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J. Biol. Chem., Vol. 283, Issue 18, 12478-12488, May 2, 2008

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Domain and Functional Analysis of a Novel Platelet-Endothelial Cell Surface Protein, SCUBE1^*

Cheng-Fen Tu¹, Yu-Ting Yan¹, Szu-Yao Wu, Bambang Djoko, Ming-Tzu Tsai, Chien-Jui Cheng, and Ruey-Bing Yang^¶2

From the Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Sec. 2, Taipei 115, the Graduate Institute of Clinical Medicine and Department of Pathology, College of Medicine, Taipei Medical University Hospital, Taipei 110, and the ^¶Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan

SCUBE1 (signal peptide-CUB-EGF domain-containing protein 1) is a novel, secreted, cell surface glycoprotein expressed during early embryogenesis and found in platelet and endothelial cells. This protein is composed of an N-terminal signal peptide sequence followed by nine tandemly arranged epidermal growth factor (EGF)-like repeats, a spacer region, three cysteine-rich repeat motifs, and one CUB domain at the C terminus. However, little is known about its domain and biological function. Here, we generated a comprehensive panel of domain deletion constructs and a new genetic mouse model with targeted disruption of Scube1 (Scube1^cub/cub) to investigate the domain function and biological significance. A number of cell-based assays were utilized to define the critical role of the spacer region for membrane association and establish that the EGF-like repeats 7–9 are sufficient for the formation of SCUBE1-mediated homophilic adhesions in a calcium-dependent fashion. Biochemical and molecular analyses showed that the C-terminal cysteine-rich motifs and CUB domain could directly bind and antagonize the bone morphogenetic protein activity. Furthermore, genetic ablation of this C-terminal region resulted in brain malformation in the Scube1^cub/cub embryos. Together, our results support the dual roles of SCUBE1 on brain morphogenesis and cell-cell adhesions through its distinct domain function.

Received for publication, July 17, 2007 , and in revised form, February 20, 2008.

^* This work was supported by the National Science Council (Grants NSC 9-2752-B-006-003-PAE and NSC 9-2752-B-001-002-PAE) and Academia Sinica (Grant AS-97-FP-L16 to R. B. Y.). 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 Fig. S1.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 886-2-2652-3943; Fax: 886-2-2785-8847; E-mail: rbyang{at}ibms.sinica.edu.tw.

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