Special Issue "Phosphoinositide 3-kinase, a Field in Transition"

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: 30 June 2019

Special Issue Editor

Guest Editor
Prof. Dr. Peter K. Vogt

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
Website | E-Mail
Interests: phosphoinositide 3-kinase (PI3K) regulatory and catalytic subunits; genetic analysis; isoform-specific functions

Special Issue Information

Dear Colleagues,

The PI3K-TOR signaling axis is a core cellular regulatory component that controls cell proliferation, motility and metabolism. Gain of function in PI3K signaling is an almost universal hallmark of cancer. Several protein members of that signaling pathway, notably class I PI3Ks, have therefore been in the crosshairs of drug developers. However, after more than 20 years of effort, no breakthrough drug has emerged.

With the expansion of basic knowledge of PI3K signaling came the insight that many of the difficulties encountered with PI3K inhibitors derive from the fact that the PI3K-TOR axis is central to the functioning of normal cells and that interference with activity of wildtype proteins in this system is bound to cause side effects. However, it has also become clear that we know far too little about specific aspects of PI3K signaling, especially about isoform-specific activities and their effects in different genetic settings and different states of cellular differentiation.

The PI3K field is in a state of transition. The experiences with small molecule inhibitors define new challenges and opportunities. In this Biomolecules Special Issue “Phosphoinositide 3-kinase, a Field in Transition”, authors will address urgent fundamental questions with the ultimate goal of driving new advances in medical applications.

Prof. Dr. Peter K. Vogt
Guest Editor

Manuscript Submission Information

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Keywords

  • PI3K-AKT-TOR pathway
  • PI3K catalytic and regulatory subunits
  • isoform-specific functions
  • protein-protein interactions
  • cancer-specific somatic mutations
  • feedback inhibition
  • PI3K and immunity
  • small molecule inhibitors

Published Papers (6 papers)

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Review

Open AccessReview
Mouse Models for Exploring the Biological Consequences and Clinical Significance of PIK3CA Mutations
Biomolecules 2019, 9(4), 158; https://doi.org/10.3390/biom9040158
Received: 29 March 2019 / Revised: 18 April 2019 / Accepted: 19 April 2019 / Published: 23 April 2019
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Abstract
The phosphatidylinositol 3-kinase (PI3K) pathway is involved in a myriad of cellular signalling pathways that regulate cell growth, metabolism, proliferation and survival. As a result, alterations in the PI3K pathway are frequently associated with human cancers. Indeed, PIK3CA—the gene encoding the p110α [...] Read more.
The phosphatidylinositol 3-kinase (PI3K) pathway is involved in a myriad of cellular signalling pathways that regulate cell growth, metabolism, proliferation and survival. As a result, alterations in the PI3K pathway are frequently associated with human cancers. Indeed, PIK3CA—the gene encoding the p110α catalytic subunit of PI3K—is one of the most commonly mutated human oncogenes. PIK3CA mutations have also been implicated in non-malignant conditions including congenital overgrowth syndromes and vascular malformations. In order to study the role of PIK3CA mutations in driving tumorigenesis and tissue overgrowth and to test potential therapeutic interventions for these conditions, model systems are essential. In this review we discuss the various mouse models currently available for preclinical studies into the biological consequences and clinical significance of PIK3CA mutations. Full article
(This article belongs to the Special Issue Phosphoinositide 3-kinase, a Field in Transition)
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Graphical abstract

Open AccessReview
The PTEN–PI3K Axis in Cancer
Biomolecules 2019, 9(4), 153; https://doi.org/10.3390/biom9040153
Received: 26 March 2019 / Revised: 15 April 2019 / Accepted: 15 April 2019 / Published: 17 April 2019
Cited by 1 | PDF Full-text (674 KB) | HTML Full-text | XML Full-text
Abstract
The PI3K–AKT–mTOR signal transduction pathway regulates a variety of biological processes including cell growth, cell cycle progression and proliferation, cellular metabolism, and cytoskeleton reorganization. Fine-tuning of the phosphatidylinositol 3-kinase (PI3K) pathway signaling output is essential for the maintenance of tissue homeostasis and uncontrolled [...] Read more.
The PI3K–AKT–mTOR signal transduction pathway regulates a variety of biological processes including cell growth, cell cycle progression and proliferation, cellular metabolism, and cytoskeleton reorganization. Fine-tuning of the phosphatidylinositol 3-kinase (PI3K) pathway signaling output is essential for the maintenance of tissue homeostasis and uncontrolled activation of this cascade leads to a number of human pathologies including cancer. Inactivation of the tumor suppressor phosphatase and tensin homologue deleted on Chromosome 10 (PTEN) and/or activating mutations in the proto-typical lipid kinase PI3K have emerged as some of the most frequent events associated with human cancer and as a result the PI3K pathway has become a highly sought-after target for cancer therapies. In this review we summarize the essential role of the PTEN–PI3K axis in controlling cellular behaviors by modulating activation of key proto-oncogenic molecular nodes and functional targets. Further, we highlight important functional redundancies and peculiarities of these two critical enzymes that over the last few decades have become a central part of the cancer research field and have instructed hundreds of pre-clinical and clinical trials to better cancer treatments. Full article
(This article belongs to the Special Issue Phosphoinositide 3-kinase, a Field in Transition)
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Open AccessReview
Class II PI3Ks at the Intersection between Signal Transduction and Membrane Trafficking
Biomolecules 2019, 9(3), 104; https://doi.org/10.3390/biom9030104
Received: 30 January 2019 / Revised: 1 March 2019 / Accepted: 11 March 2019 / Published: 15 March 2019
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Abstract
Phosphorylation of inositol phospholipids by the family of phosphoinositide 3-kinases (PI3Ks) is crucial in controlling membrane lipid composition and regulating a wide range of intracellular processes, which include signal transduction and vesicular trafficking. In spite of the extensive knowledge on class I PI3Ks, [...] Read more.
Phosphorylation of inositol phospholipids by the family of phosphoinositide 3-kinases (PI3Ks) is crucial in controlling membrane lipid composition and regulating a wide range of intracellular processes, which include signal transduction and vesicular trafficking. In spite of the extensive knowledge on class I PI3Ks, recent advances in the study of the three class II PI3Ks (PIK3C2A, PIK3C2B and PIK3C2G) reveal their distinct and non-overlapping cellular roles and localizations. By finely tuning membrane lipid composition in time and space among different cellular compartments, this class of enzymes controls many cellular processes, such as proliferation, survival and migration. This review focuses on the recent developments regarding the coordination of membrane trafficking and intracellular signaling of class II PI3Ks through the confined phosphorylation of inositol phospholipids. Full article
(This article belongs to the Special Issue Phosphoinositide 3-kinase, a Field in Transition)
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Graphical abstract

Open AccessReview
Structural Determinants of Isoform Selectivity in PI3K Inhibitors
Biomolecules 2019, 9(3), 82; https://doi.org/10.3390/biom9030082
Received: 25 January 2019 / Accepted: 21 February 2019 / Published: 26 February 2019
Cited by 1 | PDF Full-text (8296 KB) | HTML Full-text | XML Full-text
Abstract
Phosphatidylinositol 3-kinases (PI3Ks) are important therapeutic targets for the treatment of cancer, thrombosis, and inflammatory and immune diseases. The four highly homologous Class I isoforms, PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ have unique, non-redundant physiological roles and as such, isoform selectivity has been a [...] Read more.
Phosphatidylinositol 3-kinases (PI3Ks) are important therapeutic targets for the treatment of cancer, thrombosis, and inflammatory and immune diseases. The four highly homologous Class I isoforms, PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ have unique, non-redundant physiological roles and as such, isoform selectivity has been a key consideration driving inhibitor design and development. In this review, we discuss the structural biology of PI3Ks and how our growing knowledge of structure has influenced the medicinal chemistry of PI3K inhibitors. We present an analysis of the available structure-selectivity-activity relationship data to highlight key insights into how the various regions of the PI3K binding site influence isoform selectivity. The picture that emerges is one that is far from simple and emphasizes the complex nature of protein-inhibitor binding, involving protein flexibility, energetics, water networks and interactions with non-conserved residues. Full article
(This article belongs to the Special Issue Phosphoinositide 3-kinase, a Field in Transition)
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Graphical abstract

Open AccessReview
Getting the Akt Together: Guiding Intracellular Akt Activity by PI3K
Biomolecules 2019, 9(2), 67; https://doi.org/10.3390/biom9020067
Received: 11 January 2019 / Revised: 11 February 2019 / Accepted: 12 February 2019 / Published: 16 February 2019
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Abstract
Intracellular signaling pathways mediate the rapid response of cells to environmental cues. To control the fidelity of these responses, cells coordinate the activities of signaling enzymes with the strength, timing, and localization of the upstream stimuli. Protein kinase Akt links the PI3K-coupled receptors [...] Read more.
Intracellular signaling pathways mediate the rapid response of cells to environmental cues. To control the fidelity of these responses, cells coordinate the activities of signaling enzymes with the strength, timing, and localization of the upstream stimuli. Protein kinase Akt links the PI3K-coupled receptors to cellular anabolic processes by phosphorylating multiple substrates. How the cells ensure that Akt activity remains proportional to upstream signals and control its substrate specificity is unclear. In this review, I examine how cell-autonomous and intrinsic allosteric mechanisms cooperate to ensure localized, context-specific signaling in the PI3K/Akt axis. Full article
(This article belongs to the Special Issue Phosphoinositide 3-kinase, a Field in Transition)
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Figure 1

Open AccessReview
Impact of p85α Alterations in Cancer
Biomolecules 2019, 9(1), 29; https://doi.org/10.3390/biom9010029
Received: 7 December 2018 / Revised: 7 January 2019 / Accepted: 11 January 2019 / Published: 15 January 2019
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Abstract
The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in the regulation of cell signaling, proliferation, survival, migration and vesicle trafficking in normal cells and is frequently deregulated in many cancers. The p85α protein is the most characterized regulatory subunit of the class [...] Read more.
The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in the regulation of cell signaling, proliferation, survival, migration and vesicle trafficking in normal cells and is frequently deregulated in many cancers. The p85α protein is the most characterized regulatory subunit of the class IA PI3Ks, best known for its regulation of the p110-PI3K catalytic subunit. In this review, we will discuss the impact of p85α mutations or alterations in expression levels on the proteins p85α is known to bind and regulate. We will focus on alterations within the N-terminal half of p85α that primarily regulate Rab5 and some members of the Rho-family of GTPases, as well as those that regulate PTEN (phosphatase and tensin homologue deleted on chromosome 10), the enzyme that directly counteracts PI3K signaling. We highlight recent data, mapping the interaction surfaces of the PTEN–p85α breakpoint cluster region homology (BH) domain, which sheds new light on key residues in both proteins. As a multifunctional protein that binds and regulates many different proteins, p85α mutations at different sites have different impacts in cancer and would necessarily require distinct treatment strategies to be effective. Full article
(This article belongs to the Special Issue Phosphoinositide 3-kinase, a Field in Transition)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Tentative Title: Function, Regulation and Biological Roles of PI3Kgamma Variants
Author: Bernd Nürnberg
Abstract: Phosphoinositide 3-kinase (PI3K) gamma is the only class IB PI3K member playing important roles in the G-protein-dependent regulation of cell signaling in health and disease. Originally found in the immune system, increasing evidence suggest a wide array of functions in the whole organism. PI3Kg occur as two different heterodimeric variants: PI3Kg(p87) and PI3Kg(p101), which share the same p110g catalytic subunit but differ in their associated non-catalytic subunit. Here we concentrate on specific PI3Kg features including its regulation and biological functions. In particular, the roles of its non-catalytic subunits to serve as the main regulators determining specificity of class IB PI3Kg enzymes are highlighted.

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