Defining the Membrane-Associated State of the PTEN Tumor Suppressor Protein

Lumb, Craig N.; Sansom, Mark S. P.

doi:10.1016/j.bpj.2012.12.002

Cited by 41 publications

(63 citation statements)

References 54 publications

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“…If this assumption is applied to PTEN, then the number of bound PI (4,5)P 2 molecules will be estimated as 3 or 4 when PTEN adopts the slower mobility state on the 10 mol% PI(4,5)P 2 membrane (D = 1.5 μm 2 s −1 ). Consistently, previous studies reported that R47 and K11/K13/R14/R15 possibly form two distinct sites for PI (4,5)P 2 binding, with K13 shared by both 18,35 . In addition, our results show that both R47A and N4 mutations cause a loss of the slower mobility state, possibly due to the reduction in the number of bound PI(4,5)P 2 molecules (Fig.…”

Section: Discussionsupporting

confidence: 89%

Single-molecule imaging of PI(4,5)P2 and PTEN in vitro reveals a positive feedback mechanism for PTEN membrane binding

et al. 2020

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PTEN, a 3-phosphatase of phosphoinositide, regulates asymmetric PI(3,4,5)P 3 signaling for the anterior-posterior polarization and migration of motile cells. PTEN acts through posterior localization on the plasma membrane, but the mechanism for this accumulation is poorly understood. Here we developed an in vitro single-molecule imaging assay with various lipid compositions and use it to demonstrate that the enzymatic product, PI(4,5)P 2 , stabilizes PTEN's membrane-binding. The dissociation kinetics and lateral mobility of PTEN depended on the PI(4,5)P 2 density on artificial lipid bilayers. The basic residues of PTEN were responsible for electrostatic interactions with anionic PI(4,5)P 2 and thus the PI(4,5)P 2dependent stabilization. Single-molecule imaging in living Dictyostelium cells revealed that these interactions were indispensable for the stabilization in vivo, which enabled efficient cell migration by accumulating PTEN posteriorly to restrict PI(3,4,5)P 3 distribution to the anterior. These results suggest that PI(4,5)P 2 -mediated positive feedback and PTEN-induced PI(4,5)P 2 clustering may be important for anterior-posterior polarization.

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Section: Discussionsupporting

confidence: 89%

Single-molecule imaging of PI(4,5)P2 and PTEN in vitro reveals a positive feedback mechanism for PTEN membrane binding

et al. 2020

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“…[12][13][14][15] PTEN contains a phosphatase domain in the N-terminal, a C2 domain and a C-terminal tail with 50 amino acids. [16][17][18] Each domain exhibits a certain function in relation to the membrane translocation of PTEN. 17 Binding of thioredoxin-1 to PTEN through a disulphide bond between the active site Cys32 of thioredoxin-1 and Cys212 of the C2 domain of PTEN inhibits PTEN membrane translocation and activation.…”

Section: Introductionmentioning

confidence: 99%

PTEN activation through K163 acetylation by inhibiting HDAC6 contributes to tumour inhibition

Meng

2015

Oncogene

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Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), an important tumour-suppressor gene, is mutated, downregulated or dysfunctional in many tumours. The phosphatase activity of PTEN depends on membrane translocation (activation). As promising anti-cancer agents, histone deacetylase (HDAC) inhibitors, particularly trichostatin A (TSA), can promote PTEN membrane translocation, but the underlying mechanism remains unknown. In this study, we revealed that non-selective HDAC inhibitors, namely, TSA or suberoylanilide hydroxamic acid (SAHA), induced PTEN membrane translocation through PTEN acetylation at K163 by inhibiting HDAC6. K163 acetylation inhibited the interaction of the PTEN C-tail with the remaining part of PTEN, resulting in PTEN membrane translocation. Overexpression of wild-type PTEN, but not K163-mutated PTEN, facilitated the inhibition of cell proliferation, migration and invasion, as well as xenograft tumour growth, induced by SAHA or tubastatin A, an HDAC6-specific inhibitor. These results indicated that PTEN activation by inhibiting HDAC6 significantly contributed to tumour inhibition. Therefore, non-selective HDAC or HDAC6-specific inhibitors may be more clinically suitable to treat tumours without PTEN mutations or deletions.

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“…One powerful simulation technique that has the potential to yield atomically detailed information on Ras membrane binding and assembly is molecular dynamics (MD), particularly coarse-grained MD (CG-MD). CG-MD has been successfully used to study protein-lipid assemblies in large spatiotemporal scales [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41]. Applying CG-MD simulations on the minimal membrane-binding motif of H-Ras (tH), we have recently shown that 30–40% of these molecules spontaneously assemble into dynamic clusters of size 4–11 [42], [43].…”

Section: Introductionmentioning

confidence: 99%

Aggregation of Lipid-Anchored Full-Length H-Ras in Lipid Bilayers: Simulations with the MARTINI Force Field

Li¹,

Gorfe²

2013

PLoS ONE

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Lipid-anchored Ras oncoproteins assemble into transient, nano-sized substructures on the plasma membrane. These substructures, called nanoclusters, were proposed to be crucial for high-fidelity signal transmission in cells. However, the molecular basis of Ras nanoclustering is poorly understood. In this work, we used coarse-grained (CG) molecular dynamics simulations to investigate the molecular mechanism by which full-length H-ras proteins form nanoclusters in a model membrane. We chose two different conformations of H-ras that were proposed to represent the active and inactive state of the protein, and a domain-forming model bilayer made up of di16:0-PC (DPPC), di18:2-PC (DLiPC) and cholesterol. We found that, irrespective of the initial conformation, Ras molecules assembled into a single large aggregate. However, the two binding modes, which are characterized by the different orientation of the G-domain with respect to the membrane, differ in dynamics and organization during and after aggregation. Some of these differences involve regions of Ras that are important for effector/modulator binding, which may partly explain observed differences in the ability of active and inactive H-ras nanoclusters to recruit effectors. The simulations also revealed some limitations in the CG force field to study protein assembly in solution, which we discuss in the context of proposed potential avenues of improvement.

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Defining the Membrane-Associated State of the PTEN Tumor Suppressor Protein

Cited by 41 publications

References 54 publications

Single-molecule imaging of PI(4,5)P2 and PTEN in vitro reveals a positive feedback mechanism for PTEN membrane binding

Single-molecule imaging of PI(4,5)P2 and PTEN in vitro reveals a positive feedback mechanism for PTEN membrane binding

PTEN activation through K163 acetylation by inhibiting HDAC6 contributes to tumour inhibition

Aggregation of Lipid-Anchored Full-Length H-Ras in Lipid Bilayers: Simulations with the MARTINI Force Field

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