Abstract
This chapter is an introduction to phosphoinositide 3-kinases (PI3K), with class I PI3Ks as the central focus. First, the various PI3K isoforms in class I are presented with emphasis on their overall structure, subunits, subunit constitutive domains, domain-domain interactions, and functional relevance. This structural analysis is followed by a comprehensive history of seminal investigations into PI3K activity. Next, we highlight the divergent roles of the isoforms: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. This section details signaling pathways in which these PI3K isoforms are involved, including the key upstream regulators of PI3K activity and some downstream cellular effects. Nodes of the PI3K pathway are also presented. Inhibitors of some isoforms are discussed to give an overview of the basis of some immunotherapies that are being used to target cell signaling. Finally, the chapter ends with a discussion of the dysregulation of PI3Ks in diseases including APDS, asthma, arthritis, and oncogenic mutations.
T. Y. Aytenfisu, H. M. Campbell, M. Chakrabarti: These authors contributed equally.
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Notes
- 1.
Some papers refer to phosphoinositide-3-kinases as phosphoinositol-3-kinases or PtdIns-3-Kinases.
Abbreviations
- ATP:
-
Adenosine triphosphate
- APDS:
-
Activated phosphoinositide 3-kinase δ syndrome
- APDS1:
-
Activated phosphoinositide 3-kinase δ syndrome type 1
- APDS2:
-
Activated phosphoinositide 3-kinase δ syndrome type 2
- ABD:
-
Adaptor-binding domain
- BCAP:
-
B-cell associated protein
- BCR:
-
B-cell receptor
- BLASTp:
-
Basic local alignment search tool for proteins
- cSH2:
-
C-terminal Src homology 2
- DNA:
-
Deoxyribonucleic acid
- DAG:
-
Diacylglycerol
- EGFR:
-
EGF receptor
- EGF:
-
Epidermal growth factor
- FYVE:
-
Fab1, YOTB, Vac1, and EEA1 (the abbreviation from the first four proteins in which the domain was discovered)
- FcRs:
-
Fc receptors
- GPCRs:
-
G-protein coupled receptors
- PIK3CA/B/D/G:
-
Genes encoding p110α/β/δ/γ
- GSV:
-
GLUT4 storage vesicles
- GMPPNP:
-
Guanosine 5ʹ-[beta,gamma-imido]triphosphate
- GLUT-4:
-
Glucose transporter type 4
- GSK-3:
-
Glycogen synthase kinase 3
- GS:
-
Glycogen synthase
- HDX:
-
Hydrogen-deuterium exchange
- HD:
-
Helical domain
- HDX-MS:
-
Hydrogen-deuterium exchange mass spectroscopy
- IGF1R:
-
IGF-1 receptor
- ITAM:
-
Immunoreceptor tyrosine-based activation motif
- ICOS:
-
Inducible T-cell co-stimulator
- IP3:
-
Inositol 1,4,5-trisphosphate
- IRS:
-
Insulin receptor substrate
- IR:
-
Insulin receptor
- IGF-1:
-
Insulin-like growth factor 1
- IGF-IR:
-
Insulin-like growth factor 1 receptor
- IGFs:
-
Insulin-like growth factors
- iSH2:
-
Inter-SH2
- IFN-α:
-
Interferon-α
- IL2:
-
Interleukin-2
- IL2R:
-
Interleukin-2 receptor
- IL4:
-
Interleukin-4
- IL4R:
-
Interleukin-4 receptor
- kDa:
-
Kilodalton
- KD:
-
Kinase domain
- mABs:
-
Monoclonal antibodies
- NGF:
-
Nerve growth factor
- nSH2:
-
N-terminal Src homology 2
- PDK1:
-
Pyruvate dehydrogenase lipoamide kinase isozyme 1
- PDB:
-
Protein data bank
- PTEN:
-
Phosphatase and tensin homolog
- PtdIns:
-
Phosphatidylinositol
- PIP3:
-
Phosphatidylinositol-3,4,5-trisphosphate
- PIP2:
-
Phosphatidylinositol-4,5-bisphosphate
- PI3Ks:
-
Phosphoinositide 3-kinases
- pYXXM:
-
Phosphorylated YXXM motif
- PDGF:
-
Platelet-derived growth factor
- PH:
-
Pleckstrin-homology
- PDK1:
-
PtdIns-3,4,5-P3-dependent protein kinase-1
- PI-3,4-P2:
-
PtdIns-3,4-bisphosphate
- PI3P:
-
PtdIns-3-phosphate
- PI4P:
-
PtdIns-4-phosphate
- GAP:
-
Rab GTPase activating protein
- RGC:
-
Ral-GTPase activating protein heterodimeric complex
- RBD:
-
Ras-binding domain
- ROS:
-
Reactive oxygen species
- RTK:
-
Receptor tyrosine kinase
- mTOR:
-
Mechanistic target of rapamycin
- RSV:
-
Rous sarcoma virus
- SDS-PAGE:
-
Sodium dodecyl sulfate polyacrylamide gel electrophoresis
- SH2:
-
Src homology 2
- SH3:
-
Src homology 3
- TLRs:
-
Toll-like
- VEGF:
-
Vascular endothelial growth factor
- WNV:
-
West Nile virus
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Acknowledgements
T.Y.A. is a PURA scholar. H.M.C. is a Sr. Alma Nicholas Science Year experience fellow. This work was partially funded by the financial support of U.S. Department of Defense, DOD CDMRP BC151831 (S.B.G.).
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Aytenfisu, T.Y., Campbell, H.M., Chakrabarti, M., Amzel, L.M., Gabelli, S.B. (2022). Class I PI3K Biology. In: Dominguez-Villar, M. (eds) PI3K and AKT Isoforms in Immunity . Current Topics in Microbiology and Immunology, vol 436. Springer, Cham. https://doi.org/10.1007/978-3-031-06566-8_1
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