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J. Biol. Chem., Vol. 279, Issue 42, 44113-44122, October 15, 2004

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Human Intestinal Epithelial Cell Survival and Anoikis

DIFFERENTIATION STATE-DISTINCT REGULATION AND ROLES OF PROTEIN KINASE B/Akt ISOFORMS^*

Geneviève Dufour, Marie-Josée Demers, David Gagné, Anders Bondo Dydensborg, Inga C. Teller, Véronique Bouchard, Isabelle Degongre, Jean-François Beaulieu, Jin Q. Cheng¶, Naoya Fujita||, Takashi Tsuruo||, Karine Vallée, and Pierre H. Vachon**

From the Canadian Institutes of Health Research Group on the Functional Development and Physiopathology of the Digestive Tract, Département d'Anatomie et de Biologie Cellulaire, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada, the ^¶Department of Pathology, H. Lee Moffitt Cancer Center, College of Medicine, University of South Florida, Tampa, Florida 33612, ^||Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan, and Thématique de Recherche en Physiopathologie Digestive du Centre de Recherches Cliniques, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada

We have shown previously that human intestinal epithelial cell survival and anoikis are distinctively regulated according to the state of differentiation. Here we analyzed the roles of protein kinase B/Akt isoforms in such differentiation state distinctions. Anoikis was induced in undifferentiated and differentiated enterocytes by inhibition of focal adhesion kinase (Fak; pharmacologic inhibition or overexpression of dominant-negative mutants) or ₁ integrins (antibody blocking) or by maintaining cells in suspension. Expression/activation parameters of Akt isoforms (Akt-1, Akt-2, and Akt-3) and Fak were analyzed. Activity of Akt isoforms was also blocked by inhibition of phosphatidylinositol 3-kinase or by overexpression of dominant-negative mutants. Here we report the following. 1) The expression/activation levels of Akt-1 increase overall during enterocytic differentiation, and those of Akt-2 decrease, whereas Akt-3 is not expressed. 2) Akt-1 activation is dependent on ₁ integrins/Fak signaling, regardless of the differentiation state. 3) Akt-2 activation is dependent on ₁ integrins/Fak signaling in undifferentiated cells only. 4) Activation of Akt-1 is phosphatidylinositol 3-kinase-dependent, whereas that of Akt-2 is not. 5) Akt-2 does not promote survival or apoptosis/anoikis. 6) Akt-1 is essential for survival. 7) Akt-2 cannot substitute for Akt-1 in the suppression of anoikis. Hence, the expression and regulation of Akt isoforms show differentiation state-specific distinctions that ultimately reflect upon their selective implication in the mediation of human intestinal epithelial cell survival. These data provide new insights into the synchronized regulation of cell survival/death that is required in the dynamic renewal process of tissues such as the intestinal epithelium.

Received for publication, May 12, 2004 , and in revised form, August 4, 2004.

^* This work was supported by the Canadian Institutes of Health Research Grant MOP-14468 (to P. H. V.). 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.

^** Chercheur-Boursier du Fonds de la Recherche en Santé du Québec and a Chercheur de la Fondation Canadienne pour l'Innovation. To whom correspondence should be addressed: Dépt. d'Anatomie et de Biologie Cellulaire, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada. Tel.: 819-564-5273; Fax: 819-564-5320; E-mail: Pierre.H.Vachon{at}USherbrooke.ca.

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