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Sci. Signal., 25 September 2012
Vol. 5, Issue 243, p. ra70
[DOI: 10.1126/scisignal.2003084]

RESEARCH ARTICLES

The Tumor Suppressor PTEN Is Exported in Exosomes and Has Phosphatase Activity in Recipient Cells

Ulrich Putz1, Jason Howitt1, Anh Doan1, Choo-Peng Goh1, Ley-Hian Low1, John Silke2, and Seong-Seng Tan1*

1 Brain Development and Regeneration Division, Florey Neuroscience Institutes, The University of Melbourne, Parkville, Victoria 3010, Australia.
2 Cell Signalling and Cell Death Laboratory, Walter and Eliza Hall Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.

Abstract: Exosomes are microvesicles of endosomal origin that are secreted, and their contents (proteins, lipids, DNA, or microRNAs) can alter the physiological states of recipient cells. We demonstrated that phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor protein normally localized in the cytoplasm and nucleus, was secreted in exosomes. Secreted PTEN was internalized by recipient cells with resultant functional activity, which resulted in reduced phosphorylation of the serine and threonine kinase Akt and reduced cellular proliferation. PTEN secretion in exosomes required Ndfip1, an adaptor protein for members of the Nedd4 family of E3 ubiquitin ligases. Without Ndfip1, neither Nedd4-1 nor Nedd4-2 promoted the recruitment of PTEN into exosomes. In addition, lysine 13 within PTEN, which is required for its ubiquitination by Nedd4-1, was required for exosomal transport of PTEN. These results implicate Ndfip1 as a molecular regulator of the exosomal export of PTEN, with consequences for non–cell-autonomous PTEN activity. Thus, we suggest that the ability of PTEN to exert phosphatase activity beyond the cell in which it is produced has implications for PTEN function during development, health, and disease.

* To whom correspondence should be addressed. E-mail: sst{at}unimelb.edu.au

Citation: U. Putz, J. Howitt, A. Doan, C.-P. Goh, L.-H. Low, J. Silke, S.-S. Tan, The Tumor Suppressor PTEN Is Exported in Exosomes and Has Phosphatase Activity in Recipient Cells. Sci. Signal. 5, ra70 (2012).

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