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J. Biol. Chem., Vol. 282, Issue 49, 35772-35786, December 7, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/49/35772    most recent M707351200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Watanabe, K. Articles by Salomon, D. S. Search for Related Content PubMed PubMed Citation Articles by Watanabe, K. Articles by Salomon, D. S. Social Bookmarking                      What's this?

Requirement of Glycosylphosphatidylinositol Anchor of Cripto-1 for trans Activity as a Nodal Co-receptor^*

Kazuhide Watanabe, Shin Hamada, Caterina Bianco, Mario Mancino, Tadahiro Nagaoka, Monica Gonzales, Veronique Bailly, Luigi Strizzi, and David S. Salomon¹

From the Tumor Growth Factor Section, Mammary Biology and Tumorigenesis Laboratory, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and Biogen Idec, Inc., Cambridge, Massachursetts 02142

Cripto-1 (CR-1) has an indispensable role as a Nodal co-receptor for patterning of body axis in embryonic development. CR-1 is reported to have a paracrine activity as a Nodal co-receptor, although CR-1 is primarily produced as a glycosylphosphatidylinositol (GPI)-anchored membrane protein. Regulation of cis and trans function of CR-1 should be important to establish the precise body patterning. However, the mechanism by which GPI-anchored CR-1 can act in trans is not well known. Here we confirmed the paracrine activity of CR-1 by fluorescent cell-labeling and immunofluorescent staining. We generated COOH-terminal-truncated soluble forms of CR-1 based on the attachment site for the GPI moiety (-site), which we identified in the present study. GPI-anchored CR-1 has a significantly higher activity than COOH-terminal-truncated soluble forms to induce Nodal signal in trans as well as in cis. Moreover, transmembrane forms of CR-1 partially retained their ability to induce Nodal signaling only when type I receptor Activin-like kinase 4 was overexpressed. NTERA2/D1 cells, which express endogenous CR-1, lost the cell-surface expression of CR-1 after phosphatidylinositol-phospholipase C treatment and became refractory to stimulation of Nodal. These observations suggest that GPI attachment of CR-1 is required for the paracrine activity as a Nodal co-receptor.

Received for publication, August 31, 2007 , and in revised form, October 4, 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.

¹ To whom correspondence should be addressed: Bldg. 37, Rm.1118B, 37 Convent Dr., Bethesda, MD 20892-4254. Tel.: 301-402-8656; Fax: 301-402-8656; E-mail: salomond{at}mail.nih.gov.

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