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

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

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

  1. Ulrich Putz1,
  2. Jason Howitt1,
  3. Anh Doan1,
  4. Choo-Peng Goh1,
  5. Ley-Hian Low1,
  6. John Silke2, and
  7. Seong-Seng Tan1,*
  1. 1Brain Development and Regeneration Division, Florey Neuroscience Institutes, The University of Melbourne, Parkville, Victoria 3010, Australia.
  2. 2Cell Signalling and Cell Death Laboratory, Walter and Eliza Hall Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
  1. *To whom correspondence should be addressed. E-mail: sst{at}unimelb.edu.au

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.

Citation:

U. Putz, J. Howitt, A. Doan, C.-P. Goh, L.-H. Low, J. Silke, and 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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J Biol Chem 290, 7141-7150 (13 March 2015)

PTEN Is a Negative Regulator of NK Cell Cytolytic Function
E. L. Briercheck, R. Trotta, L. Chen, A. S. Hartlage, J. P. Cole, T. D. Cole, C. Mao, P. P. Banerjee, H.-T. Hsu, E. M. Mace et al.
J. Immunol. 194, 1832-1840 (15 February 2015)

Molecular Pathways: Intercellular PTEN and the Potential of PTEN Restoration Therapy
B. D. Hopkins, and R. E. Parsons
Clin. Cancer Res. 20, 5379-5383 (1 November 2014)

Cellular Disposal of miR23b by RAB27-Dependent Exosome Release Is Linked to Acquisition of Metastatic Properties
M. S. Ostenfeld, D. K. Jeppesen, J. R. Laurberg, A. T. Boysen, J. B. Bramsen, B. Primdal-Bengtson, A. Hendrix, P. Lamy, F. Dagnaes-Hansen, M. H. Rasmussen et al.
Cancer Res. 74, 5758-5771 (15 October 2014)

Exosomes: Nanoparticles Involved in Cardioprotection?
D. M. Yellon, and S. M. Davidson
Circ. Res. 114, 325-332 (17 January 2014)

PTPs emerge as PIPs: protein tyrosine phosphatases with lipid-phosphatase activities in human disease
R. Pulido, A. W. Stoker, and W. J. A. J. Hendriks
Hum Mol Genet 22, R66-R76 (15 October 2013)

Oncogenic H-Ras Reprograms Madin-Darby Canine Kidney (MDCK) Cell-derived Exosomal Proteins Following Epithelial-Mesenchymal Transition
B. J. Tauro, R. A. Mathias, D. W. Greening, S. K. Gopal, H. Ji, E. A. Kapp, B. M. Coleman, A. F. Hill, U. Kusebauch, J. L. Hallows et al.
MCP 12, 2148-2159 (1 August 2013)

Where Is PTEN?
N. R. Leslie, and V. G. Brunton
Science 341, 355-356 (26 July 2013)

Molecular Pathways: Tumor-Derived Microvesicles and Their Interactions with Immune Cells In Vivo
F. Pucci, and M. J. Pittet
Clin. Cancer Res. 19, 2598-2604 (15 May 2013)

Extracellular vesicles: communication, coercion, and conditioning
D. A. Shifrin, M. D. Beckler, R. J. Coffey, and M. J. Tyska
Mol. Biol. Cell 24, 1253-1259 (1 May 2013)

PTEN: An Intercellular Peacekeeper?
N. R. Leslie, M. D. Beckler, R. J. Coffey, and M. J. Tyska
Sci Signal 5, pe50-pe50 (13 November 2012)

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