Growth Factor Induction of Cripto-1 Shedding by Glycosylphosphatidylinositol-Phospholipase D and Enhancement of Endothelial Cell Migration

Kazuhide Watanabe, Caterina Bianco, Luigi Strizzi, Shin Hamada, Mario Mancino, Veronique Bailly, Wenjun Mo, Dingyi Wen, Konrad Miatkowski, Monica Gonzales, Michele Sanicola, Masaharu Seno (+1 others)
2007 Journal of Biological Chemistry  
Cripto-1 (CR-1) is a glycosylphosphatidylinositol (GPI)-anchored membrane glycoprotein that has been shown to play an important role in embryogenesis and cellular transformation. CR-1 is reported to function as a membrane-bound co-receptor and as a soluble ligand. Although a number of studies implicate the role of CR-1 as a soluble ligand in tumor progression, it is unclear how transition from the membrane-bound to the soluble form is physiologically regulated and whether differences in
more » ... ferences in biological activity exist between these forms. Here, we demonstrate that CR-1 protein is secreted from tumor cells into the conditioned medium after treatment with serum, epidermal growth factor, or lysophosphatidic acid, and this soluble form of CR-1 exhibits the ability to promote endothelial cell migration as a paracrine chemoattractant. On the other hand, membranebound CR-1 can stimulate endothelial cell sprouting through direct cell-cell interaction. Shedding of CR-1 occurs at the GPIanchorage site by the activity of GPI-phospholipase D (GPI-PLD), because CR-1 shedding was suppressed by siRNA knockdown of GPI-PLD and enhanced by overexpression of GPI-PLD. These findings describe a novel molecular mechanism of CR-1 shedding, which may contribute to endothelial cell migration and possibly tumor angiogenesis. . 2 The abbreviations used are: EGF-CFC, epidermal growth factor-Cripto-1/ FRL-1/Cryptic; ADAM, a disintegrin and metalloproteinase domain; CR-1,
doi:10.1074/jbc.m702713200 pmid:17720976 fatcat:ov4wqhjpk5cojhiiketxkeoi5e