The lymphangiogenic vascular endothelial growth factors VEGF-C and -D are ligands for the integrin alpha9beta1

Mice homozygous for a null mutation of the integrin alpha9 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 alpha9beta1 modulates lymphangiogenesis have not been described....

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Bibliographic Details
Published in:The Journal of biological chemistry 2005-02, Vol.280 (6), p.4544
Main Authors: Vlahakis, Nicholas E, Young, Bradford A, Atakilit, Amha, Sheppard, Dean
Format: Article
Language:English
Subjects:
Animals
Blotting, Western
Cell Adhesion
Cell Line, Tumor
Cell Movement
Cells, Cultured
Cytoskeletal Proteins - metabolism
Dose-Response Relationship, Drug
Electrophoresis, Polyacrylamide Gel
Endothelium, Vascular - cytology
Extracellular Signal-Regulated MAP Kinases - metabolism
Fibroblasts - metabolism
Flow Cytometry
Homozygote
Humans
Immunoprecipitation
Integrins - metabolism
Ligands
Lymphangiogenesis
Mice
Mice, Knockout
Microcirculation
Paxillin
Phenotype
Phosphoproteins - metabolism
Phosphorylation
Protein Binding
RNA Interference
RNA, Small Interfering - metabolism
Transfection
Vascular Endothelial Growth Factor C - physiology
Vascular Endothelial Growth Factor D - physiology
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Summary:Mice homozygous for a null mutation of the integrin alpha9 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 alpha9beta1 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 alpha9beta1-dependent. Mouse embryonic fibroblasts and human colon carcinoma cells (SW-480) transfected to express alpha9beta1 adhered and/or migrated on both growth factors in a concentration-dependent fashion, and both adhesion and migration were abrogated by anti-alpha9beta1 function-blocking antibody. In SW-480 cells, which lack cognate receptors for VEGF-C and -D, both growth factors induced alpha9beta1-dependent Erk and paxillin phosphorylation. Human microvascular endothelial cells, which express both alpha9beta1 and VEGF-R3, also adhered to and migrated on both growth factors, and both responses were blocked by anti-alpha9beta1 antibody. Furthermore, in a solid phase binding assay recombinant VEGF-C and -D bound to purified alpha9beta1 integrin in a dose- and cation-dependent fashion showing that VEGF-C and VEGF-D are ligands for the integrin alpha9beta1. The interaction between alpha9beta1 and VEGF-C and/or -D may begin to explain the abnormal lymphatic phenotype of the alpha9 knock-out mice.
ISSN:0021-9258