期刊
MOLECULAR BIOLOGY OF THE CELL
卷 24, 期 7, 页码 933-944出版社
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E12-06-0481
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- Medical Faculty of the University of Munster [IMF-EB 1 2 03 23, IZKF Eb2/028/09, IZKF Ge2/016/10]
Junctional adhesion molecule-A (JAM-A) is a member of the immunoglobulin family with diverse functions in epithelial cells, including cell migration, cell contact maturation, and tight junction formation. In endothelial cells, JAM-A has been implicated in basic fibroblast growth factor (bFGF)-regulated angiogenesis through incompletely understood mechanisms. In this paper, we identify tetraspanin CD9 as novel binding partner for JAM-A in endothelial cells. CD9 acts as scaffold and assembles a ternary JAM-A-CD9-alpha v beta 3 integrin complex from which JAM-A is released upon bFGF stimulation. CD9 interacts predominantly with monomeric JAM-A, which suggests that bFGF induces signaling by triggering JAM-A dimerization. Among the two vitronectin receptors, alpha v beta 3 and alpha v beta 5 integrin, which have been shown to cooperate during angiogenic signaling with bFGF and vascular endothelial growth factor (VEGF), respectively, CD9 links JAM-A specifically to alpha v beta 3 integrin. In line with this, knockdown of CD9 blocks bFGF-but not VEGF-induced ERK1/2 activation. JAM-A or CD9 knockdown impairs endothelial cell migration and tube formation. Our findings indicate that CD9 incorporates monomeric JAM-A into a complex with alpha v beta 3 integrin, which responds to bFGF stimulation by JAM-A release to regulate mitogen-activated protein kinase (MAPK) activation, endothelial cell migration, and angiogenesis. The data also provide new mechanistic insights into the cooperativity between bFGF and alpha v beta 3 integrin during angiogenic signaling.
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