PI3K and AKT Isoforms in Immunity: Mechanisms and Therapeutic Opportunities

Contents
Abbreviations
Introduction to PI3K
Class I PI3K Biology
	1 Class I PI3Ks at a Glance
	2 Structural Analysis of Class I PI3Ks
	3 Historical Overview
		3.1 Early Discoveries in Receptor Tyrosine Kinase and Phosphoinositide Signaling
		3.2 Phosphoinositide Kinases: Toward a Molecular Understanding of PI3K Activity
	4 Phosphoinositide 3-Kinase Signaling
		4.1 Class I PI3K Signaling Downstream of RTKs
	5 Divergent Roles of Class I Isoforms
		5.1 PI3Kα
		5.2 PI3Kβ
		5.3 PI3Kδ
		5.4 PI3Kγ
	6 From Molecular Determinants to Frequency of Signal and Reaction Rates
	References
An Overview of Class II Phosphoinositide 3-Kinases
	1 Introduction
	2 Identification and Tissue Distribution
	3 Structure of Class II PI3Ks
	4 Lipid Products
		4.1 PtdIns3P
		4.2 PtdIns(3,4)P2
	5 Mechanisms of Activation
	6 Physiological Roles of Class II PI3Ks—Insights from Animal Models
		6.1 PI3K-C2α
		6.2 PI3K-C2β
		6.3 PI3K-C2γ
	7 Physiological Roles of Class II PI3Ks—First Insight from Human Studies
	8 Cellular Functions Regulated by Class II PI3Ks
		8.1 PI3K-C2α
		8.2 PI3K-C2β
		8.3 PI3K-C2γ
		8.4 Co-operative Roles?
	9 Class II PI3Ks, Immune Cells and Inflammatory Responses
	10 Conclusion
	References
Class III PI3K Biology
	1 Vps34 Structure and Complexes
	2 Vps34 Activity and Regulation
	3 Site of Actions and Cellular Roles of Vps34
	4 Organismal Functions of Vps34
	5 Vps34 in Human Diseases
	6 Conclusions
	References
PTEN in Immunity
	1 Introduction
	2 The Lipid and Protein Phosphatase PTEN: Many Functions, One Role
	3 PTEN Regulates Immune Cell Development and Function
		3.1 Germline PTEN Inactivation in Mice and Humans
		3.2 Conditional Pten Deletion in Murine Models
		3.3 Lymphocyte-Specific Pten Deletion
		3.4 Pten Loss in Myeloid Cells
		3.5 Pten Loss in HSC
	4 PTEN Loss and Resistance to Immunotherapies
	5 PTEN and Viral Infections
	6 Conclusions
	References
PHLPP Signaling in Immune Cells
	1 Introduction
		1.1 PHLPP Phosphatases: Structure and Function
		1.2 PHLPP Substrates
		1.3 PHLPP Relevance in Disease
	2 Role of PHLPP in Innate Immunity
		2.1 Transcriptional Regulation of PHLPP During Inflammation
		2.2 PHLPP Regulation of TLR4- and IFN-γ-Mediated Signaling
		2.3 PHLPP Regulation of the Immune Response upon Bacterial Infection
	3 Role of PHLPP in Adaptive Immunity
		3.1 PHLPP Signaling in CD4+ T Cells and Regulatory T Cells
		3.2 PHLPP Signaling in B Cells and Chronic Lymphocytic Leukemia
	4 Role of PHLPP in Inflammatory Bowel Disease and Colorectal Cancer
	5 Concluding Remarks
	References
PI3K and AKT Isoforms in Immune Cells
PI3K Isoforms in Cell Signalling and Innate Immune Cell Responses
	1 Introduction
	2 The General Role of PI3K in Neutrophil-Mediated Inflammation
	3 The Role of PI3K in Neutrophil Activation and Function
	4 The Role of PI3K in Neutrophil Migration
	5 Role of PI3Ks in the Maintenance of Neutrophil Survival
	6 The Role of PI3K in Other Innate Immune Cells
	7 Conclusion
	References
AKT Isoforms in Macrophage Activation, Polarization, and Survival
	1 Introduction
	2 AKT Isoforms: Structural and Functional Similarities and Differences
	3 The Role of AKT in TLR and Cytokine Signaling
		3.1 TLR-Induced AKT Activation and Downstream Functions
		3.2 Cytokine-Induced AKT Signaling
		3.3 AKT Isoform-Specific Signaling Downstream of TLRs
	4 Contribution of AKT Kinases to Macrophage Polarization
	5 Role of AKT Kinases in Metabolic and Epigenetic Regulation of Macrophage Activation
	6 Contribution of AKT Kinases to Macrophage Survival and Apoptosis
		6.1 AKT Isoforms in Macrophage Survival
		6.2 PI3K/AKT Regulates Macrophage Survival Through Bcl-2 Family Proteins
		6.3 AKT Promotes Macrophage Survival Through NFκB and mTORC2
		6.4 P38 MAPK and JNK Affect Macrophage Survival Through AKT Signaling
		6.5 MiRs Regulate AKT-Mediated Macrophage Apoptosis
	7 Conclusions
	References
Control of CD4+ T Cell Differentiation and Function by PI3K Isoforms
	1 Introduction
	2 Lessons Learned from Patients with Immunodeficiencies Due to Mutations on PI3K Subunits
	3 T Cell Activation, Proliferation, and Survival
	4 T Helper (Th) Cell Generation and Maintenance
		4.1 Th1 Cells
		4.2 Th2 Cells
		4.3 Th9 Cells
		4.4 Th17 Cells
	5 Conclusion
	References
PI3K Isoforms in CD8+ T Cell Development and Function
	1 Activation of PI3K in CD8+ T Cells
	2 Role of PI3K Pathway in CD8+ T Cells
		2.1 CD8+ T Cell Migration
		2.2 Role of PI3K in CD8+ T Cell Development, Survival, and Proliferation
		2.3 CD8+ T Cell Activation, Differentiation, and Memory
		2.4 Effect of PI3K Downstream Signaling on the Regulation of CD8+ T Cell Memory
	3 PI3K Pathway and Lessons from Clinical Trials
	4 Perspectives
	References
PI3K Isoforms in B Cells
	1 Introduction
	2 Class I PI3K
		2.1 Class IA PI3K
		2.2 Class IB PI3K
	3 Class II PI3K
	4 Class III PI3K
	5 Conclusion
	References
PI3K Isoform Signalling in Platelets
	1 Platelet Structure
	2 The Role of Platelets in Haemostasis and Beyond
	3 Signalling in Platelets
		3.1 Platelet Signalling During Primary Haemostasis
		3.2 Platelet Signalling During Platelet-Leukocyte Interplay
	4 PI3K Isoforms in Platelets
		4.1 Class I
		4.2 Class II
		4.3 Class III
		4.4 PI3K Antagonists in Platelets
	5 PI3K Inhibitors and Platelets in Clinical Practice
	References
PI3K and AKT Isoforms in Immune-Mediated Diseases
PI3K Isoforms in Vascular Biology, A Focus on the Vascular System-Immune Response Connection
	1 Introduction
	2 PI3Ks and Vascular Biology
		2.1 PI3Ks and Endothelial Cell Functions
		2.2 PI3Ks and Smooth Muscle Cell Functions
	3 PI3Ks and the Vascular-Immune Connection
	4 Conclusions
	References
PI3K and AKT at the Interface of Signaling and Metabolism
	1 Introduction
	2 PI3K/AKT Signaling Mediates Insulin Action in Metabolic Homeostasis
		2.1 Insulin Integrates Glucose and Lipid Homeostasis
		2.2 PI3K/AKT Signaling is Essential for Insulin Action in Metabolism
		2.3 PI3K/AKT Signaling Controls Pancreatic β-Cell Mass and Function
	3 The Role of Insulin/PI3K/AKT Signaling in PI3K Targeted Therapies
		3.1 Iatrogenic Diabetes Dampens the Efficacy of Pan-PI3K Inhibition
		3.2 Specificities and Redundancies of Class I PI3Ks in Cell Signaling
	4 PI3K/AKT Signaling Drives Anabolic Metabolism and Cell Growth
	5 Insulin and PI3K/AKT Signaling Promote Obesity
	6 PI3K/AKT Signaling in Neurons Controls Metabolic Homeostasis
	7 Role of Specific Catalytic PI3K Subunits in Insulin Signaling and Obesity
		7.1 PI3Kα is a Major but not the Only Mediator of Insulin action in Metabolism
		7.2 PI3Kβ Activity Plays an Important Role in Growth and Metabolism
		7.3 Insulin Signaling in the Hepatocyte and Hepatic Glucose Production Depend on Redundant PI3Kα and PI3Kβ Activities
		7.4 PI3Kδ Promotes Lymphocyte-Driven Inflammation in Obesity
		7.5 PI3Kγ Promotes Adiposity, Metabolic Inflammation, and Insulin Resistance
	8 Closing Remarks
	References
The Role of PI3K Isoforms in Autoimmune Disease
	1 Introduction
	2 Rheumatoid Arthritis
	3 Systemic Lupus Erythematous
	4 Multiple Sclerosis
	5 Type 1 Diabetes
	6 Concluding Remarks
	References
AKT Isoforms in the Immune Response in Cancer
	1 Introduction
	2 AKT Structure and Regulation
	3 The Role of AKT in Immune Cells
	4 AKT1
	5 AKT2
	6 AKT3
	7 AKT Modulation in Oncotherapy
	References
PI3K Isoform Inhibitors in the Clinic
PI3K Isoform Immunotherapy for Solid Tumours
	1 Introduction
	2 Immune Mechanisms of Action in Preclinical Studies
		2.1 PI3Kδ Inhibitors as a Treg Targeted Therapy
		2.2 PI3Kδ Inhibitors as an Adjuvant to Improve T Cell Therapy in Cancer
		2.3 Inhibition of Myeloid Populations Within the Tumour Microenvironment via Specific PI3K Isoform Inhibitors
	3 Clinical Trials and Human Studies
		3.1 PI3Kδ Inhibitor: Idelalisib
		3.2 PI3Kδ Inhibitor: Parsaclisib
		3.3 Novel PI3Kδ Inhibitors
		3.4 PI3Kγ Inhibitor: IPI-549
		3.5 Dual PI3Kδ/γ Inhibitor: Duvelisib
	4 Future Perspectives
	References
PI3K Targeting in Non-solid Cancer
	1 Cell Adhesion-Mediated Drug Resistance Triggers PI3K/AKT Signaling in Leukemia
	2 The Significance of the PI3K/AKT Pathway in Leukemic Cell
		2.1 Regulation of PI3K/AKT Signaling in Leukemia
	3 Isoforms of PI3K
		3.1 PI3K Mutations in Leukemia
	4 Preclinical Inhibition of PI3K and PI3Kδ in ALL
	5 PI3K Inhibitors in Clinical Trial in ALL
	6 PI3K Targeting Drugs in Clinical Trials
	7 Discussion
	References
AKT Isoforms as a Target in Cancer and Immunotherapy
	1 PI3K/AKT/mTOR Signaling in Cancer
	2 AKT as Prognostic Marker in Cancer
	3 Inhibitors of AKT
		3.1 ATP Competitive AKT1/2/3 Inhibitors
		3.2 Allosteric AKT1/2/3 Inhibitors
		3.3 AKT1 Specific Inhibitors
		3.4 AKT2 Specific Inhibitors
		3.5 AKT1/2 Specific Inhibitors
		3.6 AKT3 Specific Inhibitors
		3.7 Adverse Events Following AKT Inhibition
	4 Immune Evasion
		4.1 AKT Involvement in the Efficacy of Immune Checkpoint Inhibitors
	5 Conclusions
	References
Developing PI3K Inhibitors for Respiratory Diseases
	1 Introduction
	2 PI3K and Bronchial Asthma
		2.1 Background
		2.2 Are the Expression and Functional Profile of PI3K Relevant to the Pathogenesis of Bronchial Asthma?
		2.3 Are PI3K Inhibitors Safe and Clinically Relevant in Allergic Bronchial Asthma?
		2.4 Closing Remarks
	3 PI3K and Chronic Obstructive Pulmonary Disease (COPD)
		3.1 Background
		3.2 Are the Expression and Functional Profile of PI3K Relevant to the Pathogenesis of COPD?
		3.3 Are PI3K Inhibitors Safe and Clinically Relevant in COPD?
		3.4 Closing Remarks
	4 PI3K and Idiopathic Pulmonary Fibrosis
		4.1 Background
		4.2 Are the Expression and Functional Profile of PI3K Relevant to the Pathogenesis of IPF?
		4.3 Are PI3K Inhibitors Safe and Clinically Relevant in IPF?
		4.4 Closing Remarks
	5 PI3K and Lung Cancer
		5.1 Background
		5.2 Are PI3K Inhibitors Safe and Clinically Relevant in Lung Cancer?
		5.3 Closing Remarks
	6 PI3K and ARDS
		6.1 Background
		6.2 Are the Expression and Functional Profile of PI3K Relevant to the Pathogenesis of ARDS?
		6.3 Are PI3K Inhibitors Safe and Clinically Relevant in ARDS?
		6.4 Closing Remarks
	7 General Conclusions
	References