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J. Biol. Chem., Vol. 282, Issue 43, 31643-31655, October 26, 2007

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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^¶, and David S. Salomon¹

From the Tumor Growth Factor Section, Mammary Biology & Tumorigenesis Laboratory, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, Biogen Idec Inc., Cambridge, Massachusetts 02142, and the ^¶Department of Medical and Bioengineering Science, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan

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.

Received for publication, March 29, 2007 , and in revised form, August 21, 2007.

^* This work was supported by National Institutes of Health Intramural Funding. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

¹ To whom correspondence should be addressed: Tumor Growth Factor Section, Mammary Biology & Tumorigenesis Laboratory, Center for Cancer Research, NCI, National Institutes of Health, Bldg. 37, Rm. 1118B, 37 Convent Drive, Bethesda, MD 20892-4254. Tel.: 301-496-9536; Fax: 301-402-8656; E-mail: salomond{at}mail.nih.gov.

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