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Molecular and Cellular Biology, October 2008, p. 5996-6009, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.00114-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Freud-1/Aki1, a Novel PDK1-Interacting Protein, Functions as a Scaffold To Activate the PDK1/Akt Pathway in Epidermal Growth Factor Signaling{triangledown}

Akito Nakamura,1,2 Mikihiko Naito,2 Takashi Tsuruo,1 and Naoya Fujita1*

Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan,1 Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan2

Received 21 January 2008/ Returned for modification 25 February 2008/ Accepted 22 July 2008

The phosphoinositide 3-kinase (PI3K)/3-phosphoinositide-dependent protein kinase 1 (PDK1)/Akt pathway regulates various cellular functions, especially cell survival and cell cycle progression. In contrast to other survival pathways, there have been few reports of scaffold proteins that regulate signaling cascade specificity in this pathway. Here we identify a 5' repressor element under dual-repression binding protein 1 (Freud-1)/Akt kinase-interacting protein 1 (Aki1) as a novel scaffold for the PDK1/Akt pathway. Freud-1/Aki1 (also known as CC2D1A) expression induced formation of a PDK1/Akt complex and regulated Akt activation in a concentration-dependent biphasic manner. Freud-1/Aki1 also associated with epidermal growth factor (EGF) receptor in response to EGF stimulation and was required for Akt activation induced by EGF, but not by insulin-like growth factor 1. Freud-1/Aki1 gene silencing decreased Akt kinase activity, resulting in induction of apoptosis and increased sensitivity toward chemotherapeutic agents. Our results suggest that Freud-1/Aki1 is a novel receptor-selective scaffold protein for the PDK1/Akt pathway and present a new activation mechanism of Akt.

* Corresponding author. Mailing address: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan. Phone: 81-3-3520-0111, ext. 5421. Fax: 81-3-3570-0484. E-mail: naoya.fujita{at}jfcr.or.jp

{triangledown} Published ahead of print on 28 July 2008.

Molecular and Cellular Biology, October 2008, p. 5996-6009, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.00114-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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