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J. Biol. Chem. 277 (36): 32905-32914

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Signal Transduction from N-cadherin Increases Bcl-2
REGULATION OF THE PHOSPHATIDYLINOSITOL 3-KINASE/Akt PATHWAY BY HOMOPHILIC ADHESION AND ACTIN CYTOSKELETAL ORGANIZATION*

Nhan L. TranDagger , Deanna G. Adams§, Richard R. Vaillancourt§, and Ronald L. HeimarkDagger ||

From the Dagger  Cancer Biology Graduate Program, Departments of § Pharmacology and Toxicology,  Surgery, and Cell Biology and Anatomy, University of Arizona Health Sciences Center, Tucson, Arizona 85724

Associated with the metastatic progression of epithelial tumors is the dynamic regulation of cadherins. Whereas E-cadherin is expressed in most epithelium and carcinomas, recent studies suggest that the up-regulation of other cadherin subtypes in carcinomas, such as N-cadherin, may function in cancer progression. We demonstrate that a signal transduction cascade links the N-cadherin·catenin adhesion complex to up-regulation of the anti-apoptotic protein Bcl-2. In suspension, aggregates of DU-145 cells, an E-cadherin expressing human prostate carcinoma line, survive loss of integrin-dependent adhesion by a different anti-apoptotic signaling pathway than the N-cadherin expressing lines PC3 and PC3N. N-cadherin intercellular adhesion mediates a 3.5-fold increase in Bcl-2 protein expression, whereas the level of the proapoptotic protein Bax remains constant. Only N-cadherin ligation in PC3 cells, which express both N-cadherin and E-cadherin, is sufficient to induce activation of Akt/protein kinase B. N-cadherin homophilic ligation initiates phosphatidylinositol 3-kinase-dependent activation of Akt resulting in Akt phosphorylation of Bad on serine 136. Following N-cadherin homophilic adhesion phosphatidylinositol 3-kinase was identified in immunoprecipitates of the N-cadherin·catenin complex. The recruitment of phosphatidylinositol 3-kinase to the adhesion complex is dependent on ligation of N-cadherin and an organized actin cytoskeleton because cytochalasin D blocks the recruitment. We propose that N-cadherin homophilic adhesion can initiate anti-apoptotic signaling, which enhances the Akt cell survival pathway in metastatic cancer.

* This work was supported by National Institutes of Health Grants CA5666 (to R. L. H.) and AG19710 (to R. R. V.), Cancer Biology Training Grant T32CA09213, a grant from the Achievement Rewards for College Scientists Foundation (to N. L. T.), and a Pharma Pre-doctoral Fellowship (to D. G. A.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| To whom correspondence should be addressed: University of Arizona, Health Sciences Center, P.O. Box 245084, 1501 N. Campbell Ave, Tucson, AZ 85724. Tel.: 520-626-1913; Fax: 520-626-2890; E-mail: rheimark@u.arizona.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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