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PI3K isoforms in cell signalling and vesicle trafficking

Nature Reviews Molecular Cell Biology volume 20, pages 515–534 (2019)Cite this article

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Abstract

PI3Ks are a family of lipid kinases that phosphorylate intracellular inositol lipids to regulate signalling and intracellular vesicular traffic. Mammals have eight isoforms of PI3K, divided into three classes. The class I PI3Ks generate 3-phosphoinositide lipids, which directly activate signal transduction pathways. In addition to being frequently genetically activated in cancer, similar mutations in class I PI3Ks have now also been found in a human non-malignant overgrowth syndrome and a primary immune disorder that predisposes to lymphoma. The class II and class III PI3Ks are regulators of membrane traffic along the endocytic route, in endosomal recycling and autophagy, with an often indirect effect on cell signalling. Here, we summarize current knowledge of the different PI3K classes and isoforms, focusing on recently uncovered biological functions and the mechanisms by which these kinases are activated. Deeper insight into the PI3K isoforms will undoubtedly continue to contribute to a better understanding of fundamental cell biological processes and, ultimately, of human disease.

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Fig. 1: Substrate specificity and domain organization of the PI3K isoforms and their lipid products.
Fig. 2: Isoform-selective regulation of class I PI3Ks and AKT family members.
Fig. 3: Cell biological functions and activation of class II PI3K isoforms.
Fig. 4: Cell biological functions and activation of VPS34.

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Acknowledgements

Work in the laboratory of B.V. is supported by PTEN Research, Cancer Research UK (C23338/A25722), the UK Biotechnology and Biological Sciences Research Council (BB/I007806/1, BB/M013278/1 and BB/R017972/1) and the UK NIHR University College London Hospitals Biomedical Research Centre. Y.P. has been supported by a long-term EMBO fellowship (ALTF 1227-2014) and an EU Marie Skłodowska-Curie fellowship (656778). The authors thank R. Madsen, M. Graupera and K. Okkenhaug for excellent feedback on the manuscript.

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Nature Reviews Molecular Cell Biology thanks V. Haucke, and other anonymous reviewer(s), for their contribution to the peer review of this work.

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Authors and Affiliations

  1. UCL Cancer Institute, University College London, London, UK

    Benoit Bilanges, York Posor & Bart Vanhaesebroeck

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  1. Benoit Bilanges
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  3. Bart Vanhaesebroeck
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B.B., Y.P. and B.V. contributed equally to writing the article and to the review and editing of the manuscript before submission.

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Correspondence to Benoit Bilanges, York Posor or Bart Vanhaesebroeck.

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B.V. is a consultant for Karus Therapeutics (Oxford, UK), iOnctura (Geneva, Switzerland) and Venthera (Palo Alto, CA, USA) and has received speaker fees from Gilead. The other authors declare no conflict of interest.

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Glossary

Phosphatidylinositol

A phospholipid with myo-inositol as its head group. The 3′-OH, 4′-OH and 5′-OH groups of the inositol ring can be reversibly phosphorylated, resulting in a total of seven lipid species, collectively referred to as phosphoinositides. PI3Ks phosphorylate the 3′ position of the inositol ring.

Autophagy

A cellular ‘self-eating’ process that involves breaking down subcellular components (for example, protein and damaged organelles) through the lysosomal pathway in response to nutrient depletion or stress. It is characterized by membrane trafficking events that sequester cytoplasmic material in double-membrane structures, called autophagosomes, followed by degradation and recycling of cellular components by the lysosome.

Small GTPases

GTP-binding proteins that bind to and hydrolyse GTP to GDP and are mostly active in the GTP-bound state. Most activities in cells are regulated to some extent by small GTPases.

C2 domain

A membrane-binding domain homologous to the C2 domain of protein kinase C with mostly only moderate lipid specificity. Some C2 domains associate with membranes in a Ca2+-dependent manner.

G protein-coupled receptors

Receptors that contain seven transmembrane helices. They activate heterotrimeric G proteins, which, in turn, regulate the function of various proteins.

Early endosomes

Membrane-bound intracellular vesicles marked by RAB5 and EEA1 and high levels of phosphatidylinositol 3-phosphate. Endocytic vesicles fuse with early endosomes and endocytic cargo is sorted for recycling or degradation. Early endosomes then mature into late endosomes.

AKT

A group of Ser/Thr-specific protein kinases, also known as protein kinase B, that are activated by PI3K.

Hormone therapy

Also known as endocrine therapy, this treatment interferes with hormone signalling in hormone receptor-positive cancers, such as some types of breast or prostate cancer.

Insulin receptor substrate proteins

Proteins that bind to the intracellular domains of activated receptors for insulin and cytokines. These adaptor proteins then engage with other downstream signalling molecules.

Neomorphic proteins

Proteins that, as a result of mutation, acquire new functions beyond their normal physiological roles.

Pleckstrin homology (PH) domains

Sequences of approximately 100 amino acids that can mediate specific binding to phosphoinositide lipids and are present in many signalling molecules. Only a minority of PH domains actually bind lipids, with the PH representing a conserved structural fold in proteins without necessarily a specific biological function.

GTPase-activating proteins

(GAPs). Proteins that inactivate small GTP-binding proteins, such as RAS and RHEB family members, by increasing their rate of GTP hydrolysis.

Guanine nucleotide exchange factors

Proteins that facilitate the exchange of GDP for GTP in the nucleotide-binding pocket of GTP-binding proteins.

PDK1

A Ser/Thr-specific protein kinase. It is a master kinase that is involved in the activation of many other Ser/Thr kinases belonging to the cAMP-dependent, cGMP-dependent protein kinase C (AGC) family of protein kinases, which includes AKT, protein kinase C and S6 kinase. It is now clear that the activation of PDK1 is not dependent on phosphoinositides, as its name would imply.

mTOR complex 2

(mTORC2). A multiprotein complex consisting of mTOR, rapamycin-insensitive companion of mTOR (Rictor), mammalian stress-activated protein kinase interacting protein 1 (mSIN1), protein observed with Rictor 1 (Protor 1), mammalian lethal with SEC13 protein 8 (mLST8) and DEP domain-containing mTOR-interacting protein (DEPTOR). mTORC2 is insensitive to short-term treatment with rapamycin. This complex phosphorylates AKT on Ser473 in its hydrophobic motif.

Forkhead box protein O

(FOXO). A transcription factor family characterized by a winged-helix DNA-binding motif and the forkhead domain. The mammalian FOXO family has four members: FOXO1, FOXO3, FOXO4 and FOXO6. They are involved in a wide range of cellular processes, such as metabolism, cell cycle arrest, stress resistance and apoptosis.

mTOR complex 1

(mTORC1). This complex controls metabolic processes in response to environmental cues, including nutrient and growth factor availability as well as stress. mTORC1 is a multiprotein complex consisting of mTOR, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (mLST8; also known as GβL) and the negative regulators proline-rich AKT substrate of 40 kDa (PRAS40) and DEP domain-containing mTOR-interacting protein (DEPTOR) and is sensitive to rapamycin.

Clathrin-mediated endocytosis

The internalization of plasma membrane and receptors present therein into small vesicles that is mediated by a protein coat containing clathrin, adaptors and accessory proteins.

FYVE domain

A phosphatidylinositol 3-phosphate-binding domain of approximately 60–65 amino acids that is named after the four Cys-rich proteins — FAB1, YOTB (also known as ZK632.12), VAC1 and EEA1 — in which it has been found.

Paclitaxel

An anticancer agent that acts by stabilizing microtubules through binding to tubulin.

Regulatory T cells

A subset of T lymphocytes that are involved in the suppression of immune responses.

Nurse-like cells

A specialized subset of tumour-associated macrophages that regulate leukaemic cell functions.

Phox homology (PX) domain

A domain mediating lipid and protein interactions that consists of 100–130 amino acids and is defined by sequences that are found in two components of the phagocyte NADPH oxidase (phox) complex.

Late endosomes

Membrane-bound compartments late on the endocytic route just before fusion with the lysosome. Late endosomes are marked by RAB7 and other proteins also present on lysosomes, such as lysosome-associated membrane glycoproteins.

Kinetochore fibres

Bundles of spindle microtubules that attach to the kinetochore, a protein complex at the centromere of each chromosome.

Endosomal sorting and recycling

A process in which endocytosed cargo proteins are sorted in early endosomes for degradation in lysosomes, recycling to the plasma membrane or retrograde trafficking to the trans-Golgi network.

Haemocytes

The circulating blood cells that form the innate immune system in insects.

BAR domain

A membrane-curvature-inducing and membrane-curvature-sensing protein domain.

Dynamin

A large mechanochemical GTPase that assembles into a helical oligomer on highly curved membranes. GTP hydrolysis by dynamin is coupled to conformational changes that catalyse constriction and eventually fission of the underlying tubular membrane.

Sonic hedgehog

A key morphogen, that is, a secreted signalling molecule that acts along a local concentration gradient, which is crucial during vertebrate embryonic development.

Primary cilia

Solitary elongated protrusions of the plasma membrane supported by a microtubule-based axoneme of nine doublet microtubules anchored at the centriole. Primary cilia serve as sensory structures and specialized signalling platforms that are of particular importance in development.

RAB11

A small GTPase required for multiple steps during endocytic recycling, including the formation of vesicles travelling to and from the endocytic recycling compartment.

APPL1

An effector of the small GTPase RAB5 that operates as a scaffolding protein on endosomes, interacting with numerous signalling molecules, including receptor tyrosine kinases and AKT.

Thrombus

A blood clot formed in a blood vessel.

Phospholipase D1

A phosphodiesterase that hydrolyses phosphatidylcholine and other glycerophospholipids to generate phosphatidic acid and the free head group of the substrate lipid.

X-linked centronuclear myopathy

(XLCNM). Also called myotubular myopathy, a severe paediatric neuromuscular disorder causing muscle weakness.

Phagocytosis

A largely actin-driven form of endocytosis that serves to ingest large particles, such as cellular debris or whole microorganisms.

Macropinocytosis

An evolutionarily conserved endocytic pathway that allows internalization of extracellular fluid via large endocytic vesicles called macropinosomes.

Phagophore

Also called isolation membrane, a double-membrane cup-shaped structure that engulfs cytoplasmic material during autophagy. It is the precursor of the autophagosome.

BARA domain

β-α-Repeated, autophagy-specific domain.

BATS domain

Barkor/ATG14 autophagosome targeting domain, which binds to the autophagosome membrane via the hydrophobic surface of an intrinsic amphipathic α-helix.

Amphipathic helix

α-Helical sequence in which polar and charged amino acids are oriented to one side and hydrophobic ones are oriented to the other side. The lipophilic side dips into bent membranes displaying packing defects in the outer leaflet, thereby providing a means of sensing membrane curvature.

Autophagy cargo receptors

Receptors or adaptors that can recognize material or cargo destined for autophagic degradation and bind to a component of the forming autophagosomes.

LC3-associated phagocytosis-engaged phagosomes

Also known as LAPosomes, they are dead-cell-containing phagosomes that recruit the autophagy machinery and ultimately become LC3-associated phagosomes.

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Bilanges, B., Posor, Y. & Vanhaesebroeck, B. PI3K isoforms in cell signalling and vesicle trafficking. Nat Rev Mol Cell Biol 20, 515–534 (2019). https://doi.org/10.1038/s41580-019-0129-z

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