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

• Published in: The Journal of biological chemistry Vol. 282; no. 43; pp. 31643 - 31655
• Main Authors: Watanabe, Kazuhide, Bianco, Caterina, Strizzi, Luigi, Hamada, Shin, Mancino, Mario, Bailly, Veronique, Mo, Wenjun, Wen, Dingyi, Miatkowski, Konrad, Gonzales, Monica, Sanicola, Michele, Seno, Masaharu, Salomon, David S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.10.2007; American Society for Biochemistry and Molecular Biology
• Subjects: Adenocarcinoma - pathology; Animals; Cell Line; Cell Line, Tumor; Cell Movement; Chlorocebus aethiops; Coculture Techniques; Colonic Neoplasms - pathology; COS Cells; Dogs; Endothelial Cells - physiology; Endothelium, Vascular - cytology; Epidermal Growth Factor - metabolism; Fluorescent Dyes; Glycosylphosphatidylinositols - genetics; Glycosylphosphatidylinositols - metabolism; GPI-Linked Proteins; Growth Substances - physiology; Humans; Indoles; Intercellular Signaling Peptides and Proteins; Kidney - cytology; Mass Spectrometry; Membrane Glycoproteins - metabolism; Neoplasm Proteins - metabolism; Phalloidine; Phospholipase D - genetics; Phospholipase D - metabolism; Rhodamines; RNA, Small Interfering - metabolism; Umbilical Veins - cytology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M702713200

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 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, membrane-bound CR-1 can stimulate endothelial cell sprouting through direct cell-cell interaction. Shedding of CR-1 occurs at the GPI-anchorage 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.