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J. Cell Biol. 160 (7): 1001-1008

Copyright © 2003 by the Rockefeller University Press.

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CH-ILKBP regulates cell survival by facilitating the membrane translocation of protein kinase B/Akt

Tomohiko Fukuda, Lida Guo, Xiaohua Shi, and Chuanyue Wu

Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261

Address correspondence to Chuanyue Wu, 707B Scaife Hall, Dept. of Pathology, University of Pittsburgh, 3550 Terrace St., Pittsburgh, PA 15261. Tel.: (412) 648-2350. Fax: (509) 561-4062. E-mail: carywu{at}pitt.edu

Abstract: Cell survival depends on proper propagation of protective signals through intracellular signaling intermediates. We report here that calponin homology domain–containing integrin-linked kinase (ILK)–binding protein (CH-ILKBP), a widely expressed adaptor protein localized at plasma membrane-actin junctions, is essential for transmission of survival signals. Cells that are depleted of CH-ILKBP undergo extensive apoptosis despite the presence of cell–extracellular matrix contacts and soluble growth factors. The activating phosphorylation of protein kinase B (PKB/Akt), a key regulator of apoptosis, is impaired in the absence of CH-ILKBP. Importantly, loss of CH-ILKBP prevents the membrane translocation of PKB/Akt. Furthermore, forced membrane targeting of PKB/Akt bypasses the requirement of CH-ILKBP for the activating phosphorylation of PKB/Akt, suggesting that CH-ILKBP is required for the membrane translocation but not the subsequent phosphorylation of PKB/Akt. Finally, we show that loss of CH-ILKBP is also required for the full activation of extracellular signal–regulated kinase (ERK)1/2. However, restoration of the PKB/Akt activation is sufficient for protection of cells from apoptosis induced by the depletion of CH-ILKBP despite the persistent suppression of the ERK1/2 activation. Thus, CH-ILKBP is an important component of the prosurvival signaling pathway functioning primarily by facilitating the membrane translocation of PKB/Akt and consequently the activation of PKB/Akt in response to extracellular survival signals.

Key Words: apoptosis; CH-ILKBP; protein kinase B/Akt; membrane translocation; ILK

* Abbreviations used in this paper: CH-ILKBP, calponin homology domain–containing ILK-binding protein; ERK, extracellular signal–regulated kinase; IGF, insulin-like growth factor; ILK, integrin-linked kinase; PKB, protein kinase B; RNAi, RNA interference; siRNA, small interfering RNA.

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