Heterodimerization with vascular endothelial growth factor receptor-2 (VEGFR-2) is necessary for VEGFR-3 activity

Alam, Antoine; Hérault, Jean-Pascal; Barron, Pauline; Favier, Benoît; Fons, Pierre; Delesque-Touchard, Nathalie; Senegas, Isabelle; Laboudie, Patricia; Bonnin, Jacques; Cassan, Cécile; Savi, Pierre; Ruggeri, Bruce; Carmeliet, Peter; Bono, Françoise; Herbert, Jean‐Marc

doi:10.1016/j.bbrc.2004.08.237

Cited by 58 publications

(45 citation statements)

References 27 publications

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“…This suggests that additional ligands exist or that ligand-independent signaling occurs. Indeed, whereas VEGFA binds only to VEGFR-2, we and others have shown that VEGFA may induce formation of VEGFR-2/-3 heterodimers (13,14). This suggests that when cells express both receptors, VEGFR-3 inhibitors may also block some VEGFA signaling.…”

Section: Introductionmentioning

confidence: 75%

SAR131675, a Potent and Selective VEGFR-3–TK Inhibitor with Antilymphangiogenic, Antitumoral, and Antimetastatic Activities

Alam

Blanc

Gueguen-Dorbes

et al. 2012

Molecular Cancer Therapeutics

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SAR131675 is a potent and selective VEGFR-3 inhibitor. It inhibited VEGFR-3 tyrosine kinase activity and VEGFR-3 autophosphorylation in HEK cells with IC 50 values of 20 and 45 nmol/L, respectively. SAR131675 dose dependently inhibited the proliferation of primary human lymphatic cells, induced by the VEGFR-3 ligands VEGFC and VEGFD, with an IC 50 of about 20 nmol/L. SAR131675 was found to be highly selective for VEGFR-3 versus 107 receptors, enzymes, ion channels, and 65 kinases. However, it was moderately active on VEGFR-2 with a VEGFR-3/VEGFR-2 ratio of about 10. SAR131675 had no antiproliferative activity on a panel of 30 tumors and primary cells, further showing its high specificity and indicating that SAR131675 is not a cytotoxic or cytostatic agent. SAR131675 was very well tolerated in mice and showed a potent antitumoral effect in several orthotopic and syngenic models, including mammary 4T1 carcinoma and RIP1.Tag2 tumors. Interestingly, it significantly reduced lymph node invasion and lung metastasis, showing its antilymphangiogenic activity in vivo. Moreover, treatment of mice before resection of 4T1 primary tumors was sufficient to prevent metastasis. Tumor-associated macrophages (TAM) play an important role in tumor growth and metastasis. The expression of VEGFR-3 on TAMs has been recently described. F4/80 immunostaining clearly showed that SAR131675 significantly reduced TAM infiltration and aggregation in 4T1 tumors. Taken together, SAR131675 is the first highly specific VEGFR-3-TK inhibitor described to date, displaying significant antitumoral and antimetastatic activities in vivo through inhibition of lymphangiogenesis and TAM invasion.

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Section: Introductionmentioning

confidence: 75%

SAR131675, a Potent and Selective VEGFR-3–TK Inhibitor with Antilymphangiogenic, Antitumoral, and Antimetastatic Activities

Alam

Blanc

Gueguen-Dorbes

et al. 2012

Molecular Cancer Therapeutics

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“…VEGFR also form homo-and heterodimers, which drives a complex series of signaling events leading to activation of many common growth factor signaling pathways (1). VEGFR-1 for example can synergize with VEGFR-2 and facilitate full activation of VEGFR-2 signaling (32,33), and VEGFR-3 also forms a heterodimer (34). Formation of these heterodimers would be prevented by an inhibitor of VEGFR-2 dimerization.…”

Section: Numbmentioning

confidence: 99%

An Antibody Targeted to VEGFR-2 Ig Domains 4-7 Inhibits VEGFR-2 Activation and VEGFR-2–Dependent Angiogenesis without Affecting Ligand Binding

Kendrew

Eberlein

Hedberg

et al. 2011

Molecular Cancer Therapeutics

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Inhibition of VEGFR-2 signaling reduces angiogenesis and retards tumor growth. Current biotherapeutics that inhibit VEGFR-2 signaling by either sequestering VEGF ligand or inhibiting VEGF binding to VEGFR-2 may be compromised by high VEGF concentrations. Here we describe a biotherapeutic that targets VEGFR-2 signaling by binding to Ig domains 4-7 of VEGFR-2 and therefore has the potential to work independently of ligand concentration. 33C3, a fully human VEGFR-2 antibody, was generated using XenoMouse technology. To elucidate the mechanism of action of 33C3, we have used a number of competition and binding assays. We show that 33C3 binds VEGFR-2 Ig domains 4-7, has no impact on VEGF-A binding to VEGFR-2, and does not compete with an antibody that interacts at the ligand binding site. 33C3 has a high affinity for VEGFR-2 (KD < 1 nmol/L) and inhibits VEGF-A induced phosphorylation of VEGFR-2 with an IC50 of 99 ± 3 ng/mL. In vitro, in a 2D angiogenesis assay, 33C3 potently inhibits both tube length and number of branch points, and endothelial tubule formation in a 3D assay. In vivo, 33C3 is a very effective inhibitor of angiogenesis in both a human endothelial angiogenesis assay and in a human skin chimera model. These data show targeting VEGFR-2 outside of the ligand binding domain results in potent inhibition of VEGFR-2 signaling and inhibition of angiogenesis in vitro and in vivo. Mol Cancer Ther; 10(5); 770–83. ©2011 AACR.

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“…14,37,38 However, it has been demonstrated that VEGFR-3 activity requires heterodimerization with VEGFR-2, which is also expressed on lymphatic vessels. [39][40][41] In this study, we have investigated the ability of NRP2 to interact with VEGFR-2 and VEGFR-3 and analyzed the consequences of such interactions on human endothelial cell survival and migration.…”

Section: Introductionmentioning

confidence: 99%

Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration

Favier

Alam

Barron

et al. 2006

Blood

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249

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Neuropilin 2 (NRP2) is a receptor for the vascular endothelial growth factor (VEGF) and the semaphorin (SEMA) families, 2 unrelated ligand families involved in angiogenesis and neuronal guidance. NRP2 specifically binds VEGF-A and VEGF-C, although the biological relevance of these interactions in human endothelial cells is poorly understood. In this study, we show that both VEGF-A and VEGF-C induce the interaction of NRP2 with VEGFR-2. This interaction correlated with an enhancement of the VEGFR-2 phosphorylation threshold. Overexpression of NRP2 in primary human endothelial cells promoted cell survival induced by VEGF-A and VEGF-C. In contrast, SEMA3F, another ligand for NRP2, was able to inhibit human endothelial cell survival and migration induced by VEGF-A and VEGF-C. Moreover, a siRNA targeting specifically NRP2 was a potent inhibitor of human endothelial cell migration induced by VEGF-A and VEGF-C. Thus, our data indicate that NRP2 acts as a coreceptor that enhances human endothelial cell biological responses induced by VEGF-A and VEGF-C.

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Heterodimerization with vascular endothelial growth factor receptor-2 (VEGFR-2) is necessary for VEGFR-3 activity

Cited by 58 publications

References 27 publications

SAR131675, a Potent and Selective VEGFR-3–TK Inhibitor with Antilymphangiogenic, Antitumoral, and Antimetastatic Activities

SAR131675, a Potent and Selective VEGFR-3–TK Inhibitor with Antilymphangiogenic, Antitumoral, and Antimetastatic Activities

An Antibody Targeted to VEGFR-2 Ig Domains 4-7 Inhibits VEGFR-2 Activation and VEGFR-2–Dependent Angiogenesis without Affecting Ligand Binding

Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration

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