Growth factor induction of Cripto-1 shedding by glycosylphosphatidylinositol-phospholipase D and enhancement of endothelial cell migration.
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.
Watanabe
Kazuhide
K
Tumor Growth Factor Section, Mammary Biology & Tumorigenesis Laboratory, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Bianco
Caterina
C
Strizzi
Luigi
L
Hamada
Shin
S
Mancino
Mario
M
Bailly
Veronique
V
Mo
Wenjun
W
Wen
Dingyi
D
Miatkowski
Konrad
K
Gonzales
Monica
M
Sanicola
Michele
M
Seno
Masaharu
M
Salomon
David S
DS
D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D002522:Chlorocebus aethiops; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000473:pathology; D004285:Dogs; D042783:Endothelial Cells / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005456:Fluorescent Dyes; D058851:GPI-Linked Proteins; D017261:Glycosylphosphatidylinositols / Q000235:genetics / Q000378:metabolism*; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D007668:Kidney / Q000166:cytology; D013058:Mass Spectrometry; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D010590:Phalloidine; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012235:Rhodamines; D014471:Umbilical Veins / Q000166:cytology
D005456:Fluorescent Dyes; D058851:GPI-Linked Proteins; D017261:Glycosylphosphatidylinositols; D006133:Growth Substances; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D012235:Rhodamines; C070636:TDGF1 protein, human; D010590:Phalloidine; C007293:DAPI; D004815:Epidermal Growth Factor; D010739:Phospholipase D