297
Pathway
Bevacizumab Action Pathway
Bevacizumab is a humanized anti-VEGF monoclonal antibody used in the treatment of cancer. Cancer cells tend to overexpress VEGF, which stimulates angiogenesis, facilitating cancer growth and metastasis. The majority of VEGF’s effects are mediated through its binding to the VEGFR-2 receptor on endothelial cell surfaces. Upon binding, the receptor autophosphorylates and initiates a signalling cascade, starting with the activation of CSK. CSK phosphorylates Raf-1, which subsequently phosphorylates MAP kinase kinase, which phosphorylates MAP kinase. The activated MAP kinase enters the nucleus and stimulates the expression of angiogenic factors resulting in increased cell proliferation, migration, permeability, invasion, and survival.
Binding of VEGF to VEGFR-2 also activates phospholipase C PIP2 into DAG and IP3. DAG may be involved in the activation of Raf-1 leading to angiogenesis, while IP3 activates PI3K and triggers calcium release from the endoplasmic reticulum. This ultimately leads to the activation of nitric oxide synthase and the production of nitric oxide, which stimulates vasodilation and increases vascular permeability.
In cancer, VEGF has also been shown to bind to the VEGFR-1 receptor. However, its effects on angiogenesis are unclear at the moment. There are some evidence to show that VEGFR-1 may cross-talk with VEGFR-2 and initiate the signalling cascades described above.
Bevacizumab exerts its effect by binding to extracellular VEGF and preventing its binding to receptors on the endothelial cell surfaces. This in turns inhibits the MAP and IP3 and supresses angiogenesis.
Drug Action
PW000236
Top
PathwayVisualizationContext252
1300
1300
#000099
PathwayVisualization156
297
Bevacizumab Pathway
Bevacizumab is a humanized anti-VEGF monoclonal antibody used in the treatment of cancer. Cancer cells tend to overexpress VEGF, which stimulates angiogenesis, facilitating cancer growth and metastasis. The majority of VEGF’s effects are mediated through its binding to the VEGFR-2 receptor on endothelial cell surfaces. Upon binding, the receptor autophosphorylates and initiates a signalling cascade, starting with the activation of CSK. CSK phosphorylates Raf-1, which subsequently phosphorylates MAP kinase kinase, which phosphorylates MAP kinase. The activated MAP kinase enters the nucleus and stimulates the expression of angiogenic factors resulting in increased cell proliferation, migration, permeability, invasion, and survival.
Binding of VEGF to VEGFR-2 also activates phospholipase C PIP2 into DAG and IP3. DAG may be involved in the activation of Raf-1 leading to angiogenesis, while IP3 activates PI3K and triggers calcium release from the endoplasmic reticulum. This ultimately leads to the activation of nitric oxide synthase and the production of nitric oxide, which stimulates vasodilation and increases vascular permeability.
In cancer, VEGF has also been shown to bind to the VEGFR-1 receptor. However, its effects on angiogenesis are unclear at the moment. There are some evidence to show that VEGFR-1 may cross-talk with VEGFR-2 and initiate the signalling cascades described above.
Bevacizumab exerts its effect by binding to extracellular VEGF and preventing its binding to receptors on the endothelial cell surfaces. This in turns inhibits the MAP and IP3 and supresses angiogenesis.
Drug
1
410
Bevacizumab inhibition of Vascular endothelial growth factor A
InhibitorySubPathway
630
726
ProteinComplex
15
631
727
ProteinComplex
15
411
Vascular endothelial growth factor A Activation of Vascular endothelial growth factor receptor 2
ActivatingSubPathway
632
727
ProteinComplex
15
633
728
ProteinComplex
14
412
Vascular endothelial growth factor A Activation of Vascular endothelial growth factor receptor 1
ActivatingSubPathway
634
727
ProteinComplex
15
635
729
ProteinComplex
14
1407
15585754
Hicklin DJ, Ellis LM: Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005 Feb 10;23(5):1011-27. doi: 10.1200/JCO.2005.06.081. Epub 2004 Dec 7.
297
Pathway
1408
16842197
Ranieri G, Patruno R, Ruggieri E, Montemurro S, Valerio P, Ribatti D: Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic. Curr Med Chem. 2006;13(16):1845-57.
297
Pathway
1
Cell
CL:0000000
1
Homo sapiens
9606
Eukaryote
Human
11
Extracellular Space
GO:0005615
10
Cell Membrane
GO:0005886
2
Endothelium
BTO:0000393
15
11
1
PW_BS000015
14
10
1
PW_BS000014
82
2
10
1
1
PW_BS000082
5727
Bevacizumab
A recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF). Bevacizumab contains human framework regions and the complementarity-determining regions of a murine antibody that binds to VEGF. Bevacizumab is produced in a Chinese Hamster Ovary mammalian cell expression system in a nutrient medium containing the antibiotic gentamicin and has a molecular weight of approximately 149 kilodaltons.
DB00112
1
2923
15
1800
Vascular endothelial growth factor A
P15692
Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth. Induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels. Binds to the FLT1/VEGFR1 and KDR/VEGFR2 receptors, heparan sulfate and heparin. NRP1/Neuropilin-1 binds isoforms VEGF-165 and VEGF-145. Isoform VEGF165B binds to KDR but does not activate downstream signaling pathways, does not activate angiogenesis and inhibits tumor growth
HMDBP02130
VEGFA
6p12
BC065522
1
2924
15
1193
Vascular endothelial growth factor receptor 2
P35968
Receptor for VEGF or VEGFC. Has a tyrosine-protein kinase activity. The VEGF-kinase ligand/receptor signaling system plays a key role in vascular development and regulation of vascular permeability. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions
HMDBP01272
KDR
4q11-q12
AF063658
1
2.7.10.1
2926
14
4150
82
1357
Vascular endothelial growth factor receptor 1
P17948
Receptor for VEGF, VEGFB and PGF. Has a tyrosine-protein kinase activity. The VEGF-kinase ligand/receptor signaling system plays a key role in vascular development and regulation of vascular permeability. Isoform SFlt1 may have an inhibitory role in angiogenesis
HMDBP01462
FLT1
13q12
DQ836395
1
2.7.10.1
2928
14
726
Bevacizumab
1
PW_P000726
820
5727
727
Vascular endothelial growth factor A
1
PW_P000727
821
1800
2
2922
15
728
Vascular endothelial growth factor receptor 2
1
PW_P000728
822
1193
2925
14
729
Vascular endothelial growth factor receptor 1
1
PW_P000729
823
1357
2927
14
2421
5727
15
159
false
200
140
8
subunit
regular
150
70
2422
1800
15
6
false
555
135
8
subunit
regular
160
80
2423
1193
14
80
false
340
482
8
subunit
regular
200
130
2424
1357
14
80
false
705
487
8
subunit
regular
200
130
2165
726
156
15
2414
2421
2166
727
156
15
2415
2422
2167
728
156
14
2416
2423
2168
729
156
14
2417
2424
8950
M350 175 C380 175 525 175 555 175
148
false
18
false
true
M 290 175 L 290 160 L 290 145
8951
M560 170 C530 170 470 160 440 160
5
true
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8952
M635 215 C635 281 445 407 445 507
149
false
18
true
M 745.5184081049707 122.47265855734058 L 752 136 L 760.4742253874945 123.62310604061163
false
8953
M340 442 C310 442 832 177 802 177
5
true
18
8954
M635 215 C636 283 808 401 810 512
149
false
18
true
M 779.0096189432334 184.5 L 792 177 L 779.0096189432334 169.5
false
8955
M705 442 C675 442 972 177 942 177
5
true
18
436
410
156
14
true
290
125
16
regular
116
2165
8950
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117
2166
8951
Right
437
411
156
14
true
652
142
16
regular
118
2166
8952
Left
119
2167
8953
Right
438
412
156
14
true
792
142
16
regular
120
2166
8954
Left
121
2168
8955
Right
356
M185 655 C185 605 235 555 285 555 C501 555 781 555 997 555 C1047 555 1097 605 1097 655 C1097 756 1097 887 1097 988 C1097 1038 1047 1088 997 1088 C781 1088 501 1088 285 1088 C235 1088 185 1038 185 988 C185 887 185 756 185 655
1
true
6
912.0
533.0