Apaf-1<br />
ICAD<br />
CAD<br />
amp, trans<br />
mut<br />
mut,del<br />
IκB<br />
p53<br />
Gab1<br />
PI3K<br />
RTK<br />
Gab2<br />
IRS-1<br />
Cbl<br />
PTEN<br />
PI3K<br />
mut<br />
PFK<br />
mut<br />
CytC<br />
IκB<br />
PDK1<br />
Ras<br />
G-6-P<br />
F-6-P<br />
Fructose<br />
Bisphosphate<br />
amp, trans<br />
IDH1<br />
mut<br />
Su(Fu)<br />
KIF-7<br />
Su(Fu)<br />
KIF-7<br />
mut, del<br />
citrate<br />
IDH2<br />
Akt<br />
Bax<br />
Bcl-2 JNK<br />
tBid<br />
ASK<br />
MKK7<br />
Bid<br />
TAB2<br />
TAB3<br />
IKKα<br />
IKKβ<br />
mut<br />
trans<br />
citrate<br />
MEKK3<br />
NUMB<br />
Hardcover<br />
Paperback<br />
Glucose<br />
mut<br />
FLIPs<br />
NIK<br />
Ras<br />
mut<br />
amp<br />
trans<br />
del<br />
vir<br />
exp<br />
mut<br />
Dsh<br />
Presenilin<br />
IRAK<br />
TRAF6<br />
Myd88<br />
RAIDD<br />
TRAF2<br />
mut<br />
mut<br />
mut<br />
mut<br />
mut<br />
Amplification<br />
Translocation<br />
Deletion<br />
Viral infection<br />
amp, mut, exp<br />
from PDB<br />
oncogene<br />
Hh<br />
Fas/DR<br />
mut<br />
trans<br />
Delta<br />
Jagged<br />
TACE<br />
trans<br />
/ NF-<br />
N otch g<br />
S ignalin<br />
Signalin<br />
Section I: Research Areas<br />
chapter 02: Signaling<br />
Calcium, cAMP,<br />
and Lipid Signaling<br />
Kinase-Disease<br />
Associations<br />
Name Group Disease Type Molecular Notes<br />
PKACα AGC Cancer Multiple mutations of regulatory subunit (PRKAR1A; OMIM:188830)<br />
cause Carney complex tumors and sporadic adrenal and thyroid<br />
tumors. Altered PRKAR1A transcript editing associated with lupus.<br />
PKACa knockout mouse has phenotypes similar to Carney complex<br />
(Medline:18413734). OMIM:601639.<br />
PKC<br />
(multi-isoform)<br />
AGC CNS Inh Multiple agonists and antagonists of the PKC family have consistent<br />
effects on inhibiting or activating manic behavior in humans and rats.<br />
Tamoxifen has secondary effect as PKC inhibitor and shown antimanic<br />
activity in rat model and a clinical trial (Medline:18316672,<br />
17641532).<br />
Pathways in<br />
PKCα AGC Cancer<br />
Cardiovascular<br />
Mut,<br />
Del, OE,<br />
Act<br />
A point mutation is seen in several pituitary and thyroid tumors (Medline:9167945).<br />
Deleted in a melanoma cell line. Complex expression<br />
pattern in breast cancer (Medline 15459489, 15454252). Therapeutic<br />
target in lung, gastric and prostate cancer (Medline:15447994,<br />
15313921, 15174974). May mediate multidrug resistance (Medline:12390766).<br />
Mouse models indicate a role in heart contractility<br />
(Medline:14966518). Inhibitors: LY-900003 (antisense. aka Affinitak/<br />
ISIS 3521/aprinocarsen), Safingol, Go6976. OMIM:176960.<br />
Human Cancer<br />
The Pathways in Human Cancer Poster summarizes the signaling nodes implicated<br />
in cancer initiation and progression and features peer-reviewed protein mapping with<br />
scientifically accurate rendering of the molecular structures of proteins. The poster<br />
accompanies the text A Biology of Cancer by Robert A. Weinberg (Second Edition).<br />
PKCβ AGC Autism<br />
Cancer<br />
Diabetes<br />
PKCγ AGC Neurodegeneration<br />
Pain<br />
PKCδ AGC Cancer<br />
Cardiovascular<br />
CNS<br />
PKCε AGC Cancer<br />
Cardiovascular<br />
CNS<br />
PKCθ AGC Cancer<br />
Immunity<br />
SNP<br />
Two promoter SNPs associated with diabetic nephropathy<br />
(Medline:12874455), correlating with induction of renal expression<br />
by high glucose, reduction in renal function by a specific PKCβ<br />
inhibitor and successful inhibitor treatment of rodent models of<br />
diabetic nephropathy (Medline:12955673). PKCβ inhibition has also<br />
been proposed to treat diabetic retinopathy (Medline:12507628)<br />
and diabetic vascular complications (Medline:11903393). Ectopic<br />
expression in mouse heart leads to cardiac hypertrophy. Elevated<br />
expression is seen in and promotes early stages of colon cancer<br />
in mouse models (Medline:11245437). May mediate multidrug<br />
resistance (Medline:12697075). Activation protects astrocytes from<br />
ischemic injury (Medline:15165841). SNPs associated with autism<br />
(Medline:16027742). Inhibitors: LY333531 (ruboxistaurin; Phase 3<br />
for diabetic neuropathy and retinopathy), LY317615 (Eli Lilly: isoform<br />
selective). OMIM:176970.<br />
Mut Point mutations linked to dominant spinocerebellar ataxia type 14<br />
[OMIM:605361]. Knockout and inhibitor studies show role in pain<br />
perception (Medline:14762097, 9323205). OMIM:176980.<br />
Expr<br />
Amp,<br />
Mut<br />
Pro-apoptotic. Reduced expression correlated with progression of colon<br />
and other cancers (Medline:15054085, 12657722, 12591726).<br />
Inhibition may drive chemo-resistant cancers to apoptosis. Activated<br />
and promotes apoptosis in cardiac and neuronal cells after ischemicreperfusion<br />
injury (Medline:14654063, 15295022). Activator:<br />
bistrane A. Inhibitors: rottlerin, KAI-9803 (KAI; Phase 2 trials for<br />
reperfusion injury), dV1-1. OMIM:176977.<br />
Amplified and rearranged in thyroid cancers (Medline:9683604,<br />
10438519, 11994357). Promotes growth of an androgen-independent<br />
prostate cancer cell line (Medline:11956106) and transforms<br />
fibroblasts in culture (Medline:11968018). Activation protects cardiac<br />
myocytes and neurons from ischemic injury (Medline:15165841)<br />
and antagonizes PKCδ. Amyloid β peptide inhibits PKCε activity<br />
and may contribute to the pathogenesis of Alzheimer's disease<br />
(Medline:15207847). Inhibitor studies indicate role in pain perception<br />
(Medline:1043272). Multi-isoform inhibitors include: Bryostatin-1<br />
(BRYO) from Aphios and Perifosine/D-21266 from Baxter while KAI-<br />
1678 is a selective inhibitor. OMIM:176975.<br />
Required for activation and proliferation of mature T cells. Proposed<br />
as a target for T cell leukemias (Medline:12188914). Knockout is<br />
resistant to fat-induced insulin resistance. OMIM:600448.<br />
Molecular: Act Activated • Amp Amplified • Del Deleted • Expr Expression • GOF Gain-of-function • Inh Inhibitor<br />
Studies • LOF Loss-of-function • LOH Loss-of-heterozygosity • Meth Methylation • Model model organism studies •<br />
Mut Mutation OE Overexpression • SNP Single Nucleotide Polymorphism • Splice Splicing change • Trans Translocation<br />
Features<br />
Peer-reviewed protein mapping and accurate molecular rendering of proteins.<br />
Summarizes the latest signaling nodes implicated in cancer signaling.<br />
Pathway-specific color-coded nodes.<br />
Revised Edition<br />
Angiogenesis<br />
Wnt Signaling<br />
H ippo g<br />
GPCR Signaling<br />
R-spondin<br />
T GF β g<br />
R-spondin<br />
Frizzled<br />
Frizzled<br />
Receptor Tyrosine Kinase (RTK)<br />
E-cadherin<br />
CD44<br />
FAT4<br />
LGR4,5,6<br />
γ<br />
β<br />
α<br />
γ<br />
β<br />
α<br />
ZNRF3/RNF43<br />
β-catenin<br />
γ<br />
β<br />
α<br />
Dsh Akt<br />
α 12/13<br />
γ<br />
β<br />
α s<br />
Smad1/5/8<br />
Smad2/3<br />
TGFβ RII<br />
EGFR<br />
HER2<br />
FRMD<br />
Mer<br />
Smad1/5/8<br />
Smad2/3<br />
Ras Signaling<br />
β-catenin<br />
TAK<br />
RasGRP<br />
RasGAP<br />
Normoxia<br />
Hypoxia<br />
SynGAP<br />
β-catenin<br />
YAP/TAZ<br />
Smad1/5/8<br />
Smad2/3<br />
TAK p38<br />
C<br />
PI3K ILK<br />
RIAM/Talin<br />
RasGAP<br />
RhoGEFs<br />
β-catenin<br />
MKK7 JNK<br />
HIF-1α(-2α)<br />
other TFs<br />
YAP/TAZ<br />
myc, cyclin D, CD44<br />
Smad1/5/8<br />
Smad2/3<br />
Cyclin H<br />
Regulated<br />
Exocytosis<br />
Exocyst<br />
Complex<br />
Atg16/12/5<br />
Rab8a (c-Mel)<br />
p90 RSK JNK<br />
HIF-1α(-2α)<br />
Fos<br />
Jun<br />
myc, cyclin D<br />
Cyclin B<br />
p15, p21, p27<br />
Smad2/3<br />
DNA Repair<br />
Myc<br />
Max<br />
autophagosome<br />
Myc<br />
Max<br />
cyclin D, myc<br />
cyclin D, myc<br />
SQSTM1<br />
Autophagy<br />
Fos<br />
Jun<br />
phagopore<br />
membrane<br />
nucleation<br />
p15 p16 p18 p19<br />
UV<br />
Cyclin D<br />
DNA Damage<br />
Cyclin D<br />
STAT STAT<br />
(Inactive) (Active)<br />
IR<br />
* *<br />
ATM<br />
ATR<br />
Scienstists at Cell Signaling Technology co laborate<br />
with key opinion leaders in cance research to create<br />
reference pathway diagrams that reflect the latest<br />
thinking in the research community. Over 40 pathway<br />
diagrams cu rently exist, including the pathways<br />
represented here and many others.<br />
www.ce lsignal.com/<strong>CST</strong>cancer<br />
DNA-<br />
PK<br />
p53<br />
p53<br />
Nutrients<br />
cyclin D<br />
The Pathways in Human Cancer poster summarize some of the key<br />
signaling pathways implicated in tumorigenesis and tumor<br />
progression in humans. Within each pathway, gene products known<br />
to be mutated in human tumors—oncogenes and tumor suppressor<br />
genes—are coded with information on types of genetic alterations<br />
and confe red capabilities to the tumor. Proteins are shown using<br />
structural representatives. New to this revised poster edition are<br />
signaling pathways for Hippo Signaling, Autophagy, Warburg E fect,<br />
and Epigenetic Regulation.<br />
This poster was created by scientists at Ce l Signaling Technology in<br />
co laboration with Robert A. Weinberg and others a the forefront of<br />
cance research. Expanded versions of each pathway, including<br />
additional downstream signaling nodes, can be found at<br />
www.ce lsignal.com/<strong>CST</strong>cancer.<br />
R<br />
Cyclin H<br />
Cytokine<br />
Receptor<br />
Aurora<br />
A<br />
Transcription<br />
MDM2 Bcl-x L<br />
Bad<br />
p53<br />
myc, cyclin D, cyclin E<br />
cyclin D<br />
CSL/CBF1<br />
Gli PKA<br />
KMT2/MLL<br />
KDM6A/UTX<br />
KMT4/DOT1L<br />
SWI/SNF<br />
KMT6/EZH2<br />
NFκB1/2<br />
CSL/CBF1<br />
p300<br />
Epigenetic Signaling<br />
Ce l Signaling Technology would like to thank<br />
digizyme for their co laboration on the design<br />
and concept of this poster. Please visit<br />
www.digizyme.com to see more of their work.<br />
NICD<br />
[PIP 3 ]<br />
lactate<br />
Casp-9<br />
Casp-3,6,7<br />
HAT HES1<br />
Akt Signaling<br />
NICD<br />
Gli<br />
[PIP 3 ]<br />
Hexokinase<br />
Krebs<br />
Cycle<br />
Bak TRADD<br />
IKKα IKKβ<br />
NFκB1/2<br />
RelA<br />
Gli<br />
Fatty acid<br />
synthesis<br />
TAK<br />
NEMO<br />
Direct stimulatory modification<br />
Direct inhibitory modification<br />
Multistep stimulatory modification<br />
Tentative stimulatory modification<br />
Transcriptional contribution<br />
TYPES OF GENETIC ALTERATIONS:<br />
Point mutation<br />
Increased expression<br />
(unknown mechanism)<br />
TYPES OF CONFERRED CAPABILITIES:<br />
Evading apoptosis<br />
Self-su ficiency in growth signals<br />
Insensitivity to anti-growth signals<br />
Tissue invasion & metastasis<br />
Limitless replicative potential<br />
Sustained angiogenesis<br />
∞<br />
transporter<br />
Ras Common protein name<br />
Structural representative<br />
tumor suppressor<br />
Type of genetic alteration<br />
Type of confe red capability<br />
Warburg Effect<br />
FADD<br />
Casp-8,10<br />
RIP TRADD<br />
TRAF<br />
2/6<br />
TRAF<br />
3<br />
Notch<br />
Furin<br />
Fringe<br />
NIC<br />
Cleaved<br />
Notch<br />
CDO<br />
BOC<br />
Ptch<br />
Smo<br />
Ptch<br />
Smo<br />
IL1R<br />
TNFR<br />
TNFR<br />
CDO<br />
BOC<br />
D eath Receptor κB g<br />
This poster accompanies the textbook The Biology of Cancer, Second Edition<br />
by Robert A. Weinberg and published by Garland Science.<br />
Dr. Weinberg is a founding member of the Whitehead Institute for Biomedical<br />
Research and the Daniel K. Ludwig Professor of Cancer Research a the<br />
Massachuse ts Institute of Technology.<br />
ISBN 978-0-8153-4219-9<br />
ISBN 978-0-8153-4220-5 www.garlandscience.com<br />
Signalin<br />
H edgehog g<br />
Pathways in<br />
Human Cancer<br />
Poster<br />
To request free copies of this<br />
poster please visit our website.<br />
www.cellsignal.com/phcposter<br />
Cancer<br />
Research<br />
84 For Research Use Only. Not For Use in Diagnostic Procedures. See pages 302 & 303 for Pathway Diagrams, Application, and Reactivity keys.<br />
Please visit our website to learn<br />
more about the scientific tools and<br />
educational resources we have online<br />
for cancer signaling and proteomic<br />
analysis, including discussion of key<br />
disease drivers.<br />
www.cellsignal.com/cancerguide<br />
85
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