CST Guide:

Section I: Research Areas
These protein targets represent key
nodes within angiogenesis signaling
pathways and are commonly studied
in angiogenesis research. Primary
antibodies, antibody conjugates, and
antibody sampler kits containing these
targets are available from CST.
Listing as of September 2014. See our
website for current product information.
M Monoclonal Antibody
P Polyclonal Antibody
E PathScan ® ELISA Kits
S SignalSilence ® siRNA
C Antibody Conjugate
163
2012–2014 citations
CST antibodies for VEGF Receptor 2
have been cited over 163 times in highimpact,
peer-reviewed publications from
the global research community.
Commonly Studied Angiogenesis Targets
Target M P E S C
ADAMTS1
•
Angiopoietin-2
•
CA9
•
CBP
• •
Acetyl-CBP (Lys1535)/p300 (Lys1499) •
CD31 (PECAM-1)
•
Cripto
• •
CYR61
•
DLL4
•
eNOS
• •
EphA2
• •
Phospho-EphA2 (Tyr594) •
EphB1
•
Acidic FGF
•
FGF Receptor 1 • • • •
FGF Receptor 2
• • • •
FGF Receptor 3
• •
FGF Receptor 4 • • •
FIH
•
Gremlin
•
HIF-1α
• •
Hydroxy-HIF-1α (Pro564) • •
HIF-1β/ARNT
• •
HO-1
• •
Integrin α6
•
Integrin αV
•
Integrin β1
• •
Integrin β3
• •
Integrin β5
• •
Jagged1
•
Maspin
•
MMP-2
• •
MMP-7
•
MMP-9
• •
NDRG1 • • •
Select Citations:
Whiteus, C. et al. (2014) Perturbed neural activity disrupts
cerebral angiogenesis during a postnatal critical period.
Nature 505, 407−411.
Behjati, S. et al. (2014) Recurrent PTPRB and PLCG1 mutations
in angiosarcoma. Nat. Genet. 46, 376−379.
Chen, P.Y., Qin, L., Zhuang, Z.W., Tellides, G., Lax, I.,
Schlessinger, J., Simons, M. (2014) The docking protein
FRS2alpha is a critical regulator of VEGF receptors signaling.
Proc. Natl. Acad. Sci. USA 111, 5514−5519.
Ria, R. et al. (2014) HIF-1alpha of bone marrow endothelial
cells implies relapse and drug resistance in patients with
multiple myeloma and may act as a therapeutic target. Clin.
Cancer Res. 20, 847−858.
Blosser, W. et al. (2014) A method to assess target gene involvement
in angiogenesis in vitro and in vivo using lentiviral
vectors expressing shRNA. PLoS One 9, e96036
Riquelme, E. et al. (2014) VEGF/VEGFR-2 Upregulates EZH2
Expression in Lung Adenocarcinoma Cells and EZH2 Depletion
Enhances the Response to Platinum-Based and VEGFR-
2-Targeted Therapy. Clin. Cancer Res. 20, 3849−3861.
Yang, Y. et al. (2013) GAB2 induces tumor angiogenesis in
NRAS-driven melanoma. Oncogene 32, 3627−3637.
Nakayama, M. et al. (2013) Spatial regulation of VEGF receptor
endocytosis in angiogenesis. Nat. Cell Biol. 15, 249−260.
Target M P E S C
NDRG2
•
NDRG3
•
NDRG4
•
Neuropilin-2
•
Notch1 • •
Cleaved Notch1 (Val1744) • • •
Notch2
•
Notch3
• •
Notch4
•
NT5E/CD73
• •
PDGF Receptor α • • • •
Phospho-PDGF Receptor α (Tyr754) •
PDGF Receptor β • • •
Phospho-PDGF Receptor β (Tyr740) •
Phospho-PDGF Receptor β (Tyr771) •
Phospho-PDGF Receptor β (Tyr1009) •
PHD-2/Egln1
• •
RECK
•
Ron
•
Phospho-Ron (panTyr)
•
Spry1
• •
Tenascin C
•
TGF-β Receptor I
•
TGF-β Receptor III
• •
Tie2
•
TIMP1
•
TIMP2
•
TIMP3
•
uPAR
• •
VE-Cadherin
• •
VEGF Receptor 1
•
VEGF Receptor 2 • • • •
VEGF Receptor 3
• •
VHL
•
Planas-Paz, L. et al. (2012) Mechanoinduction of lymph
vessel expansion. EMBO J. 31, 788−804.
Fang, L. et al. (2013) Control of angiogenesis by AIBPmediated
cholesterol efflux. Nature 498, 118−122.
Harris, N.C. et al. (2013) The propeptides of VEGF-D
determine heparin binding, receptor heterodimerization, and
effects on tumor biology. J. Biol. Chem. 288, 8176−8186.
Mujahid, S. et al. (2013) MiR-221 and miR-130a regulate
lung airway and vascular development. PLoS One 8,
e55911.
Singh, N.K. et al. (2013) Both Kdr and Flt1 play a vital role in
hypoxia-induced Src-PLD1-PKCgamma-cPLA(2) activation
and retinal neovascularization. Blood 121, 1911−1923.
Gourlaouen, M. et al. (2013) Essential role for endocytosis
in the growth factor-stimulated activation of ERK1/2 in
endothelial cells. J. Biol. Chem. 288, 7467−7480.
Breitbach, C.J. et al. (2013) Oncolytic vaccinia virus disrupts
tumor-associated vasculature in humans. Cancer Res. 73,
1265−1275.
Tang, J.R. et al. (2013) The NF-kappaB inhibitory proteins
IkappaBalpha and IkappaBbeta mediate disparate responses
to inflammation in fetal pulmonary endothelial cells.
J. Immunol. 190, 2913−2923.
170 For Research Use Only. Not For Use in Diagnostic Procedures. See pages 302 & 303 for Pathway Diagrams, Application, and Reactivity keys.
Angiogenesis Signaling in Tumor Neovascularization
Endothelial
Cell
Key
Angiopoietin 1
Angiopoietin 2
bFGF
Ephrin
PDGF
SLIT
VEGF
Tie2
EPH
ROBO3
ROBO1/2
Pericyte
Integrins
MMPs
Basement
Membrane
Tip Cell
FGFR
Integrins
VEGFR2
Akt
4E-
BP1
Tie2
Neuropilin
elF4E1
• Growth Factors
• Cytokines
• ECM Proteases
Tumor Cell
chapter 06: Development and differentiation
PHDs
Erk1/2
HIF-1α
Precursor
Endothelial Cell
OH
HRE
OH
HIF-1α
HIF-1α
CBP/p300
HIF-1β
Normoxia
HIF-1β
Hypoxia
Target Genes
Platelet
MMPs
Nucleus
PDGFR
• Growth Factors
• Cytokines
• ECM Proteases
Ets2
HIF-1α
Stat3
Target Genes
Tumor Associated
Macrophage (TAM)
Angiogenesis, the formation of new blood vessels from pre-existing blood vessels, plays a key role in tumorigenesis. When a small dormant tumor initiates angiogenesis,
referred to as the ‘angiogenic switch’, it secretes factors that induce sprouting and chemotaxis of endothelial cells (ECs) towards the tumor mass. Within the hypoxic environment
of the inner tumor mass the transcription factor Hypoxia-Inducible-Factor-1-α (HIF-1α) is stabilized and activates the expression of multiple genes contributing to the angiogenic
process. HIF-1α induced proteins include Vascular Endothelial Growth Factor (VEGF) and Basic Fibroblast Growth Factor (bFGF), which promote vascular permeability and EC
growth, respectively. Other secreted factors, such as PDGF, angiopoietin 1 and angiopoietin 2 facilitate chemotaxis, while ephrins guide newly formed blood vessels through
maintenance of cell-cell separation. Other HIF-1α induced gene products include matrix metalloproteinases (MMPs) that breakdown the extracellular matrix to facilitate EC
migration and release associated growth factors. Certain integrins such as αVβ3 found on the surface of angiogenic ECs help the sprouting ECs adhere to the provisional Extracellular
Matrix (ECM), migrate and survive. Factors secreted into the microenvironment surrounding the tumor activate tumor-associated macrophages (TAMs), that subsequently
produce angiogenic factors, such as VEGF and MMPs, further promoting angiogenesis. Pericytes function as support cells enveloping the basolateral surface of ECs and regulate
vasoconstriction and dilation under normal physiologic conditions. During the process of tumor angiogenesis sprouting vessels lack pericytes, which are later recruited by
ECs to provide structural support that indirectly promotes tumor survival. For example, PDGF secreted by ECs acts as a ligand for PDGF receptor located on the pericyte
membrane, causing pericytes to produce and secrete VEGF that signals through the endothelial VEGF receptor.
Select Reviews:
Folkman, J. (2007) Nat. Rev. Drug Disc. 6, 273–286. • Guo, C., Buranych, A., Sarkar, D., et al. (2013) Vasc. Cell. 5, 20. • Keith, B., Johnson, R.S., and Simon, M.C.
(2012) Nat. Rev. Cancer 12, 9–22. • Klagsbrun, M. and Eichmann, A. (2005) Cytokine and Growth Factor Rev. 16, 535–548. • Raza, A., Franklin, M.J., and Dudek, A.Z.
(2010) J. Hematol. 85, 593–598. • Sakurai, T. and Kudo, M. (2011) Oncology 81 Suppl. 1, 24–29. • Senger, D.R. and Davis, G.E. (2011) Cold Spring Harb. Perspect. Biol.
3, a005090. • van Hinsbergh, V.W. and Koolwijk, P. (2008) Cardiovasc. Res. 78, 203–212.
© 2008–2015 Cell Signaling Technology, Inc. • We would like to thank Prof. Diane Bielenberg, Harvard Medical School, Children’s Hospital, Boston, MA, for reviewing this diagram.
www.cellsignal.com/cstpathways 171