VEGF - VEGF R2 Signaling Pathways

Click on one of the biological effects of VEGF-VEGF R2 signaling listed below to see the specific molecules involved in promoting each effect and the phosphorylation sites on VEGF R2 that are necessary for recruitment of key downstream adaptor proteins or kinases.

Integrin
alphaV beta3
Integrin
alphaV beta3
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Rap1
Rap1
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Crk
Crk
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SHB
SHB
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FAK
FAK
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Paxillin
Paxillin
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p38
p38
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MAPKAPK2
MAPKAPK2
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HSP27
HSP27
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Cdc42
Cdc42
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NCK
NCK
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Fyn
Fyn
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PAK2
PAK2
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SH2D2A
SH2D2A
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Src
Src
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Yes
Yes
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VE-Cadherin
VE-Cadherin
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VEGF
VEGF
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VEGF R2
VEGF R2
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Jak
Jak
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STAT3
STAT3
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STAT3 Dimer
STAT3 Dimer
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STAT3 Dimer
STAT3 Dimer
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GRB2
GRB2
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SHP-2
SHP-2
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Src
Src
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Rac1
Rac1
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NADPH
Oxidase
NADPH
Oxidase
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IQGAP1
IQGAP1
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PI 3-K
PI 3-K
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Rac1
Rac1
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PDK-1
PDK-1
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Akt/PKB
Akt/PKB
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eNOS
eNOS
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ROS
ROS
Caspase-9
Caspase-9
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Bad
Bad
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FoxO1/FKHR
FoxO1/FKHR
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FoxO1/FKHR
FoxO1/FKHR
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IP3 Receptor
IP3 Receptor
PGE2
PGE2
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eNOS
eNOS
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PLC-gamma
PLC-gamma
PKC
PKC
PRKD
PRKD
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CREB
CREB
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CREB Dimer
CREB Dimer
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GRB2
GRB2
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SOS
SOS
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Shc
Shc
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SPHK
SPHK
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Sphingosine
Sphingosine
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S1P
S1P
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Ras
Ras
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Raf
Raf
MEK1/2
MEK1/2
ERK1/2
ERK1/2
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cPLA2
cPLA2
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PGI2
PGI2
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AP-1
AP-1
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IP3
IP3
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PIP2
PIP2
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DAG
DAG
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Sck
Sck
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Vav2
Vav2
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GAB1
GAB1
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PIP2
PIP2
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PIP3
PIP3
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PRAK
PRAK
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C3G
C3G
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Ca2+
Ca2+
Vascular
Permeability
Vascular
Permeability
Cell Adhesion
Cell Adhesion
Focal Adhesion Turnover
and Cell Migration
Focal Adhesion Turnover
and Cell Migration
Actin Remodeling
and Cell Migration
Actin Remodeling
and Cell Migration
Actin Remodeling
and Cell Migration
Actin Remodeling
and Cell Migration
Vascular
Permeability
Vascular
Permeability
Cell Migration
and Proliferation
Cell Migration
and Proliferation
Cell Proliferation
Cell Proliferation
Vascular
Permeability
Vascular
Permeability
Cell Proliferation
Cell Proliferation
Cell Migration
Cell Migration
Cell Survival
Cell Survival
VEGF R2
VEGF
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Y801*
Y951
Y951
Y1054*
Y1059*
Y1175
Y1214
Y1223
Y1305
Y1309
Y1319
Unknown
Phosphorylation Site
*Autophosphorylation at these sites
is required for downstream
kinase activity.
Src
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GRB2/SOS/Shc
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PLC-gamma
GRB2/GAB1
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PI 3-K
SH2D2A
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VEGF R2
VEGF
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Y801*
Y951
Y1054*
Y1059*
Y1175
Y1214
Y1214
Y1223
Y1305
Y1309
Y1319
Unknown
Phosphorylation Site
Src
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GRB2/GAB1
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PI 3-K
SHB,PI 3-K
NCK/Fyn
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SHB
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CDC42
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C3G/Crk
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*Autophosphorylation at these sites
is required for downstream kinase
activity.
VEGF R2 Phosphorylation Sites Required for
VEGF-induced Cell Proliferation
VEGF R2 Phosphorylation Sites
Required for VEGF-induced
Cell Survival
VEGF R2 Phosphorylation Sites Required for
VEGF-induced Vascular Permeability
VEGF R2 Phosphorylation Sites
Required for VEGF-induced
Cell Migration
VEGF R2 Phosphorylation Sites
Required for VEGF-induced
Cell Adhesion
NRP-1 or
NRP-2
HSPG

Overview of VEGF-VEGF R2 Signaling

Members of the vascular endothelial growth factor (VEGF) family are master regulators of physiological and pathological vasculogenesis, angiogenesis, and lymphangiogenesis. The VEGF family consists of six members VEGF-A (VEGF), VEGF-B, VEGF-C, VEGF-D, viral VEGF-E, and placental growth factor (PlGF). Human VEGF is composed of eight exons and can exist as multiple alternatively spliced isoforms including VEGF110, VEGF121, VEGF145, VEGF148, VEGF162, VEGF165, VEGF165b, VEGF183, VEGF189, and VEGF206, each with differing biological properties. The biological activities of the different VEGF isoforms are mediated via binding and activation of membrane-localized VEGF receptor tyrosine kinases (VEGF R). While three VEGF Rs have been identified (VEGF R1, VEGF R2, and VEGF R3), signaling through VEGF R2 is strongly associated with the initiation of angiogenesis. VEGF R2 is highly expressed by vascular endothelial cells and their embryonic precursors. It is also expressed by multiple non-endothelial cell types and is upregulated in some cancer cells. Multiple VEGF family members and isoforms bind and activate VEGF R2 in an isoform-specific manner including human VEGF110, VEGF121, VEGF145, VEGF148, VEGF162, VEGF165, VEGF165b, VEGF-C, VEGF-D, and VEGF-E. Similarly, mouse VEGF R2 binds mouse VEGF isoforms that correspond to the human isoform orthologs. VEGF binding and activation of VEGF R2 is further modulated by co-receptors such as neuropilins and heparin sulfate proteoglycans (HSPGs).

VEGF binding to the extracellular portion of VEGF R2 leads to receptor dimerization, activation of its intracellular tyrosine kinase domains, and autophosphorylation. Major sites of human VEGF R2 phosphorylation have been characterized and include Tyr801, Tyr951, Tyr1054, Tyr1059, Tyr1175, and Tyr1214. Additional phosphorylation sites on VEGF R2 include Tyr1223, Tyr1305, Tyr1309, and Tyr1319, however the function of phosphorylation at these sites is not well-defined. Autophosphorylation of VEGF R2 on Tyr1054 and Tyr1059 upon receptor dimerization is critical for downstream kinase activity and may be preceded by autophosphorylation on Tyr801. The other major phosphorylation sites on VEGF R2 are necessary for the recruitment of downstream signaling molecules such as Src, SHB, PI 3-K, NCK/Fyn, CDC42, PLC-gamma, GRB2/SOS/Shc, and SH2D2A. Interaction sites on VEGF R2 for the recruitment of GRB2/GAB1, C3G/Crk, and Jak have not been identified. Common downstream signaling cascades initiated by VEGF R2 recruitment of these signaling molecules include the ERK1/2 MAP Kinase, FAK, p38 MAP Kinase, Akt, and Jak-STAT pathways, which result in the activation of a full range of biological responses that regulate angiogenesis including endothelial cell proliferation, survival, adhesion, and migration, as well as vascular permeability.

To learn more, please visit our VEGF Family Research Area.

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