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Molecular and Cellular Biology, October 2009, p. 5377-5388, Vol. 29, No. 19
0270-7306/09/$08.00+0     doi:10.1128/MCB.01649-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

p85 Associates with Unphosphorylated PTEN and the PTEN-Associated Complex {triangledown} ,{dagger} ,{ddagger}

Rosalia Rabinovsky,1 Panisa Pochanard,1 Chontelle McNear,1 Saskia M. Brachmann,1,§ Jonathan S. Duke-Cohan,1 Levi A. Garraway,1,2* and William R. Sellers1*

Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115,1 Broad Institute, Cambridge, Massachusetts 021422

Received 22 October 2008/ Returned for modification 27 January 2009/ Accepted 20 July 2009

The lipid phosphatase PTEN functions as a tumor suppressor by dephosphorylating the D3 position of phosphoinositide-3,4,5-trisphosphate, thereby negatively regulating the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. In mammalian cells, PTEN exists either as a monomer or as a part of a >600-kDa complex (the PTEN-associated complex [PAC]). Previous studies suggest that the antagonism of PI3K/AKT signaling by PTEN may be mediated by a nonphosphorylated form of the protein resident within the multiprotein complex. Here we show that PTEN associates with p85, the regulatory subunit of PI3K. Using newly generated antibodies, we demonstrate that this PTEN-p85 association involves the unphosphorylated form of PTEN engaged within the PAC and also includes the p110β isoform of PI3K. The PTEN-p85 association is enhanced by trastuzumab treatment and linked to a decline in AKT phosphorylation in some ERBB2-amplified breast cancer cell lines. Together, these results suggest that integration of p85 into the PAC may provide a novel means of downregulating the PI3K/AKT pathway.

* Corresponding author. Mailing address for Levi A. Garraway: Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Phone: (617) 632-6689. Fax: (617) 582-7880. E-mail: levi_garraway{at}dfci.harvard.edu. Present address for William R. Sellers: Novartis Institutes for BioMedical Research, Oncology Disease Area, 250 Massachusetts Avenue, Cambridge, MA 02139. Phone: (617) 871-7069. Fax: (617) 871-4130. E-mail: william.sellers{at}novartis.com

{triangledown} Published ahead of print on 27 July 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} The authors have paid a fee to allow immediate free access to this article.

§ Present address: Novartis Institutes for Biomedical Research, Basel CH-4057, Switzerland.

Molecular and Cellular Biology, October 2009, p. 5377-5388, Vol. 29, No. 19
0270-7306/09/$08.00+0     doi:10.1128/MCB.01649-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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