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The emerging mechanisms of isoform-specific PI3K signalling

Nature Reviews Molecular Cell Biology volume 11, pages 329–341 (2010)Cite this article

Subjects

Key Points

  • Phosphoinositide 3-kinases (PI3Ks) generate lipid second messengers inside cells, which control many biological functions. PI3K signalling is important in immune signalling, and deregulated PI3K has been implicated in most forms of cancer. Many companies are developing PI3K inhibitors for intervention in human disease and PI3K drugs have recently entered clinical trials in oncology.

  • There are eight isoforms of PI3K, which have been grouped into three classes: class I, class II and class III. The distinct classes of PI3K generate different lipids in cells and control different aspects of cell biology.

  • Class I PI3Ks are stimulated by Tyr kinases, G protein-coupled receptors and Ras, and are the main PI3K isoforms currently pursued in drug development, especially in cancer and inflammation. Mammals have four class I PI3K isoforms, which have non-redundant roles in untransformed cells. Their roles in cancer are less clear, although PIK3CA, which encodes p110α, one of the class I PI3K isoforms, is the only PI3K gene found to be mutated in cancer, often at high frequency. It is not clear why this is the case.

  • The signalling and biological roles of the class II PI3Ks are unclear.

  • There is a single class III PI3K isoform, which mainly controls the trafficking of intracellular vesicles in the context of autophagy, endocytosis and phagocytosis. The class III PI3K might also be involved in signal transduction, but this is not yet clear.

  • An important aspect of drug development is to know what functions PI3K isoforms have in normal physiology and in the diseased state. One line of thought is to use isoform-selective inhibitors for pharmacological intervention, the rationale being that this will have fewer side effects in the patient.

Abstract

Phosphoinositide 3-kinases (PI3Ks) function early in intracellular signal transduction pathways and affect many biological functions. A further level of complexity derives from the existence of eight PI3K isoforms, which are divided into class I, class II and class III PI3Ks. PI3K signalling has been implicated in metabolic control, immunity, angiogenesis and cardiovascular homeostasis, and is one of the most frequently deregulated pathways in cancer. PI3K inhibitors have recently entered clinical trials in oncology. A better understanding of how the different PI3K isoforms are regulated and control signalling could uncover their roles in pathology and reveal in which disease contexts their blockade could be most beneficial.

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Figure 1: The 3-phosphoinositide lipid network.
Figure 2: Classification and domain structure of mammalian PI3Ks.
Figure 3: Upstream signals feeding into class I PI3Ks.
Figure 4: Vps34–Vps15 complexes in yeast and mammals.
Figure 5: Subcellular localization, activation and function of VPS34 in mammalian cells.

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Acknowledgements

We thank our colleagues and collaborators for critically reading the manuscript, in particular J. Backer, Albert Einstein College of Medicine, New York. Research in the B.V. Laboratory is supported by Cancer Research UK, the Medical Research Council, the Ludwig Institute for Cancer Research and Queen Mary University of London. Personal support for J.G. was by a European Union Marie Curie fellowship (MEIF-CT-2006-039,676). We apologize to the many authors whose primary papers could not be cited owing to space constraints.

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  1. Centre for Cell Signalling, Institute of Cancer, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK

    Bart Vanhaesebroeck, Julie Guillermet-Guibert, Mariona Graupera & Benoit Bilanges

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Bart Vanhaesebroeck is an advisor to Intellikine (San Diego, USA) and Karus Therapeutics (Southampton, UK).

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COSMIC

Glossary

Pleckstrin homology (PH) domain

A sequence of approximately 100 amino acids that is present in many signalling molecules. A minority of PH domains bind PtdIns lipids.

Phox homology (PX) domain

A lipid- and protein-interaction domain 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.

FYVE domain

A PtdIns3P-binding domain of ∼ 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.

G protein-coupled receptor

A transmembrane receptor that contains seven membrane-spanning helical domains and functions as a ligand-dependent GEF that activates heterotrimeric G proteins to interact with other signalling proteins.

BCR homology (BH) domain

(Breakpoint cluster region-homology (BH) domain). A 200-residue region that has GAP activity for small GTPases. It is debated whether or not this domain is functional in the p85 regulatory subunits of PI3K.

GAP

A protein that inactivates small GTP-binding proteins, such as Ras family members, by increasing their rate of GTP hydrolysis.

Clathrin-coated vesicle

A small vesicle containing a protein (clathrin) that forms and reorganizes a coat on the cytoplasmic face of a membrane and facilitates endocytosis of receptors.

Early endosome

A membrane-bound intracellular vesicle that is characterized by specific markers such as RAB5 and by high levels of PtdIns3P. Early endosomes are involved in the first steps of endocytosis and mature to form late endosomes.

GEF

A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein.

Heterotrimeric G proteins

Guanine nucleotide-binding proteins composed of three subunits: Gα, Gβ and Gγ. Gα cycles between an inactive GDP-bound conformation and an active GTP-bound conformation, which is released from its Gβγ partners. Both Gα and Gβγ can then modulate the activity of downstream effector proteins.

Myristoylated

A protein modification whereby a hydrophobic myristoyl group is covalently attached to the N-terminal Gly residue of a nascent polypeptide.

Autophagy

A lysosomal pathway of cellular 'self-digestion' that occurs under cellular 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.

Phagocytosis

A form of endocytosis to ingest large particles, such as cellular debris or whole microorganisms.

Endosomal trafficking

The trafficking of vesicles, called endosomes, from the plasma membrane through endosomal compartments to terminate in the lysosome.

Late endosome

A membrane-bound intracellular vesicle characterized by specific markers such as RAB7. Late endosomes are involved in the later steps of endocytosis, just before fusion with the lysosome.

Multivesicular body

An intracellular compartment containing multiple intraluminal vesicles. Multivesicular bodies fuse with endosomes, lysosomes and sometimes the plasma membrane.

WD repeat

A repeat of 40 amino acids with a characteristic central Trp–Asp motif that is thought to form a circular β-propeller structure, which acts as a platform for the stable association of protein binding partners.

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Vanhaesebroeck, B., Guillermet-Guibert, J., Graupera, M. et al. The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol 11, 329–341 (2010). https://doi.org/10.1038/nrm2882

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