Biomolecules

Review

19 pages, 603 KiB

Open AccessFeature PaperReview

The Mechanisms Underlying PTEN Loss in Human Tumors Suggest Potential Therapeutic Opportunities

by Hyeyoun Chang, Zhenying Cai and Thomas M. Roberts

Biomolecules 2019, 9(11), 713; https://doi.org/10.3390/biom9110713 - 7 Nov 2019

Cited by 24 | Viewed by 3977

In this review, we will first briefly describe the diverse molecular mechanisms associated with PTEN loss of function in cancer. We will then proceed to discuss the molecular mechanisms linking PTEN loss to PI3K activation and demonstrate how these mechanisms suggest possible therapeutic [...] Read more.

In this review, we will first briefly describe the diverse molecular mechanisms associated with PTEN loss of function in cancer. We will then proceed to discuss the molecular mechanisms linking PTEN loss to PI3K activation and demonstrate how these mechanisms suggest possible therapeutic approaches for patients with PTEN-null tumors. Full article

(This article belongs to the Special Issue Phosphoinositide 3-kinase, a Field in Transition)

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28 pages, 1485 KiB

Open AccessEditor’s ChoiceReview

Function, Regulation and Biological Roles of PI3Kγ Variants

by Bernd Nürnberg and Sandra Beer-Hammer

Biomolecules 2019, 9(9), 427; https://doi.org/10.3390/biom9090427 - 30 Aug 2019

Cited by 39 | Viewed by 6122

Abstract

Phosphatidylinositide 3-kinase (PI3K) γ is the only class IB PI3K member playing significant 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. [...] Read more.

Phosphatidylinositide 3-kinase (PI3K) γ is the only class IB PI3K member playing significant 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. PI3Kγ occur as two different heterodimeric variants: PI3Kγ (p87) and PI3Kγ (p101), which share the same p110γ catalytic subunit but differ in their associated non-catalytic subunit. Here we concentrate on specific PI3Kγ features including its regulation and biological functions. In particular, the roles of its non-catalytic subunits serving as the main regulators determining specificity of class IB PI3Kγ enzymes are highlighted. Full article

(This article belongs to the Special Issue Phosphoinositide 3-kinase, a Field in Transition)

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26 pages, 2247 KiB

Open AccessEditor’s ChoiceReview

For Better or Worse: The Potential for Dose Limiting the On-Target Toxicity of PI 3-Kinase Inhibitors

by Christina M. Buchanan, Kate L. Lee and Peter R. Shepherd

Biomolecules 2019, 9(9), 402; https://doi.org/10.3390/biom9090402 - 22 Aug 2019

Cited by 16 | Viewed by 6861

Abstract

The hyper-activation of the phosphoinositide (PI) 3-kinase signaling pathway is a hallmark of many cancers and overgrowth syndromes, and as a result, there has been intense interest in the development of drugs that target the various isoforms of PI 3-kinase. Given the key [...] Read more.

The hyper-activation of the phosphoinositide (PI) 3-kinase signaling pathway is a hallmark of many cancers and overgrowth syndromes, and as a result, there has been intense interest in the development of drugs that target the various isoforms of PI 3-kinase. Given the key role PI 3-kinases play in many normal cell functions, there is significant potential for the disruption of essential cellular functions by PI 3-kinase inhibitors in normal tissues; so-called on-target drug toxicity. It is, therefore, no surprise that progress within the clinical development of PI 3-kinase inhibitors as single-agent anti-cancer therapies has been slowed by the difficulty of identifying a therapeutic window. The aim of this review is to place the cellular, tissue and whole-body effects of PI 3-kinase inhibition in the context of understanding the potential for dose limiting on-target toxicities and to introduce possible strategies to overcome these. Full article

(This article belongs to the Special Issue Phosphoinositide 3-kinase, a Field in Transition)

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18 pages, 1060 KiB

Open AccessEditor’s ChoiceReview

Perspective: Potential Impact and Therapeutic Implications of Oncogenic PI3K Activation on Chromosomal Instability

by Bart Vanhaesebroeck, Benoit Bilanges, Ralitsa R. Madsen, Katie L. Dale, Evelyn Lau and Elina Vladimirou

Biomolecules 2019, 9(8), 331; https://doi.org/10.3390/biom9080331 - 1 Aug 2019

Cited by 9 | Viewed by 5762

Abstract

Genetic activation of the class I PI3K pathway is very common in cancer. This mostly results from oncogenic mutations in PIK3CA, the gene encoding the ubiquitously expressed PI3Kα catalytic subunit, or from inactivation of the PTEN tumour suppressor, a lipid phosphatase that [...] Read more.

Genetic activation of the class I PI3K pathway is very common in cancer. This mostly results from oncogenic mutations in PIK3CA, the gene encoding the ubiquitously expressed PI3Kα catalytic subunit, or from inactivation of the PTEN tumour suppressor, a lipid phosphatase that opposes class I PI3K signalling. The clinical impact of PI3K inhibitors in solid tumours, aimed at dampening cancer-cell-intrinsic PI3K activity, has thus far been limited. Challenges include poor drug tolerance, incomplete pathway inhibition and pre-existing or inhibitor-induced resistance. The principle of pharmacologically targeting cancer-cell-intrinsic PI3K activity also assumes that all cancer-promoting effects of PI3K activation are reversible, which might not be the case. Emerging evidence suggests that genetic PI3K pathway activation can induce and/or allow cells to tolerate chromosomal instability, which—even if occurring in a low fraction of the cell population—might help to facilitate and/or drive tumour evolution. While it is clear that such genomic events cannot be reverted pharmacologically, a role for PI3K in the regulation of chromosomal instability could be exploited by using PI3K pathway inhibitors to prevent those genomic events from happening and/or reduce the pace at which they are occurring, thereby dampening cancer development or progression. Such an impact might be most effective in tumours with clonal PI3K activation and achievable at lower drug doses than the maximum-tolerated doses of PI3K inhibitors currently used in the clinic. Full article

(This article belongs to the Special Issue Phosphoinositide 3-kinase, a Field in Transition)

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17 pages, 1372 KiB

Open AccessReview

Mouse Models for Exploring the Biological Consequences and Clinical Significance of PIK3CA Mutations

by Camilla B. Mitchell and Wayne A. Phillips

Biomolecules 2019, 9(4), 158; https://doi.org/10.3390/biom9040158 - 23 Apr 2019

Cited by 15 | Viewed by 5163

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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11 pages, 674 KiB

Open AccessReview

The PTEN–PI3K Axis in Cancer

by Antonella Papa and Pier Paolo Pandolfi

Biomolecules 2019, 9(4), 153; https://doi.org/10.3390/biom9040153 - 17 Apr 2019

Cited by 235 | Viewed by 11714

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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14 pages, 2343 KiB

Open AccessReview

Class II PI3Ks at the Intersection between Signal Transduction and Membrane Trafficking

by Jean Piero Margaria, Edoardo Ratto, Luca Gozzelino, Huayi Li and Emilio Hirsch

Biomolecules 2019, 9(3), 104; https://doi.org/10.3390/biom9030104 - 15 Mar 2019

Cited by 43 | Viewed by 6901

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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35 pages, 8296 KiB

Open AccessEditor’s ChoiceReview

Structural Determinants of Isoform Selectivity in PI3K Inhibitors

by Michelle S. Miller, Philip E. Thompson and Sandra B. Gabelli

Biomolecules 2019, 9(3), 82; https://doi.org/10.3390/biom9030082 - 26 Feb 2019

Cited by 67 | Viewed by 10172

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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14 pages, 1730 KiB

Open AccessReview

Getting the Akt Together: Guiding Intracellular Akt Activity by PI3K

by Ivan Yudushkin

Biomolecules 2019, 9(2), 67; https://doi.org/10.3390/biom9020067 - 16 Feb 2019

Cited by 67 | Viewed by 9247

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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17 pages, 4868 KiB

Open AccessReview

Impact of p85α Alterations in Cancer

by Jeremy D. S. Marshall, Dielle E. Whitecross, Paul Mellor and Deborah H. Anderson

Biomolecules 2019, 9(1), 29; https://doi.org/10.3390/biom9010029 - 15 Jan 2019

Cited by 23 | Viewed by 5171

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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