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Special Issue "Phosphoinositides and Downstream Signalling Molecules"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 July 2020).

Special Issue Editors

Prof. Dr. Marco Falasca
E-Mail Website
Guest Editor
Dr. Tania Maffucci
E-Mail Website
Guest Editor
Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Interests: signal transduction; prostate and skin cancers; phosphoinositide signalling; phosphoinositide 3-kinases-dependent pathways
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Phosphoinositides (PIs) are phospholipids comprising a water-soluble myo-inositol head group linked to two fatty acid chains by a glycerol moiety. The enzyme phosphatidylinositol (PtdIns) catalyses the synthesis of the founding member of the family, PtdIns, by linking the 1-position of the myo-inositol to the diester phosphate of a glycerophospholipid. PIs derive from differential phosphorylation of the hydroxyls at the 3-, 4- and 5-position within the myo-inositol headgroup of PtdIns. All seven PIs are naturally occurring in all higher eukaryotes, and their levels can be modified by the action of specific kinases or phosphatases. Because of their lipid tail, PIs are obligatorily membrane-bound; therefore, they can mark specific membrane compartments, or subdomains within a membrane. On the other hand, PIs can also act as signalling molecules, either by modulating activation of target proteins or by acting as precursors of other, “PIs-derived”, signalling molecules such as lysophosphatidylinositol and inositol phosphates. This Special Issue will provide an overview of the long journey of PIs and their downstream signalling molecules from mere cellular components to their identification as key regulators of several cellular signalling, including the most recent evidence reporting several intracellular roles for the least investigated members of this family.

Prof. Dr. Marco Falasca
Dr. Tania Maffucci
Guest Editors

Manuscript Submission Information

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Keywords

  • phosphoinositides
  • inositol phosphates
  • lysophosphatidylinositol
  • PI-binding domains
  • PI-kinases

Published Papers (8 papers)

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Research

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Article
Growth and Viability of Cutaneous Squamous Cell Carcinoma Cell Lines Display Different Sensitivities to Isoform-Specific Phosphoinositide 3-Kinase Inhibitors
Int. J. Mol. Sci. 2021, 22(7), 3567; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073567 - 30 Mar 2021
Viewed by 497
Abstract
Cutaneous squamous cell carcinomas (cSCCs) account for about 20% of keratinocyte carcinomas, the most common cancer in the UK. Therapeutic options for cSCC patients who develop metastasis are limited and a better understanding of the biochemical pathways involved in cSCC development/progression is crucial [...] Read more.
Cutaneous squamous cell carcinomas (cSCCs) account for about 20% of keratinocyte carcinomas, the most common cancer in the UK. Therapeutic options for cSCC patients who develop metastasis are limited and a better understanding of the biochemical pathways involved in cSCC development/progression is crucial to identify novel therapeutic targets. Evidence indicates that the phosphoinositide 3-kinases (PI3Ks)/Akt pathway plays an important role, in particular in advanced cSCC. Questions remain of whether all four PI3K isoforms able to activate Akt are involved and whether selective inhibition of specific isoform(s) might represent a more targeted strategy. Here we determined the sensitivity of four patient-derived cSCC cell lines to isoform-specific PI3K inhibitors to start investigating their potential therapeutic value in cSCC. Parallel experiments were performed in immortalized keratinocyte cell lines. We observed that pan PI3Ks inhibition reduced the growth/viability of all tested cell lines, confirming the crucial role of this pathway. Selective inhibition of the PI3K isoform p110α reduced growth/viability of keratinocytes and of two cSCC cell lines while affecting the other two only slightly. Importantly, p110α inhibition reduced Akt phosphorylation in all cSCC cell lines. These data indicate that growth and viability of the investigated cSCC cells display differential sensitivity to isoform-specific PI3K inhibitors. Full article
(This article belongs to the Special Issue Phosphoinositides and Downstream Signalling Molecules)
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Article
Using Phosphatidylinositol Phosphorylation as Markers for Hyperglycemic Related Breast Cancer
Int. J. Mol. Sci. 2020, 21(7), 2320; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072320 - 27 Mar 2020
Cited by 3 | Viewed by 828
Abstract
Studies have suggested that type 2 diabetes (T2D) is associated with a higher incidence of breast cancer and related mortality rates. T2D postmenopausal women have an ~20% increased chance of developing breast cancer, and women with T2D and breast cancer have a 50% [...] Read more.
Studies have suggested that type 2 diabetes (T2D) is associated with a higher incidence of breast cancer and related mortality rates. T2D postmenopausal women have an ~20% increased chance of developing breast cancer, and women with T2D and breast cancer have a 50% increase in mortality compared to breast cancer patients without diabetes. This correlation has been attributed to the general activation of insulin receptor signaling, glucose metabolism, phosphatidylinositol (PI) kinases, and growth pathways. Furthermore, the presence of breast cancer specific PI kinase and/or phosphatase mutations enhance metastatic breast cancer phenotypes. We hypothesized that each of the breast cancer subtypes may have characteristic PI phosphorylation profiles that are changed in T2D conditions. Therefore, we sought to characterize the PI phosphorylation when equilibrated in normal glycemic versus hyperglycemic serum conditions. Our results suggest that hyperglycemia leads to: 1) A reduction in PI3P and PIP3, with increased PI4P that is later converted to PI(3,4)P2 at the cell surface in hormone receptor positive breast cancer; 2) a reduction in PI3P and PI4P with increased PIP3 surface expression in human epidermal growth factor receptor 2-positive (HER2+) breast cancer; and 3) an increase in di- and tri-phosphorylated PIs due to turnover of PI3P in triple negative breast cancer. This study begins to describe some of the crucial changes in PIs that play a role in T2D related breast cancer incidence and metastasis. Full article
(This article belongs to the Special Issue Phosphoinositides and Downstream Signalling Molecules)
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Article
Targeted Deletion of PTEN in Kisspeptin Cells Results in Brain Region- and Sex-Specific Effects on Kisspeptin Expression and Gonadotropin Release
Int. J. Mol. Sci. 2020, 21(6), 2107; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062107 - 19 Mar 2020
Cited by 1 | Viewed by 901
Abstract
Kisspeptin-expressing neurons in the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC) of the hypothalamus relay hormonal and metabolic information to gonadotropin-releasing hormone neurons, which in turn regulate pituitary and gonadal function. Phosphatase and tensin homolog (PTEN) blocks phosphatidylinositol 3-kinase (PI3K), a [...] Read more.
Kisspeptin-expressing neurons in the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC) of the hypothalamus relay hormonal and metabolic information to gonadotropin-releasing hormone neurons, which in turn regulate pituitary and gonadal function. Phosphatase and tensin homolog (PTEN) blocks phosphatidylinositol 3-kinase (PI3K), a signaling pathway utilized by peripheral factors to transmit their signals. However, whether PTEN signaling in kisspeptin neurons helps to integrate peripheral hormonal cues to regulate gonadotropin release is unknown. To address this question, we generated mice with a kisspeptin cell-specific deletion of Pten (Kiss-PTEN KO), and first assessed kisspeptin protein expression and gonadotropin release in these animals. Kiss-PTEN KO mice displayed a profound sex and region-specific kisspeptin neuron hyperthrophy. We detected both kisspeptin neuron hyperthrophy as well as increased kisspeptin fiber densities in the AVPV and ARC of Kiss-PTEN KO females and in the ARC of Kiss-PTEN KO males. Moreover, Kiss-PTEN KO mice showed a reduced gonadotropin release in response to gonadectomy. We also found a hyperactivation of mTOR, a downstream PI3K target and central regulator of cell metabolism, in the AVPV and ARC of Kiss-PTEN KO females but not males. Fasting, known to inhibit hypothalamic kisspeptin expression and luteinizing hormone levels, failed to induce these changes in Kiss-PTEN KO females. We conclude that PTEN signaling regulates kisspeptin protein synthesis in both sexes and that its role as a metabolic signaling molecule in kisspeptin neurons is sex-specific. Full article
(This article belongs to the Special Issue Phosphoinositides and Downstream Signalling Molecules)
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Review

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Review
PTEN and Other PtdIns(3,4,5)P3 Lipid Phosphatases in Breast Cancer
Int. J. Mol. Sci. 2020, 21(23), 9189; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239189 - 02 Dec 2020
Cited by 4 | Viewed by 678
Abstract
The phosphoinositide 3-kinase (PI3K)/AKT signalling pathway is hyperactivated in ~70% of breast cancers. Class I PI3K generates PtdIns(3,4,5)P3 at the plasma membrane in response to growth factor stimulation, leading to AKT activation to drive cell proliferation, survival and migration. PTEN negatively regulates [...] Read more.
The phosphoinositide 3-kinase (PI3K)/AKT signalling pathway is hyperactivated in ~70% of breast cancers. Class I PI3K generates PtdIns(3,4,5)P3 at the plasma membrane in response to growth factor stimulation, leading to AKT activation to drive cell proliferation, survival and migration. PTEN negatively regulates PI3K/AKT signalling by dephosphorylating PtdIns(3,4,5)P3 to form PtdIns(4,5)P2. PtdIns(3,4,5)P3 can also be hydrolysed by the inositol polyphosphate 5-phosphatases (5-phosphatases) to produce PtdIns(3,4)P2. Interestingly, while PTEN is a bona fide tumour suppressor and is frequently mutated/lost in breast cancer, 5-phosphatases such as PIPP, SHIP2 and SYNJ2, have demonstrated more diverse roles in regulating mammary tumourigenesis. Reduced PIPP expression is associated with triple negative breast cancers and reduced relapse-free and overall survival. Although PIPP depletion enhances AKT phosphorylation and supports tumour growth, this also inhibits cell migration and metastasis in vivo, in a breast cancer oncogene-driven murine model. Paradoxically, SHIP2 and SYNJ2 are increased in primary breast tumours, which correlates with invasive disease and reduced survival. SHIP2 or SYNJ2 overexpression promotes breast tumourigenesis via AKT-dependent and independent mechanisms. This review will discuss how PTEN, PIPP, SHIP2 and SYNJ2 distinctly regulate multiple functional targets, and the mechanisms by which dysregulation of these distinct phosphoinositide phosphatases differentially affect breast cancer progression. Full article
(This article belongs to the Special Issue Phosphoinositides and Downstream Signalling Molecules)
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Review
Review of PIP2 in Cellular Signaling, Functions and Diseases
Int. J. Mol. Sci. 2020, 21(21), 8342; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218342 - 06 Nov 2020
Viewed by 603
Abstract
Phosphoinositides play a crucial role in regulating many cellular functions, such as actin dynamics, signaling, intracellular trafficking, membrane dynamics, and cell–matrix adhesion. Central to this process is phosphatidylinositol bisphosphate (PIP2). The levels of PIP2 in the membrane are rapidly altered by the activity [...] Read more.
Phosphoinositides play a crucial role in regulating many cellular functions, such as actin dynamics, signaling, intracellular trafficking, membrane dynamics, and cell–matrix adhesion. Central to this process is phosphatidylinositol bisphosphate (PIP2). The levels of PIP2 in the membrane are rapidly altered by the activity of phosphoinositide-directed kinases and phosphatases, and it binds to dozens of different intracellular proteins. Despite the vast literature dedicated to understanding the regulation of PIP2 in cells over past 30 years, much remains to be learned about its cellular functions. In this review, we focus on past and recent exciting results on different molecular mechanisms that regulate cellular functions by binding of specific proteins to PIP2 or by stabilizing phosphoinositide pools in different cellular compartments. Moreover, this review summarizes recent findings that implicate dysregulation of PIP2 in many diseases Full article
(This article belongs to the Special Issue Phosphoinositides and Downstream Signalling Molecules)
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Review
Histone Deacetylase Inhibitors as Multitarget-Directed Epi-Drugs in Blocking PI3K Oncogenic Signaling: A Polypharmacology Approach
Int. J. Mol. Sci. 2020, 21(21), 8198; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218198 - 02 Nov 2020
Cited by 2 | Viewed by 621
Abstract
Genetic mutations and aberrant epigenetic alterations are the triggers for carcinogenesis. The emergence of the drugs targeting epigenetic aberrations has provided a better outlook for cancer treatment. Histone deacetylases (HDACs) are epigenetic modifiers playing critical roles in numerous key biological functions. Inappropriate expression [...] Read more.
Genetic mutations and aberrant epigenetic alterations are the triggers for carcinogenesis. The emergence of the drugs targeting epigenetic aberrations has provided a better outlook for cancer treatment. Histone deacetylases (HDACs) are epigenetic modifiers playing critical roles in numerous key biological functions. Inappropriate expression of HDACs and dysregulation of PI3K signaling pathway are common aberrations observed in human diseases, particularly in cancers. Histone deacetylase inhibitors (HDACIs) are a class of epigenetic small-molecular therapeutics exhibiting promising applications in the treatment of hematological and solid malignancies, and in non-neoplastic diseases. Although HDACIs as single agents exhibit synergy by inhibiting HDAC and the PI3K pathway, resistance to HDACIs is frequently encountered due to activation of compensatory survival pathway. Targeted simultaneous inhibition of both HDACs and PI3Ks with their respective inhibitors in combination displayed synergistic therapeutic efficacy and encouraged the development of a single HDAC-PI3K hybrid molecule via polypharmacology strategy. This review provides an overview of HDACs and the evolution of HDACs-based epigenetic therapeutic approaches targeting the PI3K pathway. Full article
(This article belongs to the Special Issue Phosphoinositides and Downstream Signalling Molecules)
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Review
Inositol Polyphosphate-Based Compounds as Inhibitors of Phosphoinositide 3-Kinase-Dependent Signaling
Int. J. Mol. Sci. 2020, 21(19), 7198; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197198 - 29 Sep 2020
Cited by 1 | Viewed by 524
Abstract
Signaling pathways regulated by the phosphoinositide 3-kinase (PI3K) enzymes have a well-established role in cancer development and progression. Over the past 30 years, the therapeutic potential of targeting this pathway has been well recognized, and this has led to the development of a [...] Read more.
Signaling pathways regulated by the phosphoinositide 3-kinase (PI3K) enzymes have a well-established role in cancer development and progression. Over the past 30 years, the therapeutic potential of targeting this pathway has been well recognized, and this has led to the development of a multitude of drugs, some of which have progressed into clinical trials, with few of them currently approved for use in specific cancer settings. While many inhibitors compete with ATP, hence preventing the catalytic activity of the kinases directly, a deep understanding of the mechanisms of PI3K-dependent activation of its downstream effectors led to the development of additional strategies to prevent the initiation of this signaling pathway. This review summarizes previously published studies that led to the identification of inositol polyphosphates as promising parent molecules to design novel inhibitors of PI3K-dependent signals. We focus our attention on the inhibition of protein–membrane interactions mediated by binding of pleckstrin homology domains and phosphoinositides that we proposed 20 years ago as a novel therapeutic strategy. Full article
(This article belongs to the Special Issue Phosphoinositides and Downstream Signalling Molecules)
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Review
Phosphoinositide-Dependent Signaling in Cancer: A Focus on Phospholipase C Isozymes
Int. J. Mol. Sci. 2020, 21(7), 2581; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072581 - 08 Apr 2020
Cited by 4 | Viewed by 1113
Abstract
Phosphoinositides (PI) form just a minor portion of the total phospholipid content in cells but are significantly involved in cancer development and progression. In several cancer types, phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] play significant roles in regulating [...] Read more.
Phosphoinositides (PI) form just a minor portion of the total phospholipid content in cells but are significantly involved in cancer development and progression. In several cancer types, phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] play significant roles in regulating survival, proliferation, invasion, and growth of cancer cells. Phosphoinositide-specific phospholipase C (PLC) catalyze the generation of the essential second messengers diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (InsP3) by hydrolyzing PtdIns(4,5)P2. DAG and InsP3 regulate Protein Kinase C (PKC) activation and the release of calcium ions (Ca2+) into the cytosol, respectively. This event leads to the control of several important biological processes implicated in cancer. PLCs have been extensively studied in cancer but their regulatory roles in the oncogenic process are not fully understood. This review aims to provide up-to-date knowledge on the involvement of PLCs in cancer. We focus specifically on PLCβ, PLCγ, PLCδ, and PLCε isoforms due to the numerous evidence of their involvement in various cancer types. Full article
(This article belongs to the Special Issue Phosphoinositides and Downstream Signalling Molecules)
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