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J. Biol. Chem., Vol. 282, Issue 17, 13114-13122, April 27, 2007

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Disabled-2 Is an Epithelial Surface Positioning Gene^*

From the Ovarian Cancer and Tumor Cell Biology Programs, Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111

The formation of the primitive endoderm layer on the surface of the inner cell mass is one of the earliest epithelial morphogenesis in mammalian embryos. In mouse embryos deficient of Disabled-2 (Dab2), the primitive endoderm cells lose the ability to position on the surface, resulting in defective morphogenesis. Embryonic stem cells lacking Dab2 are also unable to position on the surface of cell aggregates and fail to form a primitive endoderm outer layer in the embryoid bodies. The cellular function of Dab2, a cargo-selective adaptor, in mediating endocytic trafficking of clathrin-coated vesicles is well established. We show here that Dab2 mediates directional trafficking and polarized distribution of cell surface proteins such as megalin and E-cadherin and propose that loss of polarity is the underlying mechanism for the loss of epithelial cell surface positioning in Dab2-deficient embryos and embryoid bodies. Thus, the findings indicate that Dab2 is a surface positioning gene and suggest a novel mechanism of epithelial cell surface targeting.

Received for publication, December 11, 2006 , and in revised form, March 2, 2007.

^* This work was supported by Grants R01 CA095071, CA79716, and CA75389 (to X.-X. X.) from the NCI, National Institutes of Health. This work was also supported by Core Grant CA006927 and by an appropriation from the Commonwealth of Pennsylvania. 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 Present address: Dept. of Pathology and Laboratory Medicine, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854.

² To whom correspondence should be addressed: Ovarian Cancer and Tumor Cell Biology Programs, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111-2497. Tel.: 215-728-2188; Fax: 215-728-2741; E-mail: Xiangxi.Xu{at}fccc.edu.

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