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15 pages, 7336 KiB

Open AccessArticle

by Ethan S. Chi, Elizabeth A. Stivison and Raymond D. Blind

Biomolecules 2023, 13(10), 1509; https://doi.org/10.3390/biom13101509 - 12 Oct 2023

Viewed by 1317

Metazoan cell nuclei contain non-membrane pools of the phosphoinositide lipid PI(4,5)P2 (PIP2), but how this hydrophobic lipid exists within the aqueous nucleoplasm remains unclear. Steroidogenic Factor-1 (NR5A1, SF-1) is a nuclear receptor that binds PIP2 in vitro, and a co-crystal structure of the [...] Read more.

Metazoan cell nuclei contain non-membrane pools of the phosphoinositide lipid PI(4,5)P2 (PIP2), but how this hydrophobic lipid exists within the aqueous nucleoplasm remains unclear. Steroidogenic Factor-1 (NR5A1, SF-1) is a nuclear receptor that binds PIP2 in vitro, and a co-crystal structure of the complex suggests the acyl chains of PIP2 are hidden in the hydrophobic core of the SF-1 protein while the PIP2 headgroup is solvent-exposed. This binding mode explains how SF-1 can solubilize nuclear PIP2; however, cellular evidence that SF-1 expression associates with nuclear PIP2 has been lacking. Here, we examined if tetracycline induction of SF-1 expression would associate with nuclear accumulation of PIP2, using antibodies directed against the PIP2 headgroup. Indeed, tetracycline induction of wild-type SF-1 induced a signal in the nucleus of HEK cells that cross-reacts with PIP2 antibodies, but did not cross-react with antibodies against the lower abundance phosphoinositide PI(3,4,5)P3 (PIP3). The nuclear PIP2 signal co-localized with FLAG-tagged SF-1 in the nuclear compartment. To determine if the nuclear PIP2 signal was dependent on the ability of SF-1 to bind PIP2, we examined a “pocket mutant” of SF-1 (A270W, L345F) shown to be deficient in phospholipid binding by mass spectrometry. Tetracycline induction of this pocket mutant SF-1 in HEK cells failed to induce a detectable PIP2 antibody cross-reactive signal, despite similar Tet-induced expression levels of the wild-type and pocket mutant SF-1 proteins in these cells. Together, these data are the first to suggest that expression of SF-1 induces a PIP2 antibody cross-reactive signal in the nucleus, consistent with X-ray crystallographic and biochemical evidence suggesting SF-1 binds PIP2 in human cells. Full article

(This article belongs to the Special Issue Versatility of a Cellular Signaling Scaffold: The Inositol Ring Rules! – Honorary Special Issue Commemorating the Work of Prof. Lucio I. M. Cocco)

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15 pages, 2355 KiB

Open AccessArticle

ITPK1 Regulates Jasmonate-Controlled Root Development in Arabidopsis thaliana

by Naga Jyothi Pullagurla, Supritam Shome, Ranjana Yadav and Debabrata Laha

Biomolecules 2023, 13(9), 1368; https://doi.org/10.3390/biom13091368 - 09 Sep 2023

Cited by 2 | Viewed by 1290

Abstract

Jasmonic acid (JA) is a plant hormone that regulates a plethora of physiological processes including immunity and development and is perceived by the F-Box protein, Coronatine-insensitive protein 1 (COI1). The discovery of inositol phosphates (InsPs) in the COI1 receptor complex highlights their role [...] Read more.

Jasmonic acid (JA) is a plant hormone that regulates a plethora of physiological processes including immunity and development and is perceived by the F-Box protein, Coronatine-insensitive protein 1 (COI1). The discovery of inositol phosphates (InsPs) in the COI1 receptor complex highlights their role in JAperception. InsPs are phosphate-rich signaling molecules that control many aspects of plant physiology. Inositol pyrophosphates (PP-InsPs) are diphosphate containing InsP species, of which InsP₇ and InsP₈ are the best characterized ones. Different InsP and PP-InsP species are linked with JA-related plant immunity. However, role of PP-InsP species in regulating JA-dependent developmental processes are poorly understood. Recent identification of ITPK1 kinase, responsible for the production of 5-InsP₇ from InsP₆ in planta, provides a platform to investigate the possible involvement of ITPK-derived InsP species in JA-related plant development. Here, in this study, we report that ITPK1-defective plants exhibit increased root growth inhibition to bioactive JA treatment. The itpk1 plants also show increased lateral root density when treated with JA. Notably, JA treatment does not increase ITPK1 protein levels. Gene expression analyses revealed that JA-biosynthetic genes are not differentially expressed in ITPK1-deficient plants. We further demonstrate that genes encoding different JAZ repressor proteins are severely down-regulated in ITPK1-defective plants. Taken together, our study highlights the role of ITPK1 in regulating JA-dependent root architecture development through controlling the expression of different JAZ repressor proteins. Full article

(This article belongs to the Special Issue Versatility of a Cellular Signaling Scaffold: The Inositol Ring Rules! – Honorary Special Issue Commemorating the Work of Prof. Lucio I. M. Cocco)

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13 pages, 2465 KiB

Open AccessArticle

Assigning the Absolute Configuration of Inositol Poly- and Pyrophosphates by NMR Using a Single Chiral Solvating Agent

by Kevin Ritter, Nikolaus Jork, Anne-Sophie Unmüßig, Maja Köhn and Henning J. Jessen

Biomolecules 2023, 13(7), 1150; https://doi.org/10.3390/biom13071150 - 19 Jul 2023

Viewed by 1147

Abstract

Inositol phosphates constitute a family of highly charged messenger molecules that play diverse roles in cellular processes. The various phosphorylation patterns they exhibit give rise to a vast array of different compounds. To fully comprehend the biological interconnections, the precise molecular identification of [...] Read more.

Inositol phosphates constitute a family of highly charged messenger molecules that play diverse roles in cellular processes. The various phosphorylation patterns they exhibit give rise to a vast array of different compounds. To fully comprehend the biological interconnections, the precise molecular identification of each compound is crucial. Since the myo-inositol scaffold possesses an internal mirror plane, enantiomeric pairs can be formed. Most commonly employed methods for analyzing InsPs have been geared towards resolving regioisomers, but they have not been capable of resolving enantiomers. In this study, we present a general approach for enantiomer assignment using NMR measurements. To achieve this goal, we used ³¹P-NMR in the presence of L-arginine amide as a chiral solvating agent, which enables the differentiation of enantiomers. Using chemically synthesized standard compounds allows for an unambiguous assignment of the enantiomers. This method was applied to highly phosphorylated inositol pyrophosphates, as well as to lowly phosphorylated inositol phosphates and bisphosphonate analogs. Our method will facilitate the assignment of biologically relevant isomers when isolating naturally occurring compounds from biological specimens. Full article

(This article belongs to the Special Issue Versatility of a Cellular Signaling Scaffold: The Inositol Ring Rules! – Honorary Special Issue Commemorating the Work of Prof. Lucio I. M. Cocco)

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9 pages, 668 KiB

Open AccessCommunication

Multiple Inositol Polyphosphate Phosphatase Compartmentalization Separates Inositol Phosphate Metabolism from Inositol Lipid Signaling

by Jia Yu, Barbara Leibiger, Shao-Nian Yang, Stephen B. Shears, Ingo B. Leibiger, Per-Olof Berggren and Christopher J. Barker

Biomolecules 2023, 13(6), 885; https://doi.org/10.3390/biom13060885 - 24 May 2023

Viewed by 1662

Abstract

Multiple inositol polyphosphate phosphatase (MINPP1) is an enigmatic enzyme that is responsible for the metabolism of inositol hexakisphosphate (InsP₆) and inositol 1,3,4,5,6 pentakisphosphate (Ins(1,3,4,5,6)P₅ in mammalian cells, despite being restricted to the confines of the ER. The reason [...] Read more.

Multiple inositol polyphosphate phosphatase (MINPP1) is an enigmatic enzyme that is responsible for the metabolism of inositol hexakisphosphate (InsP₆) and inositol 1,3,4,5,6 pentakisphosphate (Ins(1,3,4,5,6)P₅ in mammalian cells, despite being restricted to the confines of the ER. The reason for this compartmentalization is unclear. In our previous studies in the insulin-secreting HIT cell line, we expressed MINPP1 in the cytosol to artificially reduce the concentration of these higher inositol phosphates. Undocumented at the time, we noted cytosolic MINPP1 expression reduced cell growth. We were struck by the similarities in substrate preference between a number of different enzymes that are able to metabolize both inositol phosphates and lipids, notably IPMK and PTEN. MINPP1 was first characterized as a phosphatase that could remove the 3-phosphate from inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P₄)_. This molecule shares strong structural homology with the major product of the growth-promoting Phosphatidyl 3-kinase (PI3K), phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P₃) and PTEN can degrade both this lipid and Ins(1,3,4,5)P₄. Because of this similar substrate preference, we postulated that the cytosolic version of MINPP1 (cyt-MINPP1) may not only attack inositol polyphosphates but also PtdIns(3,4,5)P₃, a key signal in mitogenesis. Our experiments show that expression of cyt-MINPP1 in HIT cells lowers the concentration of PtdIns(3,4,5)P₃. We conclude this reflects a direct effect of MINPP1 upon the lipid because cyt-MINPP1 actively dephosphorylates synthetic, di(C4:0)PtdIns(3,4,5)P₃ in vitro. These data illustrate the importance of MINPP1′s confinement to the ER whereby important aspects of inositol phosphate metabolism and inositol lipid signaling can be separately regulated and give one important clarification for MINPP1′s ER seclusion. Full article

(This article belongs to the Special Issue Versatility of a Cellular Signaling Scaffold: The Inositol Ring Rules! – Honorary Special Issue Commemorating the Work of Prof. Lucio I. M. Cocco)

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20 pages, 9458 KiB

Open AccessArticle

One Scaffold, Two Conformations: The Ring-Flip of the Messenger InsP₈ Occurs under Cytosolic Conditions

by Leonie Kurz, Peter Schmieder, Nicolás Veiga and Dorothea Fiedler

Biomolecules 2023, 13(4), 645; https://doi.org/10.3390/biom13040645 - 04 Apr 2023

Cited by 3 | Viewed by 1940

Abstract

Inositol poly- and pyrophosphates (InsPs and PP-InsPs) are central eukaryotic messengers. These very highly phosphorylated molecules can exist in two distinct conformations, a canonical one with five phosphoryl groups in equatorial positions, and a “flipped” conformation with five axial substituents. Using ¹³C-labeled [...] Read more.

Inositol poly- and pyrophosphates (InsPs and PP-InsPs) are central eukaryotic messengers. These very highly phosphorylated molecules can exist in two distinct conformations, a canonical one with five phosphoryl groups in equatorial positions, and a “flipped” conformation with five axial substituents. Using ¹³C-labeled InsPs/PP-InsPs, the behavior of these molecules was investigated by 2D-NMR under solution conditions reminiscent of a cytosolic environment. Remarkably, the most highly phosphorylated messenger 1,5(PP)₂-InsP₄ (also termed InsP₈) readily adopts both conformations at physiological conditions. Environmental factors—such as pH, metal cation composition, and temperature—strongly influence the conformational equilibrium. Thermodynamic data revealed that the transition of InsP₈ from the equatorial to the axial conformation is, in fact, an exothermic process. The speciation of InsPs and PP-InsPs also affects their interaction with protein binding partners; addition of Mg²⁺ decreased the binding constant K_d of InsP₈ to an SPX protein domain. The results illustrate that PP-InsP speciation reacts very sensitively to solution conditions, suggesting it might act as an environment-responsive molecular switch. Full article

(This article belongs to the Special Issue Versatility of a Cellular Signaling Scaffold: The Inositol Ring Rules! – Honorary Special Issue Commemorating the Work of Prof. Lucio I. M. Cocco)

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16 pages, 1049 KiB

Open AccessArticle

Exploring the Role of PI3P in Platelets: Insights from a Novel External PI3P Pool

by Abdulrahman Mujalli, Julien Viaud, Sonia Severin, Marie-Pierre Gratacap, Gaëtan Chicanne, Karim Hnia, Bernard Payrastre and Anne-Dominique Terrisse

Biomolecules 2023, 13(4), 583; https://doi.org/10.3390/biom13040583 - 24 Mar 2023

Cited by 1 | Viewed by 1401

Abstract

Phosphoinositides (PIs) play a crucial role in regulating intracellular signaling, actin cytoskeleton rearrangements, and membrane trafficking by binding to specific domains of effector proteins. They are primarily found in the membrane leaflets facing the cytosol. Our study demonstrates the presence of a pool [...] Read more.

Phosphoinositides (PIs) play a crucial role in regulating intracellular signaling, actin cytoskeleton rearrangements, and membrane trafficking by binding to specific domains of effector proteins. They are primarily found in the membrane leaflets facing the cytosol. Our study demonstrates the presence of a pool of phosphatidylinositol 3-monophosphate (PI3P) in the outer leaflet of the plasma membrane of resting human and mouse platelets. This pool of PI3P is accessible to exogenous recombinant myotubularin 3-phosphatase and ABH phospholipase. Mouse platelets with loss of function of class III PI 3-kinase and class II PI 3-kinase α have a decreased level of external PI3P, suggesting a contribution of these kinases to this pool of PI3P. After injection in mouse, or incubation ex vivo in human blood, PI3P-binding proteins decorated the platelet surface as well as α-granules. Upon activation, these platelets were able to secrete the PI3P-binding proteins. These data sheds light on a previously unknown external pool of PI3P in the platelet plasma membrane that recognizes PI3P-binding proteins, leading to their uptake towards α-granules. This study raises questions about the potential function of this external PI3P in the communication of platelets with the extracellular environment, and its possible role in eliminating proteins from the plasma. Full article

(This article belongs to the Special Issue Versatility of a Cellular Signaling Scaffold: The Inositol Ring Rules! – Honorary Special Issue Commemorating the Work of Prof. Lucio I. M. Cocco)

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19 pages, 5207 KiB

Open AccessArticle

PIP2-Effector Protein MPRIP Regulates RNA Polymerase II Condensation and Transcription

by Can Balaban, Martin Sztacho, Ludovica Antiga, Ana Miladinović, Masahiko Harata and Pavel Hozák

Biomolecules 2023, 13(3), 426; https://doi.org/10.3390/biom13030426 - 24 Feb 2023

Cited by 5 | Viewed by 1958

Abstract

The specific post-translational modifications of the C-terminal domain (CTD) of the Rpb1 subunit of RNA polymerase II (RNAPII) correlate with different stages of transcription. The phosphorylation of the Ser5 residues of this domain associates with the initiation condensates, which are formed through liquid-liquid [...] Read more.

The specific post-translational modifications of the C-terminal domain (CTD) of the Rpb1 subunit of RNA polymerase II (RNAPII) correlate with different stages of transcription. The phosphorylation of the Ser5 residues of this domain associates with the initiation condensates, which are formed through liquid-liquid phase separation (LLPS). The subsequent Tyr1 phosphorylation of the CTD peaks at the promoter-proximal region and is involved in the pause-release of RNAPII. By implementing super-resolution microscopy techniques, we previously reported that the nuclear Phosphatidylinositol 4,5-bisphosphate (PIP2) associates with the Ser5-phosphorylated-RNAPII complex and facilitates the RNAPII transcription. In this study, we identified Myosin Phosphatase Rho-Interacting Protein (MPRIP) as a novel regulator of the RNAPII transcription that recruits Tyr1-phosphorylated CTD (Tyr1P-CTD) to nuclear PIP2-containing structures. The depletion of MPRIP increases the number of the initiation condensates, indicating a defect in the transcription. We hypothesize that MPRIP regulates the condensation and transcription through affecting the association of the RNAPII complex with nuclear PIP2-rich structures. The identification of Tyr1P-CTD as an interactor of PIP2 and MPRIP further points to a regulatory role in RNAPII pause-release, where the susceptibility of the transcriptional complex to leave the initiation condensate depends on its association with nuclear PIP2-rich structures. Moreover, the N-terminal domain of MPRIP, which is responsible for the interaction with the Tyr1P-CTD, contains an F-actin binding region that offers an explanation of how nuclear F-actin formations can affect the RNAPII transcription and condensation. Overall, our findings shed light on the role of PIP2 in RNAPII transcription through identifying the F-actin binding protein MPRIP as a transcription regulator and a determinant of the condensation of RNAPII. Full article

(This article belongs to the Special Issue Versatility of a Cellular Signaling Scaffold: The Inositol Ring Rules! – Honorary Special Issue Commemorating the Work of Prof. Lucio I. M. Cocco)

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12 pages, 5291 KiB

Open AccessArticle

miRNA-Induced Downregulation of IPMK in Macrophages Mediates Lipopolysaccharide-Triggered TLR4 Signaling

by Haein Lee, Eunha Kim and Seyun Kim

Biomolecules 2023, 13(2), 332; https://doi.org/10.3390/biom13020332 - 09 Feb 2023

Cited by 3 | Viewed by 1707

Abstract

Inositol polyphosphate multikinase (IPMK) is a pleiotropic enzyme responsible for the production of inositol polyphosphates and phosphoinositide. IPMK in macrophages was identified as a key factor for the full activation of the Toll-like receptor 4 (TLR4) signaling pathway and inflammation by directly interacting [...] Read more.

Inositol polyphosphate multikinase (IPMK) is a pleiotropic enzyme responsible for the production of inositol polyphosphates and phosphoinositide. IPMK in macrophages was identified as a key factor for the full activation of the Toll-like receptor 4 (TLR4) signaling pathway and inflammation by directly interacting with tumor necrosis factor receptor-associated factor 6 (TRAF6). Here, dynamic changes of IPMK levels in lipopolysaccharide (LPS)-stimulated macrophages and their functional significance were investigated. Both the mRNA and protein levels of IPMK were acutely decreased in mouse and human macrophages when cells were stimulated with LPS for between 1 and 6 h. Analysis of the 3’ untranslated region (UTR) of mouse IPMK mRNA revealed a highly conserved binding site for miR-181c. Transfection of miR-181c mimics into RAW 264.7 macrophages led to decreased IPMK 3’UTR-luciferase reporter activity and lowered endogenous IPMK levels. When the genomic deletion of a 33-bp fragment containing a putative miR-181c-binding site was introduced within the IPMK 3’UTR of RAW 264.7 macrophages (264.7^Δ3′UTR), LPS-triggered downregulation of IPMK levels was prevented. LPS treatment in 264.7^Δ3′UTR macrophages decreased TLR4-induced signaling and the expression of proinflammatory cytokines. In response to LPS stimulation, K63-linked ubiquitination of TRAF6 was impaired in 264.7^Δ3′UTR macrophages, suggesting an action of IPMK in the suppression of TRAF6 activation. Therefore, our findings reveal that LPS-mediated suppression of IPMK regulates the full activation of TLR4 signaling and inflammation in macrophages. Full article

(This article belongs to the Special Issue Versatility of a Cellular Signaling Scaffold: The Inositol Ring Rules! – Honorary Special Issue Commemorating the Work of Prof. Lucio I. M. Cocco)

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14 pages, 2396 KiB

Open AccessArticle

Nucleolar Architecture Is Modulated by a Small Molecule, the Inositol Pyrophosphate 5-InsP₇

by Soumyadip Sahu, Jacob Gordon, Chunfang Gu, Mack Sobhany, Dorothea Fiedler, Robin E. Stanley and Stephen B. Shears

Biomolecules 2023, 13(1), 153; https://doi.org/10.3390/biom13010153 - 12 Jan 2023

Cited by 3 | Viewed by 2203

Abstract

Inositol pyrophosphates (PP-InsPs); are a functionally diverse family of eukaryotic molecules that deploy a highly-specialized array of phosphate groups as a combinatorial cell-signaling code. One reductive strategy to derive a molecular-level understanding of the many actions of PP-InsPs is to individually characterize the [...] Read more.

Inositol pyrophosphates (PP-InsPs); are a functionally diverse family of eukaryotic molecules that deploy a highly-specialized array of phosphate groups as a combinatorial cell-signaling code. One reductive strategy to derive a molecular-level understanding of the many actions of PP-InsPs is to individually characterize the proteins that bind them. Here, we describe an alternate approach that seeks a single, collective rationalization for PP-InsP binding to an entire group of proteins, i.e., the multiple nucleolar proteins previously reported to bind 5-InsP₇ (5-diphospho-inositol-1,2,3,4,6-pentakisphosphate). Quantitative confocal imaging of the outer nucleolar granular region revealed its expansion when cellular 5-InsP₇ levels were elevated by either (a) reducing the 5-InsP₇ metabolism by a CRISPR-based knockout (KO) of either NUDT3 or PPIP5Ks; or (b), the heterologous expression of wild-type inositol hexakisphosphate kinase, i.e., IP6K2; separate expression of a kinase-dead IP6K2 mutant did not affect granular volume. Conversely, the nucleolar granular region in PPIP5K KO cells shrank back to the wild-type volume upon attenuating 5-InsP₇ synthesis using either a pan-IP6K inhibitor or the siRNA-induced knockdown of IP6K1+IP6K2. Significantly, the inner fibrillar volume of the nucleolus was unaffected by 5-InsP₇. We posit that 5-InsP₇ acts as an ‘electrostatic glue’ that binds together positively charged surfaces on separate proteins, overcoming mutual protein–protein electrostatic repulsion the latter phenomenon is a known requirement for the assembly of a non-membranous biomolecular condensate. Full article

(This article belongs to the Special Issue Versatility of a Cellular Signaling Scaffold: The Inositol Ring Rules! – Honorary Special Issue Commemorating the Work of Prof. Lucio I. M. Cocco)

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20 pages, 9039 KiB

Open AccessArticle

TNP Analogues Inhibit the Virulence Promoting IP_3-4 Kinase Arg1 in the Fungal Pathogen Cryptococcus neoformans

by Desmarini Desmarini, Daniel Truong, Lorna Wilkinson-White, Chandrika Desphande, Mario Torrado, Joel P. Mackay, Jacqueline M. Matthews, Tania C. Sorrell, Sophie Lev, Philip E. Thompson and Julianne Teresa Djordjevic

Biomolecules 2022, 12(10), 1526; https://doi.org/10.3390/biom12101526 - 20 Oct 2022

Viewed by 1967

Abstract

New antifungals with unique modes of action are urgently needed to treat the increasing global burden of invasive fungal infections. The fungal inositol polyphosphate kinase (IPK) pathway, comprised of IPKs that convert IP₃ to IP₈, provides a promising new target [...] Read more.

New antifungals with unique modes of action are urgently needed to treat the increasing global burden of invasive fungal infections. The fungal inositol polyphosphate kinase (IPK) pathway, comprised of IPKs that convert IP₃ to IP₈, provides a promising new target due to its impact on multiple, critical cellular functions and, unlike in mammalian cells, its lack of redundancy. Nearly all IPKs in the fungal pathway are essential for virulence, with IP_3-4 kinase (IP_3-4K) the most critical. The dibenzylaminopurine compound, N2-(m-trifluorobenzylamino)-N6-(p-nitrobenzylamino)purine (TNP), is a commercially available inhibitor of mammalian IPKs. The ability of TNP to be adapted as an inhibitor of fungal IP_3-4K has not been investigated. We purified IP_3-4K from the human pathogens, Cryptococcus neoformans and Candida albicans, and optimised enzyme and surface plasmon resonance (SPR) assays to determine the half inhibitory concentration (IC₅₀) and binding affinity (K_D), respectively, of TNP and 38 analogues. A novel chemical route was developed to efficiently prepare TNP analogues. TNP and its analogues demonstrated inhibition of recombinant IP_3-4K from C. neoformans (CnArg1) at low µM IC₅₀s, but not IP_3-4K from C. albicans (CaIpk2) and many analogues exhibited selectivity for CnArg1 over the human equivalent, HsIPMK. Our results provide a foundation for improving potency and selectivity of the TNP series for fungal IP_3-4K. Full article

(This article belongs to the Special Issue Versatility of a Cellular Signaling Scaffold: The Inositol Ring Rules! – Honorary Special Issue Commemorating the Work of Prof. Lucio I. M. Cocco)

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15 pages, 2513 KiB

Open AccessArticle

PTEN Protein Phosphatase Activity Is Not Required for Tumour Suppression in the Mouse Prostate

by Helen M. Wise, Adam Harris, Nisha Kriplani, Adam Schofield, Helen Caldwell, Mark J. Arends, Ian M. Overton and Nick R. Leslie

Biomolecules 2022, 12(10), 1511; https://doi.org/10.3390/biom12101511 - 19 Oct 2022

Viewed by 2021

Abstract

Loss PTEN function is one of the most common events driving aggressive prostate cancers and biochemically, PTEN is a lipid phosphatase which opposes the activation of the oncogenic PI3K-AKT signalling network. However, PTEN also has additional potential mechanisms of action, including protein phosphatase [...] Read more.

Loss PTEN function is one of the most common events driving aggressive prostate cancers and biochemically, PTEN is a lipid phosphatase which opposes the activation of the oncogenic PI3K-AKT signalling network. However, PTEN also has additional potential mechanisms of action, including protein phosphatase activity. Using a mutant enzyme, PTEN Y138L, which selectively lacks protein phosphatase activity, we characterised genetically modified mice lacking either the full function of PTEN in the prostate gland or only lacking protein phosphatase activity. The phenotypes of mice carrying a single allele of either wild-type Pten or Pten^Y138L in the prostate were similar, with common prostatic intraepithelial neoplasia (PIN) and similar gene expression profiles. However, the latter group, lacking PTEN protein phosphatase activity additionally showed lymphocyte infiltration around PIN and an increased immune cell gene expression signature. Prostate adenocarcinoma, elevated proliferation and AKT activation were only frequently observed when PTEN was fully deleted. We also identify a common gene expression signature of PTEN loss conserved in other studies (including Nkx3.1, Tnf and Cd44). We provide further insight into tumour development in the prostate driven by loss of PTEN function and show that PTEN protein phosphatase activity is not required for tumour suppression. Full article

(This article belongs to the Special Issue Versatility of a Cellular Signaling Scaffold: The Inositol Ring Rules! – Honorary Special Issue Commemorating the Work of Prof. Lucio I. M. Cocco)

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Review

Jump to: Research

18 pages, 2261 KiB

Open AccessReview

Regulation of Phosphoinositide Signaling by Scaffolds at Cytoplasmic Membranes

by Tianmu Wen, Narendra Thapa, Vincent L. Cryns and Richard A. Anderson

Biomolecules 2023, 13(9), 1297; https://doi.org/10.3390/biom13091297 - 24 Aug 2023

Cited by 1 | Viewed by 1292

Abstract

Cytoplasmic phosphoinositides (PI) are critical regulators of the membrane–cytosol interface that control a myriad of cellular functions despite their low abundance among phospholipids. The metabolic cycle that generates different PI species is crucial to their regulatory role, controlling membrane dynamics, vesicular [...] Read more.

Cytoplasmic phosphoinositides (PI) are critical regulators of the membrane–cytosol interface that control a myriad of cellular functions despite their low abundance among phospholipids. The metabolic cycle that generates different PI species is crucial to their regulatory role, controlling membrane dynamics, vesicular trafficking, signal transduction, and other key cellular events. The synthesis of phosphatidylinositol (3,4,5)-triphosphate (PI3,4,5P₃) in the cytoplamic PI3K/Akt pathway is central to the life and death of a cell. This review will focus on the emerging evidence that scaffold proteins regulate the PI3K/Akt pathway in distinct membrane structures in response to diverse stimuli, challenging the belief that the plasma membrane is the predominant site for PI3k/Akt signaling. In addition, we will discuss how PIs regulate the recruitment of specific scaffolding complexes to membrane structures to coordinate vesicle formation, fusion, and reformation during autophagy as well as a novel lysosome repair pathway. Full article

(This article belongs to the Special Issue Versatility of a Cellular Signaling Scaffold: The Inositol Ring Rules! – Honorary Special Issue Commemorating the Work of Prof. Lucio I. M. Cocco)

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26 pages, 2714 KiB

Open AccessEditor’s ChoiceReview

Nuclear Phosphoinositides as Key Determinants of Nuclear Functions

by Magdalena C. Vidalle, Bhavwanti Sheth, Antonietta Fazio, Maria Vittoria Marvi, Stefano Leto, Foteini-Dionysia Koufi, Irene Neri, Irene Casalin, Giulia Ramazzotti, Matilde Y. Follo, Stefano Ratti, Lucia Manzoli, Sonakshi Gehlot, Nullin Divecha and Roberta Fiume

Biomolecules 2023, 13(7), 1049; https://doi.org/10.3390/biom13071049 - 28 Jun 2023

Cited by 6 | Viewed by 1980

Abstract

Polyphosphoinositides (PPIns) are signalling messengers representing less than five per cent of the total phospholipid concentration within the cell. Despite their low concentration, these lipids are critical regulators of various cellular processes, including cell cycle, differentiation, gene transcription, apoptosis and motility. PPIns are [...] Read more.

Polyphosphoinositides (PPIns) are signalling messengers representing less than five per cent of the total phospholipid concentration within the cell. Despite their low concentration, these lipids are critical regulators of various cellular processes, including cell cycle, differentiation, gene transcription, apoptosis and motility. PPIns are generated by the phosphorylation of the inositol head group of phosphatidylinositol (PtdIns). Different pools of PPIns are found at distinct subcellular compartments, which are regulated by an array of kinases, phosphatases and phospholipases. Six of the seven PPIns species have been found in the nucleus, including the nuclear envelope, the nucleoplasm and the nucleolus. The identification and characterisation of PPIns interactor and effector proteins in the nucleus have led to increasing interest in the role of PPIns in nuclear signalling. However, the regulation and functions of PPIns in the nucleus are complex and are still being elucidated. This review summarises our current understanding of the localisation, biogenesis and physiological functions of the different PPIns species in the nucleus. Full article

(This article belongs to the Special Issue Versatility of a Cellular Signaling Scaffold: The Inositol Ring Rules! – Honorary Special Issue Commemorating the Work of Prof. Lucio I. M. Cocco)

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12 pages, 944 KiB

Open AccessReview

Phospholipases in Gliomas: Current Knowledge and Future Perspectives from Bench to Bedside

by Maria Vittoria Marvi, Irene Neri, Camilla Evangelisti, Giulia Ramazzotti, Sofia Asioli, Matteo Zoli, Diego Mazzatenta, Niccolò Neri, Luca Morandi, Caterina Tonon, Raffaele Lodi, Enrico Franceschi, James A. McCubrey, Pann-Ghill Suh, Lucia Manzoli and Stefano Ratti

Biomolecules 2023, 13(5), 798; https://doi.org/10.3390/biom13050798 - 07 May 2023

Viewed by 1825

Abstract

Phospholipases are essential intermediaries that work as hydrolyzing enzymes of phospholipids (PLs), which represent the most abundant species contributing to the biological membranes of nervous cells of the healthy human brain. They generate different lipid mediators, such as diacylglycerol, phosphatidic acid, lysophosphatidic acid, [...] Read more.

Phospholipases are essential intermediaries that work as hydrolyzing enzymes of phospholipids (PLs), which represent the most abundant species contributing to the biological membranes of nervous cells of the healthy human brain. They generate different lipid mediators, such as diacylglycerol, phosphatidic acid, lysophosphatidic acid, and arachidonic acid, representing key elements of intra- and inter-cellular signaling and being involved in the regulation of several cellular mechanisms that can promote tumor progression and aggressiveness. In this review, it is summarized the current knowledge about the role of phospholipases in brain tumor progression, focusing on low- and high-grade gliomas, representing promising prognostic or therapeutic targets in cancer therapies due to their influential roles in cell proliferation, migration, growth, and survival. A deeper understanding of the phospholipases-related signaling pathways could be necessary to pave the way for new targeted therapeutic strategies. Full article

(This article belongs to the Special Issue Versatility of a Cellular Signaling Scaffold: The Inositol Ring Rules! – Honorary Special Issue Commemorating the Work of Prof. Lucio I. M. Cocco)

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Versatility of a Cellular Signaling Scaffold: The Inositol Ring Rules! – Honorary Special Issue Commemorating the Work of Prof. Lucio I. M. Cocco

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