Supplementary information S1 (animation)
Proposed role of syndecan-1 in the regulation of αVβ3 integrin- and VEGF-dependent angiogenesis.
This interactive figure allows the user to navigate around the complex body of in vivo and in vitro data that relates to the
functional interplay between αVβ3 integrin, vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR2)
in the regulation of pathological angiogenesis. The figure specifically highlights how potentially syndecan-1 may
differentially regulate the αvβ3 integrin and VEGF–VEGFR signalling network (green boxes/arrow).
The downstream effects of perturbing β3 integrin-dependent functions can be seen by clicking on the purple
buttons to the left of the page, or on the β3 integrin functions in the top row of the figure.
Users can return to the base model by clicking the red ‘Home’ button or by re-clicking on the disrupted β3 integrin
function. The potential role of syndecan-1 in regulating these processes can be viewed by clicking the green button.
References are included throughout the slide show.
Perturbing αvβ3 integrin function in vivo can have remarkably different effects on pathological angiogenesis,
depending on the nature of the perturbation and the cell type that is expressing the integrin (tumour (red) or
host/endothelial (blue)). β3 integrin-deficient mice exhibit enhanced pathological angiogenesis as a consequence of
increased VEGFR2 expression and signalling. Perturbation of tumour-cell αvβ3 integrin activation reduces pathological
angiogenesis and tumour growth by suppressing VEGF secretion. Endothelial cell β3 integrin phosphorylation is
required for VEGF-stimulated, VEGFR2-phosphorylation-dependent, pathological angiogenesis. Cross-activation of
αVβ3 integrin and VEGFR2 is required for the formation of the αVβ3 integrin–VEGFR2 complex and endothelial cell
migration. Inhibition of αVβ3 integrin engagement induces caspase-8-dependent apoptosis of angiogenic vessels and
reduces tumour growth. In vitro studies suggest that syndecan-1, through the regulation of integrin activation and
growth-factor presentation, could possibly modulate this β3 integrin–VEGF–VEGFR2 signalling network at various
points.
Start
The avb3-integrin-VEGF/VEGFR Signalling Network
Home
Potential
Syndecan-1 Function
b3 or b3/b5
Expression
b3 Activation
b3 Signalling
avb3
Engagement
VEGF
Secretion
b3 Knock-out
Inactive b3
Normal
Endothelial
VEGFR2
Expression
b3-VEGFR2
Complex
Formation
VEGFVEGFR2
Engagement
Caspase-8
Activation
VEGFR2
Phosphorylation
Phospho-null b3
Endothelial
Cell Migration
Endothelial
Cell Apoptosis
avb3 Antagonism
Pathological
Angiogenesis
References
Boxes/Arrows:
The functional interplay between αvβ3-integrin, VEGF and
VEGFR2 in the regulation of pathological angiogenesis;
highlighting how potentially syndecan-1 may regulate this
signalling network (green boxes/arrows)
Functional regulation
Syndecan-1-regulated
Potentially Syndecan-1-regulated
Potential Syndecan-1 Function
Soluble Syndecan-1
Ectodomain
1
Shedding
Home
1
Syndecan-1
Potential
Syndecan-1 Function
1
b3 or b3/b5
Expression
b3 Knock-out
Inactive b3
b3 Activation
VEGF
Secretion
Normal
Endothelial
VEGFR2
Expression
1
VEGFVEGFR2
Engagement
1
b3 Signalling
avb3
Engagement
2, 3
2, 3
b3-VEGFR2
Complex
Formation
Caspase-8
Activation
VEGFR2
Phosphorylation
Phospho-null b3
avb3 Antagonism
References
Endothelial
Cell Migration
Endothelial
Cell Apoptosis
Pathological
Angiogenesis
Boxes/Arrows:
Functional regulation
In vitro studies suggest that syndecan-1, through regulation of
integrin activation and growth factor presentation, could possibly
modulate the β3-integrin-VEGF/VEGFR2 signalling network
Syndecan-1-regulated
Potentially Syndecan-1-regulated
Integrin b3- or b3/b5-Deficient Mice
Home
b3 or b3/b5 /- mice
4, 5
Potential
Syndecan-1 Function
b3 or b3/b5
Expression
b3 Activation
b3 Signalling
avb3
Engagement
VEGF
Secretion
b3 Knock-out
Inactive b3
Endothelial
VEGFR2
Expression &
Signalling
b3-VEGFR2
Complex
Formation
VEGFVEGFR2
Engagement
Caspase-8
Activation
VEGFR2
Phosphorylation
Phospho-null b3
Endothelial
Cell Migration
Endothelial
Cell Apoptosis
avb3 Antagonism
Pathological
Angiogenesis
References
Boxes/Arrows:
Functional regulation
β3-integrin-deficient mice exhibit enhanced pathological
angiogenesis as a consequence of increased VEGFR2
expression and signalling
Syndecan-1-regulated
Potentially Syndecan-1-regulated
Tumour Cell Expression of Inactivatable-b3
Inactivatable
b3 expression
Home
6
Potential
Syndecan-1 Function
b3 or b3/b5
Expression
b3 Activation
b3 Signalling
avb3
Engagement
VEGF
Secretion
b3 Knock-out
Inactive b3
Normal
Endothelial
VEGFR2
Expression
b3-VEGFR2
Complex
Formation
VEGFVEGFR2
Engagement
Caspase-8
Activation
VEGFR2
Phosphorylation
Phospho-null b3
Endothelial
Cell Migration
Endothelial
Cell Apoptosis
avb3 Antagonism
Pathological
Angiogenesis
References
Boxes/Arrows:
Functional regulation
Perturbation of tumour cell αvβ3-integrin activation reduces
pathological angiogenesis and tumour growth by suppressing
VEGF secretion
Syndecan-1-regulated
Potentially Syndecan-1-regulated
Phospho-null-b3 Expression
Phosphoincompetent b3
Home
7
Potential
Syndecan-1 Function
b3 or b3/b5
Expression
b3 Activation
b3 Signalling
VEGF
Secretion
8
avb3
Engagement
7
b3 Knock-out
Inactive b3
Normal
Endothelial
VEGFR2
Expression
b3-VEGFR2
Complex
Formation
VEGFVEGFR2
Engagement
Caspase-8
Activation
VEGFR2
Phosphorylation
Phospho-null b3
Endothelial
Cell Migration
Endothelial
Cell Apoptosis
avb3 Antagonism
Pathological
Angiogenesis
References
Endothelial β3-integrin phosphorylation is required for VEGFstimulated, VEGFR2-phosphorylation dependent, pathological
angiogenesis. Cross-activation of αVβ3-integrin and VEGFR2 is
required for the formation of the αVβ3-integrin–VEGFR2 complex
and endothelial cell migration.
Boxes/Arrows:
Functional regulation
Syndecan-1-regulated
Potentially Syndecan-1-regulated
avb3 Antagonism
avb3
antagonism
Home
9, 10
Potential
Syndecan-1 Function
b3 or b3/b5
Expression
b3 Activation
b3 Signalling
avb3
Engagement
VEGF
Secretion
b3 Knock-out
Inactive b3
Normal
Endothelial
VEGFR2
Expression
b3-VEGFR2
Complex
Formation
VEGFVEGFR2
Engagement
Caspase-8
Activation
VEGFR2
Phosphorylation
Phospho-null b3
Endothelial
Cell Migration
Endothelial
Cell Apoptosis
avb3 Antagonism
Pathological
Angiogenesis
References
Boxes/Arrows:
Functional regulation
Inhibition of αVβ3-integrin engagement induces caspase-8dependent apoptosis of angiogenic vessels and reduces tumour
growth
Syndecan-1-regulated
Potentially Syndecan-1-regulated
Reference List
Home
1. Beauvais, D. M., Burbach, B. J. & Rapraeger, A. C. The syndecan-1 ectodomain
regulates alphavbeta3 integrin activity in human mammary carcinoma cells. J Cell Biol
167, 171-81 (2004).
Potential
Syndecan-1 Function
2. Fuster, M. M. et al. Genetic alteration of endothelial heparan sulfate selectively inhibits
tumor angiogenesis. J Cell Biol 177, 539-49 (2007).
3. Subramanian, S. V., Fitzgerald, M. L. & Bernfield, M. Regulated shedding of syndecan-1
and -4 ectodomains by thrombin and growth factor receptor activation. J Biol Chem 272,
14713-20 (1997).
b3 Knock-out
Inactive b3
4. Reynolds, L. E. et al. Enhanced pathological angiogenesis in mice lacking beta3 integrin
or beta3 and beta5 integrins. Nat Med 8, 27-34 (2002).
5. Reynolds, A. R. et al. Elevated Flk1 (vascular endothelial growth factor receptor 2)
signaling mediates enhanced angiogenesis in beta3-integrin-deficient mice. Cancer Res
64, 8643-50 (2004).
6. De, S. et al. VEGF-integrin interplay controls tumor growth and vascularization. Proc
Natl Acad Sci U S A 102, 7589-94 (2005).
Phospho-null b3
7. Mahabeleshwar, G. H., Feng, W., Phillips, D. R. & Byzova, T. V. Integrin signaling is
critical for pathological angiogenesis. J Exp Med 203, 2495-507 (2006).
8. Mahabeleshwar, G. H., Feng, W., Reddy, K., Plow, E. F. & Byzova, T. V. Mechanisms of
Integrin-Vascular Endothelial Growth Factor Receptor Cross-Activation in Angiogenesis.
Circ Res (2007).
avb3 Antagonism
References
9. Brooks, P. C. et al. Integrin alpha v beta 3 antagonists promote tumor regression by
inducing apoptosis of angiogenic blood vessels. Cell 79, 1157-64 (1994).
10. Stupack, D. G., Puente, X. S., Boutsaboualoy, S., Storgard, C. M. & Cheresh, D. A.
Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins. J Cell
Biol 155, 459-70 (2001).