Structural determinants of vascular endothelial growth factor-D receptor binding and specificity

Leppänen, Veli-Matti; Jeltsch, Michael; Anisimov, Andrey; Tvorogov, Denis; Aho, Kukka; Kalkkinen, Nisse; Toivanen, Pekka; Ylä‐Herttuala, Seppo; Ballmer-Hofer, Kurt; Alitalo, Kari

doi:10.1182/blood-2010-08-301549

Cited by 78 publications

(72 citation statements)

References 40 publications

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“…Comparisons with the VEGFR-1 and VEGFR-2 complex structures show that all three VEGFRs share a conserved interface in D2 for ligand binding. VEGF-D has an extended N-terminal helix responsible for high-affinity binding and activation of VEGFR-3 (20), and we show here that mutation of the N-terminal Asp123 and Gln130 of VEGF-C decreases receptor binding, supporting the idea that the helix is an important Our data also provide insight into D1. Despite its importance in VEGFR-3 ligand binding (19,20), D1 protrudes away from VEGF-C and has no connections with it.…”

Section: Discussionsupporting

confidence: 70%

“…VEGF-D has an extended N-terminal helix responsible for high-affinity binding and activation of VEGFR-3 (20), and we show here that mutation of the N-terminal Asp123 and Gln130 of VEGF-C decreases receptor binding, supporting the idea that the helix is an important Our data also provide insight into D1. Despite its importance in VEGFR-3 ligand binding (19,20), D1 protrudes away from VEGF-C and has no connections with it. The bent conformation of the D1-2 module is very similar to that observed in KIT, platelet-derived growth factor receptor beta, and macrophage colony-stimulating factor 1 receptor (Fig.…”

Section: Discussionsupporting

confidence: 70%

“…For ligand binding, VEGFRs use predominantly D2, with D3 providing additional binding affinity (16-18). In addition, D1 is required for VEGFR-3 ligand binding, but the exact role of this domain remains elusive (19,20). VEGFRs and the closely related type III RTKs are activated by ligand-induced dimerization of the extracellular domain, followed by tyrosine autophosphorylation of the intracellular kinase domain to generate downstream signaling (21).…”

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confidence: 99%

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Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation

Leppänen

Tvorogov

Kisko

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are key drivers of blood and lymph vessel formation in development, but also in several pathological processes. VEGF-C signaling through VEGFR-3 promotes lymphangiogenesis, which is a clinically relevant target for treating lymphatic insufficiency and for blocking tumor angiogenesis and metastasis. The extracellular domain of VEGFRs consists of seven Ig homology domains; domains 1-3 (D1-3) are responsible for ligand binding, and the membrane-proximal domains 4-7 (D4-7) are involved in structural rearrangements essential for receptor dimerization and activation. Here we analyzed the crystal structures of VEGF-C in complex with VEGFR-3 domains D1-2 and of the VEGFR-3 D4-5 homodimer. The structures revealed a conserved ligand-binding interface in D2 and a unique mechanism for VEGFR dimerization and activation, with homotypic interactions in D5. Mutation of the conserved residues mediating the D5 interaction (Thr446 and Lys516) and the D7 interaction (Arg737) compromised VEGF-C induced VEGFR-3 activation. A thermodynamic analysis of VEGFR-3 deletion mutants showed that D3, D4-5, and D6-7 all contribute to ligand binding. A structural model of the VEGF-C/VEGFR-3 D1-7 complex derived from small-angle X-ray scattering data is consistent with the homotypic interactions in D5 and D7. Taken together, our data show that ligand-dependent homotypic interactions in D5 and D7 are essential for VEGFR activation, opening promising possibilities for the design of VEGFR-specific drugs.signal transduction | receptor tyrosine kinase V EGFs stimulate angiogenesis and lymphangiogenesis via VEGF receptors (VEGFRs) in endothelial cells. VEGF-A signaling is mediated predominantly through activation of VEGFR-2, resulting in sprouting of blood vessels from preexisting vasculature (1). In contrast, VEGFR-1 seems to have an inhibitory role by sequestering VEGF-A and thereby preventing its interaction with VEGFR-2 (2). On the other hand, VEGFR-3 plays an indispensable role in lymphangiogenesis (3). VEGFRs are involved in various pathological conditions, including solid tumor growth, tumor metastasis, and vascular retinopathies (4, 5).VEGF-C and VEGF-D compose a VEGFR-3-specific subfamily of VEGFs. They are produced with large N-and C-terminal propeptides and gain activity toward VEGFR-3 and VEGFR-2 on proteolytic processing (reviewed in ref. 5). VEGFR-3 maturation involves proteolytic cleavage of the extracellular domain (ECD) in D5 (6-8). Both VEGF-C and VEGFR-3 also interact with the coreceptor neuropilin-2 (9). Loss of the Vegfc gene results in embryonic lethality owing to a lack of lymphatic vessel formation (10), whereas mutations that interfere with VEGFR-3 signaling have been associated with hereditary lymphedema, and mice deficient in Vegfr3 die in utero due to abnormal development of the blood vasculature (11, 12). VEGFR-3 and its heterodimers with VEGFR-2 are also important for sprouting angiogenesis and vascular network formation (13-15).VEGFRs are type V rece...

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Section: Discussionsupporting

confidence: 70%

Section: Discussionsupporting

confidence: 70%

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confidence: 99%

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Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation

Leppänen

Tvorogov

Kisko

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…It has been reported that various plant lectins stimulate VEGF production [37], a proangiogenic factor that up-regulates ICAM-1 expression in microvascular endothelial cells [38]. The extracellular domain of VEGFR consists of seven immunoglobulin homology domains, that upon VEGF binding through sugar moieties, promote receptor dimerization [39]. A high proportion of immunoglobulin glycosidic structures contain GlcNAc and/or core fucose residues.…”

Section: Discussionmentioning

confidence: 99%

Effects of plant lectin and extracts on adhesion molecules of endothelial progenitors

Iordache¹,

Iordache²,

et al. 2011

Open Life Sciences

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Promise of cell therapy has advanced the use of adult stem cells towards the development of novel approaches to promote regeneration of injured endothelium. The aim of this study was to stimulate endothelial progenitor cells (EPCs) with lectin isolated from Solanum tuberosum (potato) shoot and Calendula officinalis (marigold) extracts, in order to increase EPCs proliferation and gene expression of molecules with roles in chemotaxis and adhesion for a better attachment to injured vascular tissue. EPCs were differentiated from umbilical cord blood-derived mononuclear cells and characterized by light microscopy, flow cytometry, and vascular tube-like structures formation on Matrigel. Cell proliferation was determined by MTS assay, and gene expression of molecules involved in EPCs adhesion (VCAM-1, VE-cadherin, ICAM-1, PECAM-1, P-selectin) and chemotaxis was determined (CXCR4, Tie-2) by RT-PCR. For the assessment of cell motility, wound-healing assay was employed. Both potato shoot lectin and marigold extracts stimulated EPCs proliferation in a concentration dependent manner and were able to increase expression of adhesion and chemotactic molecules. Marigold flower extract proved to be more efficient. This study demonstrates the usefulness of potato lectin and marigold extracts to increase EPCs proliferation and modulate gene expression of chemotactic and adhesion molecules, which may facilitate EPCs attachment to injured endothelium.

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“…Furthermore, this cysteine residue is considered a critical regulator of VEGF-D dimer stability. 9,19 The valine 118 residue is highly conserved across all members of the VEGF family of proteins, suggesting an essential role in VEGF structure and function as well. 19,20 Our modeling indicated that change from a compact and rigid valine 118 to a longer and more flexible methionine would cause clashes within the VEGF-D core, likely leading to rearrangements of residues that participate in dimerization ( Figure 3A).…”

Section: Vegf-d V118m Induces Aberrant Angiogenesis In Vitro and In Vivomentioning

confidence: 99%

Pulmonary Vasculopathy Associated with FIGF Gene Mutation

Bailey

Cui

Casey

et al. 2017

The American Journal of Pathology

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Structural determinants of vascular endothelial growth factor-D receptor binding and specificity

Cited by 78 publications

References 40 publications

Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation

Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation

Effects of plant lectin and extracts on adhesion molecules of endothelial progenitors

Pulmonary Vasculopathy Associated with FIGF Gene Mutation

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