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Phosphoinositides and Downstream Signalling Molecules 2.0

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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 2022) | Viewed by 11013

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Prof. Dr. Marco Falasca

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Department of Medicine and Surgery, University of Parma, Via Volturno, 39, 43125 Parma, Italy
Interests: lipid metabolism; gastrointestinal diseases; pancreatic cancer; extracellular vesicles; tumour-stroma crosstalk; cannabinoid signalling
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Dr. Tania Maffucci

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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
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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) catalyzes 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 occur naturally 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 signaling molecules, either by modulating activation of target proteins or by acting as precursors of other, “PIs-derived”, signaling molecules such as lysophosphatidylinositol and inositol phosphates. This Special Issue will provide an overview of the long journey of PIs and their downstream signaling molecules from mere cellular components to their identification as key regulators of several cellular signaling paths, 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

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Keywords

phosphoinositides
inositol phosphates
lysophosphatidylinositol
PI-binding domains
PI kinases

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Phosphoinositides and Downstream Signalling Molecules in International Journal of Molecular Sciences (9 articles)

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Research

Jump to: Review

15 pages, 2592 KiB

Open AccessArticle

Inhibition of Vps34 and p110δ PI3K Impairs Migration, Invasion and Three-Dimensional Spheroid Growth in Breast Cancer Cells

by Marzia Di Donato, Pia Giovannelli, Antimo Migliaccio and Antonio Bilancio

Int. J. Mol. Sci. 2022, 23(16), 9008; https://doi.org/10.3390/ijms23169008 - 12 Aug 2022

Cited by 10 | Viewed by 2093

Abstract

Breast cancer is a heterogeneous disease that represents the most common cancer around the world; it comprises 12% of new cases according to the World Health Organization. Despite new approaches in early diagnosis and current treatment, breast cancer is still the leading cause of death for cancer mortality. New targeted therapies against key signalling transduction molecules are required. Phosphoinositide 3-kinase (PI3K) regulates multiple biological functions such as proliferation, survival, migration, and growth. It is well established that PI3K isoform-selective inhibitors show fewer toxic side effects compared to broad spectrum inhibition of PI3K (pan-PI3K inhibitors). Therefore, we tested the PI3K p110δ-selective inhibitor, IC87114, and Vps34-selective inhibitor, Vps34-IN1, on the breast cancer cell lines MCF-7 and MDA-MB-231, representing hormone-responsive and triple-negative breast cancer cells, respectively. Our data show that both inhibitors decreased migration of MCF-7 and MDA-MB-231 cells, and Vps34 also significantly impacted MCF-7 cell proliferation. Three-dimensional (3D) in vitro culture models show that IC87114 and Vps34-IN1 treatment reduced the growth of MCF-7 and MDA-MB-231 cells in 3D tumour spheroid cultures. This study identifies IC87114 and Vps34-IN1 as potential therapeutic approaches in breast cancer. Full article

(This article belongs to the Special Issue Phosphoinositides and Downstream Signalling Molecules 2.0)

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13 pages, 10950 KiB

Open AccessArticle

Dominant Role of PI3K p110α over p110β in Insulin and β-Adrenergic Receptor Signalling

by Biqin Zhang, Cheukyau Luk, Joyce Valadares, Christos Aronis and Lazaros C. Foukas

Int. J. Mol. Sci. 2021, 22(23), 12813; https://doi.org/10.3390/ijms222312813 - 26 Nov 2021

Cited by 3 | Viewed by 2405

Abstract

Attribution of specific roles to the two ubiquitously expressed PI 3-kinase (PI3K) isoforms p110α and p110β in biological functions they have been implicated, such as in insulin signalling, has been challenging. While p110α has been demonstrated to be the principal isoform activated downstream of the insulin receptor, several studies have provided evidence for a role of p110β. Here we have used isoform-selective inhibitors to estimate the relative contribution of each of these isoforms in insulin signalling in adipocytes, which are a cell type with essential roles in regulation of metabolism at the systemic level. Consistent with previous genetic and pharmacological studies, we found that p110α is the principal isoform activated downstream of the insulin receptor under physiological conditions. p110α interaction with Ras enhanced the strength of p110α activation by insulin. However, this interaction did not account for the selectivity for p110α over p110β in insulin signalling. We also demonstrate that p110α is the principal isoform activated downstream of the β-adrenergic receptor (β-AR), another important signalling pathway in metabolic regulation, through a mechanism involving activation of the cAMP effector molecule EPAC1. This study offers further insights in the role of PI3K isoforms in the regulation of energy metabolism with implications for the therapeutic application of selective inhibitors of these isoforms. Full article

(This article belongs to the Special Issue Phosphoinositides and Downstream Signalling Molecules)

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22 pages, 4686 KiB

Open AccessArticle

Growth and Viability of Cutaneous Squamous Cell Carcinoma Cell Lines Display Different Sensitivities to Isoform-Specific Phosphoinositide 3-Kinase Inhibitors

by Viviana Mannella, Kira Boehm, Suheyla Celik, Tasnim Ali, Amnah N. Mirza, Mariam El Hasnaouy, Andreas Kaffa, Yanshuang Lyu, Donya Kafaei Golahmadi, Irene M. Leigh, Daniele Bergamaschi, Catherine A. Harwood and Tania Maffucci

Int. J. Mol. Sci. 2021, 22(7), 3567; https://doi.org/10.3390/ijms22073567 - 30 Mar 2021

Cited by 6 | Viewed by 2934

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 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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24 pages, 7269 KiB

Open AccessArticle

Using Phosphatidylinositol Phosphorylation as Markers for Hyperglycemic Related Breast Cancer

by Nirupama Devanathan, Sandra Jones, Gursimran Kaur and Ann C. Kimble-Hill

Int. J. Mol. Sci. 2020, 21(7), 2320; https://doi.org/10.3390/ijms21072320 - 27 Mar 2020

Cited by 6 | Viewed by 3522

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% 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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22 pages, 4854 KiB

Open AccessArticle

Targeted Deletion of PTEN in Kisspeptin Cells Results in Brain Region- and Sex-Specific Effects on Kisspeptin Expression and Gonadotropin Release

by Ariel L. Negrón, Guiqin Yu, Ulrich Boehm and Maricedes Acosta-Martínez

Int. J. Mol. Sci. 2020, 21(6), 2107; https://doi.org/10.3390/ijms21062107 - 19 Mar 2020

Cited by 8 | Viewed by 3882

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 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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18 pages, 1633 KiB

Open AccessReview

The PI3K/Akt Pathway in Meta-Inflammation

by Maricedes Acosta-Martinez and Maria Zulema Cabail

Int. J. Mol. Sci. 2022, 23(23), 15330; https://doi.org/10.3390/ijms232315330 - 5 Dec 2022

Cited by 62 | Viewed by 7932

Abstract

Obesity is a global epidemic representing a serious public health burden as it is a major risk factor for the development of cardiovascular disease, stroke and all-cause mortality. Chronic low-grade systemic inflammation, also known as meta-inflammation, is thought to underly obesity’s negative health consequences, which include insulin resistance and the development of type 2 diabetes. Meta-inflammation is characterized by the accumulation of immune cells in adipose tissue, a deregulation in the synthesis and release of adipokines and a pronounced increase in the production of proinflammatory factors. In this state, the infiltration of macrophages and their metabolic activation contributes to complex paracrine and autocrine signaling, which sustains a proinflammatory microenvironment. A key signaling pathway mediating the response of macrophages and adipocytes to a microenvironment of excessive nutrients is the phosphoinositide 3-kinase (PI3K)/Akt pathway. This multifaceted network not only transduces metabolic information but also regulates macrophages’ intracellular changes, which are responsible for their phenotypic switch towards a more proinflammatory state. In the present review, we discuss how the crosstalk between macrophages and adipocytes contributes to meta-inflammation and provide an overview on the involvement of the PI3K/Akt signaling pathway, and how its impairment contributes to the development of insulin resistance. Full article

(This article belongs to the Special Issue Phosphoinositides and Downstream Signalling Molecules 2.0)

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23 pages, 5988 KiB

Open AccessReview

PTEN and Other PtdIns(3,4,5)P₃ Lipid Phosphatases in Breast Cancer

by Mariah P. Csolle, Lisa M. Ooms, Antonella Papa and Christina A. Mitchell

Int. J. Mol. Sci. 2020, 21(23), 9189; https://doi.org/10.3390/ijms21239189 - 2 Dec 2020

Cited by 37 | Viewed by 4470

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 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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20 pages, 3588 KiB

Open AccessReview

Review of PIP2 in Cellular Signaling, Functions and Diseases

by Kalpana Mandal

Int. J. Mol. Sci. 2020, 21(21), 8342; https://doi.org/10.3390/ijms21218342 - 6 Nov 2020

Cited by 78 | Viewed by 11301

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 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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27 pages, 1560 KiB

Open AccessReview

Histone Deacetylase Inhibitors as Multitarget-Directed Epi-Drugs in Blocking PI3K Oncogenic Signaling: A Polypharmacology Approach

by Kasturi Ranganna, Chelliah Selvam, Amruthesh Shivachar and Zivar Yousefipour

Int. J. Mol. Sci. 2020, 21(21), 8198; https://doi.org/10.3390/ijms21218198 - 2 Nov 2020

Cited by 20 | Viewed by 3856

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 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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16 pages, 1777 KiB

Open AccessReview

Inositol Polyphosphate-Based Compounds as Inhibitors of Phosphoinositide 3-Kinase-Dependent Signaling

by Tania Maffucci and Marco Falasca

Int. J. Mol. Sci. 2020, 21(19), 7198; https://doi.org/10.3390/ijms21197198 - 29 Sep 2020

Cited by 4 | Viewed by 3145

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 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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18 pages, 1959 KiB

Open AccessReview

Phosphoinositide-Dependent Signaling in Cancer: A Focus on Phospholipase C Isozymes

by Eric Owusu Obeng, Isabella Rusciano, Maria Vittoria Marvi, Antonietta Fazio, Stefano Ratti, Matilde Yung Follo, Jie Xian, Lucia Manzoli, Anna Maria Billi, Sara Mongiorgi, Giulia Ramazzotti and Lucio Cocco

Int. J. Mol. Sci. 2020, 21(7), 2581; https://doi.org/10.3390/ijms21072581 - 8 Apr 2020

Cited by 59 | Viewed by 7848

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 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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