PTEN Functions by Recruitment to Cytoplasmic Vesicles

Naguib, Adam; Bencze, Gyula; Cho, Hyejin; Wu, Zheng; Tocilj, Ante; Elkayam, Elad; Faehnle, C.R.; Jaber, Nadia; Pratt, Christopher P.; Chen, Muhan; Zong, Wei Xing; Marks, Michael S.; Joshua‐Tor, Leemor; Pappin, Darryl; Trotman, Lloyd C.

doi:10.1016/j.molcel.2015.03.011

Cited by 97 publications

(91 citation statements)

References 68 publications

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“…Akt activity activates the PtdIns 5-kinase PIKfyve, resulting in phosphorylation of PtdIns(3)P to PtdIns(3,5)P 2 , and is required for endosome maturation (Er et al, 2013). PTEN has also been shown to localise to early endosomes through a specific interaction with PtdIns(3)P (Naguib et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Endomembrane PtdIns(3,4,5)P3 activates the PI3K/Akt pathway

Jethwa

Chung

Lete

et al. 2015

Journal of Cell Science

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PKB/Akt activation is a common step in tumour growth, proliferation and survival. Akt activation is understood to occur at the plasma membrane of cells in response to growth factor stimulation and local production of the phosphoinositide lipid phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P 3 ] following phosphoinositide 3-kinase (PI3K) activation. The metabolism and turnover of phosphoinositides is complex -they act as signalling molecules as well as structural components of biological membranes. The localisation and significance of internal pools of PtdIns(3,4,5)P 3 has long been speculated upon. By using transfected and recombinant protein probes for PtdIns(3,4,5)P 3 , we show that PtdIns(3,4,5)P 3 is enriched in the nuclear envelope and early endosomes. By exploiting an inducible dimerisation device to recruit Akt to these compartments, we demonstrate that Akt can be locally activated in a PtdIns(3,4,5)P 3 -dependent manner and has the potential to phosphorylate compartmentally localised downstream substrates. This could be an important mechanism to regulate Akt isoform substrate specificity or influence the timing and duration of PI3K pathway signalling. Defects in phosphoinositide metabolism and localisation are known to contribute to cancer, suggesting that interactions at subcellular compartments might be worthwhile targets for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Endomembrane PtdIns(3,4,5)P3 activates the PI3K/Akt pathway

Jethwa

Chung

Lete

et al. 2015

Journal of Cell Science

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“…PTEN, a lipid and protein phosphatase, is primarily tethered to plasma and endosomal membranes where it antagonizes the phosphatidylinositide 3-kinase (PI3K) pathway by dephosphorylating the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) (8,14), thereby controlling a host of cellular processes including proliferation, survival, and migration. In addition, nucleus-localized PTEN regulates centromere stability, DNA-damage response, cell-cycle progression, and cellular senescence (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

microRNA-143/145 loss induces Ras signaling to promote aggressive Pten-deficient basal-like breast cancer

Wang

Liu

et al. 2017

JCI Insight

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“…PTEN maintains low amounts of cellular PtdIns(3,4,5)P 3 (56) by dephosphorylating this lipid at the 3 position (5). PTEN is enriched on membranes with high concentrations of PtdIns(3)P. The interaction of the CBR3 loop of PTEN with PtdIns(3)P tethers PTEN to these membranes (57). CBR3 of PTEN is also required for maximal PtdIns(3,4,5)P 3 dephosphorylation; when overexpressed in PTEN-null cells, CBR3-mutant PTEN fails to constitutively diminish AKT phosphorylation, unlike the wild-type protein (57).…”

Section: Generating Ptdins(345)p 3 On Appl1-positive Vesiclesmentioning

confidence: 99%

“…PTEN is enriched on membranes with high concentrations of PtdIns(3)P. The interaction of the CBR3 loop of PTEN with PtdIns(3)P tethers PTEN to these membranes (57). CBR3 of PTEN is also required for maximal PtdIns(3,4,5)P 3 dephosphorylation; when overexpressed in PTEN-null cells, CBR3-mutant PTEN fails to constitutively diminish AKT phosphorylation, unlike the wild-type protein (57). Thus, PTEN associated with PtdIns(3)P-rich membranes forms a roadblock-a region of PtdIns(3,4,5)P 3 dephosphorylating activity-in the path of endocytosed, receptor-enriched, and PI3K-enriched membranes.…”

Section: Generating Ptdins(345)p 3 On Appl1-positive Vesiclesmentioning

confidence: 99%

Following the trail of lipids: Signals initiated by PI3K function at multiple cellular membranes

Naguib

2016

Sci. Signal.

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Phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P 3 ] is the signaling currency of the phosphoinositide 3-kinase (PI3K)/AKT pathway; transduction through this axis depends on this signaling lipid. Formation of PtdIns(3,4,5)P 3 is dictated not only by PI3K activation but also by the localization and access of PI3K to its substrate PtdIns(4,5)P 2 (phosphatidylinositol 4,5-bisphosphate). PI3K/AKT-mediated signaling is antagonized by PtdIns(3,4,5)P 3 dephosphorylation. Although previously typically considered an event associated with the plasma membrane, it is now appreciated that the formation and metabolism of PtdIns(3,4,5)P 3 occur on multiple membranes with distinct kinetics. Modulated activity of phosphatidylinositol lipid kinases and phosphatases contributes to intricately orchestrated lipid gradients that define the signaling status of the pathway at multiple sites within the cell. Introducing the PI3K/AKT PathwayThe response to extracellular mitogenic stimuli requires the transduction of signals from the cell periphery to the interior of the cell. Extracellular mitogenic signals bind and activate receptor tyrosine kinases at the plasma membrane, thereby recruiting and subsequently activating phosphoinositide 3-kinases (PI3Ks). Activated PI3K catalyzes the formation of phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P 3 ]. AKTand the kinase PDK1, which phosphorylates and activates AKT, both bind PtdIns(3,4,5)P 3 and are brought into proximity at sites where PtdIns(3,4,5)P 3 is abundant, thereby instigating their signal transduction properties. The PI3K/AKT signaling axis transduces signals generated by a plethora of extracellular stimuli and modulates multiple cellular processes, including metabolism, proliferation, survival, and protein synthesis (1, 2). Components of the PI3K pathway contribute to one of two main functions: the synthesis of PtdIns(3,4,5)P 3 or the interpretation of or response to the lipid signals generated.Enzymatic control of the synthesis and metabolism of PtdIns(3,4,5)P 3 is regulated by mitogens. Class I PI3K enzymes produce PtdIns(3,4,5)P 3 (3) by catalyzing the addition of phosphate to the substrate PtdIns(4,5)P 2 (phosphatidylinositol 4,5-bisphosphate) (4). Hydrolysis of PtdIns(3,4,5)P 3 is mostly, although not exclusively, achieved by two classes of enzymes. One is known as phosphatase and tensin homolog, deleted on chromosome ten (PTEN), which dephosphorylates PtdIns(3,4,5)P 3 at the 3 position generating PtdIns(4,5)P 2 (5). The other is the SH2 (Src homology 2)-containing inositol phosphatase (SHIP) enzymes, which hydrolyze the 5′ position of PtdIns(3,4,5)P 3 , thus generating PtdIns(3,4)P 2 (6). Consequently, the locale of active class I PI3K, the accessibility of PI3K to their PtdIns(4,5)P 2 substrate, and the subcellular distributions of PTEN, SHIP, and other PtdIns(3,4,5)P 3 -dephosphorylating enzymes define the spatiotemporal activity of the PI3K/AKT axis.In addition to AKT-mediated mitogen-induced signaling, PI3K-dependent formation of PtdIns(3,4,5)P 3 contrib...

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PTEN Functions by Recruitment to Cytoplasmic Vesicles

Cited by 97 publications

References 68 publications

Endomembrane PtdIns(3,4,5)P3 activates the PI3K/Akt pathway

Endomembrane PtdIns(3,4,5)P3 activates the PI3K/Akt pathway

microRNA-143/145 loss induces Ras signaling to promote aggressive Pten-deficient basal-like breast cancer

Following the trail of lipids: Signals initiated by PI3K function at multiple cellular membranes

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