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J. Biol. Chem., Vol. 283, Issue 20, 13753-13761, May 16, 2008

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Role of Cadherin-mediated Cell-Cell Adhesion in Pancreatic Exocrine-to-Endocrine Transdifferentiation^*

Kohtaro Minami, Hirotoshi Okano, Akinori Okumachi, and Susumu Seino^¶1

From the Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, the Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto 606-8507, and the ^¶Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan

Although pancreatic exocrine acinar cells have the potential to transdifferentiate into pancreatic endocrine cells, the mechanisms are poorly understood. Here we report that intracellular signaling pathways, including those involving MAPK and phosphatidylinositol 3 (PI3)-kinase, are activated by enzymatic dissociation of pancreatic acinar cells and that spherical cell clusters are formed by cadherin-mediated cell-cell adhesion during transdifferentiation. Inhibition of PI3-kinase by LY294002 prevents spheroid formation by degrading E-cadherin and β-catenin, blocking transdifferentiation into insulin-secreting cells. In addition, neutralizing antibody against E-cadherin suppresses the induction of genes characteristic of pancreatic β-cells. We also show that loss of cadherin-mediated cell-cell adhesion induces and maintains a dedifferentiated state in isolated pancreatic acinar cells. Thus, disruption and remodeling of cadherin-mediated cell-cell adhesion is critical in pancreatic exocrine-to-endocrine transdifferentiation, in which the PI3-kinase pathway plays an essential role.

Received for publication, December 10, 2007 , and in revised form, February 25, 2008.

^* This work was supported by grants-in-aid for Specially Promoted Research, Scientific Research, and for the 21st Century Center of Excellence program from the Ministry of Education, Culture, Sports, Science and Technology, and by a grant from the Juvenile Diabetes Research Foundation. 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.

This article was selected as a Paper of the Week.

¹ To whom correspondence should be addressed. Tel.: 81-78-382-5360; Fax: 81-78-382-5370; E-mail: seino{at}med.kobe-u.ac.jp.

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