Identification of PTEN at the ER and MAMs and its regulation of Ca(2+) signaling and apoptosis in a protein phosphatase-dependent manner.

Abstract

The tumor suppressor activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10) is thought to be largely attributable to its lipid phosphatase activity. PTEN dephosphorylates the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate to directly antagonize the phosphoinositide 3-kinase-Akt pathway and prevent the activating phosphorylation of Akt. PTEN has also other proposed mechanisms of action, including a poorly characterized protein phosphatase activity, protein-protein interactions, as well as emerging functions in different compartment of the cells such as nucleus and mitochondria. We show here that a fraction of PTEN protein localizes to the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs), signaling domains involved in calcium ((2+)) transfer from the ER to mitochondria and apoptosis induction. We demonstrate that PTEN silencing impairs ER Ca(2+) release, lowers cytosolic and mitochondrial Ca(2+) transients and decreases cellular sensitivity to Ca(2+)-mediated apoptotic stimulation. Specific targeting of PTEN to the ER is sufficient to enhance ER-to-mitochondria Ca(2+) transfer and sensitivity to apoptosis. PTEN localization at the ER is further increased during Ca(2+)-dependent apoptosis induction. Importantly, PTEN interacts with the inositol 1,4,5-trisphosphate receptors (IP3Rs) and this correlates with the reduction in their phosphorylation and increased Ca(2+) release. We propose that ER-localized PTEN regulates Ca(2+) release from the ER in a protein phosphatase-dependent manner that counteracts Akt-mediated reduction in Ca(2+) release via IP3Rs. These findings provide new insights into the mechanisms and the extent of PTEN tumor-suppressive functions, highlighting new potential strategies for therapeutic intervention.

• Authors: A Bononi, M Bonora, S Marchi, S Missiroli, F Poletti, C Giorgi, P P Pandolfi, P Pinton
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 20 Issue 12 Pg. 1631-43 (Dec 2013) ISSN: 1476-5403 [Electronic] England
• PMID: 23811847 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• PTEN Phosphohydrolase
• Calcium

Topics

• Animals
• Apoptosis
• Calcium (metabolism)
• Calcium Signaling
• Endoplasmic Reticulum (enzymology)
• Gene Silencing
• HEK293 Cells
• Homeostasis
• Humans
• Mice
• Mitochondrial Membranes (enzymology)
• PTEN Phosphohydrolase (metabolism)
• Subcellular Fractions (enzymology)