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

• Published in: The Journal of biological chemistry 2005-02, Vol.280 (6), p.4544-4552
• Main Authors: Vlahakis, Nicholas E., Young, Bradford A., Atakilit, Amha, Sheppard, Dean
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M412816200

Mice homozygous for a null mutation of the integrin α9 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 α9β1 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 α9β1-dependent. Mouse embryonic fibroblasts and human colon carcinoma cells (SW-480) transfected to express α9β1 adhered and/or migrated on both growth factors in a concentration-dependent fashion, and both adhesion and migration were abrogated by anti-α9β1 function-blocking antibody. In SW-480 cells, which lack cognate receptors for VEGF-C and -D, both growth factors induced α9β1-dependent Erk and paxillin phosphorylation. Human microvascular endothelial cells, which express both α9β1 and VEGF-R3, also adhered to and migrated on both growth factors, and both responses were blocked by anti-α9β1 antibody. Furthermore, in a solid phase binding assay recombinant VEGF-C and -D bound to purified α9β1 integrin in a dose- and cation-dependent fashion showing that VEGF-C and VEGF-D are ligands for the integrin α9β1. The interaction between α9β1 and VEGF-C and/or -D may begin to explain the abnormal lymphatic phenotype of the α9 knock-out mice.