Characterization of indolinones which preferentially inhibit VEGF‐C‐ and VEGF‐D‐induced activation of VEGFR‐3 rather than VEGFR‐2

Kirkin, Vladimir; Mazitschek, Ralph; Krishnan, Jaya; Steffen, Anȷa; Waltenberger, Johannes; Pepper, Michael Sean; Giannis, Athanassios; Sleeman, Jonathan P.

doi:10.1046/j.1432-1033.2001.02476.x

Cited by 93 publications

(89 citation statements)

References 40 publications

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“…The basal level of lymphatic cell sprouting observed under these conditions was improved by adding VEGF-C to the medium (2.7-fold improvement at the optimal concentration of 10 ng/ml) (P<0.05) ( Moreover, MAZ51, an inhibitor of ligand-induced VEGFR-3 autophosphorylation 21 , also reduced serum-dependent lymphatic outgrowth (52% reduction at the optimal concentration) (P<0.05) (Fig. 4c).…”

Section: Sensitivity To Lymphangiogenic Factorsmentioning

confidence: 86%

Modeling lymphangiogenesis in a three-dimensional culture system

et al. 2008

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Section: Sensitivity To Lymphangiogenic Factorsmentioning

confidence: 86%

Modeling lymphangiogenesis in a three-dimensional culture system

et al. 2008

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“…To determine whether the Hras-induced VEGFR3 increase has a functional effect on LECs, we performed a network formation assay in the presence of MAZ51, a selective kinase inhibitor of VEGFR3 (Kirkin et al, 2001). Blockage of VEGFC-induced phosphorylation of VEGFR3 in LECs was observed in the presence of 5 mM of MAZ51 in western blots (Fig.…”

Section: Enhanced Endothelial Sheet Formation By Hras-overexpressing mentioning

confidence: 99%

H-, N- and Kras cooperatively regulate lymphatic vessel growth by modulating VEGFR3 expression in lymphatic endothelial cells in mice

2010

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SUMMARYMammalian Ras, which is encoded by three independent genes, has been thought to be a versatile component of intracellular signalling. However, when, where and how Ras signalling plays essential roles in development and whether the three Ras genes have overlapping functions in particular cells remain unclear. Here, we show that the three Ras proteins dose-dependently regulate lymphatic vessel growth in mice. We find that lymphatic vessel hypoplasia is a common phenotype in Ras compound knockout mice and that overexpressed normal Ras in an endothelial cell lineage selectively causes lymphatic vessel hyperplasia in vivo. Overexpression of normal Ras in lymphatic endothelial cells leads to sustained MAPK activation, cellular viability and enhanced endothelial network formation under serum-depleted culture conditions in vitro, and knockdown of endogenous Ras in lymphatic endothelial cells impairs cell proliferation, MAPK activation, cell migration and endothelial network formation. Ras overexpression and knockdown result in up-and downregulation of vascular endothelial growth factor receptor (VEGFR) 3 expression, respectively, in lymphatic endothelial cells in vitro. The close link between Ras and VEGFR3 in vitro is consistent with the result that Ras knockout and transgenic alleles are genetic modifiers in lymphatic vessel hypoplasia caused by Vegfr3 haploinsufficiency. Our findings demonstrate a cooperative function of the three Ras proteins in normal development, and also provide a novel aspect of VEGFR3 signalling modulated by Ras in lymphangiogenesis.

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“…To assess the relative contribution of VEGF-R3 and ␣9␤1 to HMVEC cell migration, cells were treated with the ␣9␤1-blocking antibody and/or the VEGF-R3-blocking chemical MAZ51 (49). Fig.…”

Section: ␣9␤1-dependent Cell Adhesion Is Demonstrable In Primary Endomentioning

confidence: 99%

The Lymphangiogenic Vascular Endothelial Growth Factors VEGF-C and -D Are Ligands for the Integrin α9β1

Vlahakis

Young

Atakilit

et al. 2005

Journal of Biological Chemistry

184

163

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Mice homozygous for a null mutation of the integrin ␣9 subunit die 6 -12 days after birth from bilateral chylothoraces suggesting an underlying defect in lymphatic development. However, until now the mechanisms by which the integrin ␣9␤1 modulates lymphangiogenesis have not been described. In this study we show that adhesion to and migration on the lymphangiogenic vascular endothelial growth factors (VEGF-C and -D) are ␣9␤1-dependent. Mouse embryonic fibroblasts and human colon carcinoma cells (SW-480) transfected to express ␣9␤1 adhered and/or migrated on both growth factors in a concentration-dependent fashion, and both adhesion and migration were abrogated by anti-␣9␤1 function-blocking antibody. In SW-480 cells, which lack cognate receptors for VEGF-C and -D, both growth factors induced ␣9␤1-dependent Erk and paxillin phosphorylation. Human microvascular endothelial cells, which express both ␣9␤1 and VEGF-R3, also adhered to and migrated on both growth factors, and both responses were blocked by anti-␣9␤1 antibody. Furthermore, in a solid phase binding assay recombinant VEGF-C and -D bound to purified ␣9␤1 integrin in a dose-and cationdependent fashion showing that VEGF-C and VEGF-D are ligands for the integrin ␣9␤1. The interaction between ␣9␤1 and VEGF-C and/or -D may begin to explain the abnormal lymphatic phenotype of the ␣9 knock-out mice.

show abstract

Characterization of indolinones which preferentially inhibit VEGF‐C‐ and VEGF‐D‐induced activation of VEGFR‐3 rather than VEGFR‐2

Cited by 93 publications

References 40 publications

Modeling lymphangiogenesis in a three-dimensional culture system

Modeling lymphangiogenesis in a three-dimensional culture system

H-, N- and Kras cooperatively regulate lymphatic vessel growth by modulating VEGFR3 expression in lymphatic endothelial cells in mice

The Lymphangiogenic Vascular Endothelial Growth Factors VEGF-C and -D Are Ligands for the Integrin α9β1

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