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The phosphatidylinositol 3-Kinase–AKT pathway in human cancer

Key Points

  • The phosphatidylinositol 3-kinase (PI3K) pathway regulates various cellular processes, such as proliferation, growth, apoptosis and cytoskeletal rearrangement.

  • PI3Ks are heterodimeric lipid kinases that are composed of a regulatory and catalytic subunit that are encoded by different genes. The genes that encode the regulatory domains are also subject to differential splicing.

  • Class IA PI3Ks are activated by receptor tyrosine kinases, and deregulation of their function has been implicated in several human cancers.

  • One of the main functions of PI3K is to synthesize the second messenger PtdIns(3,4,5)P3 (PIP3) from PtdIns(4,5)P2 (PIP2).

  • AKT — a serine/threonine kinase that has a wide range of substrates — is activated by recruitment to the plasma membrane through direct contact of its pleckstrin-homology (PH) domain with PIP3, and phosphorylation at Thr308 and Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase PDK1, whereas Ser473 is phosphorylated by a molecularly unidentified kinase, often termed PDK2.

  • AKT acts downstream of PI3K to regulate many biological processes, such as proliferation, apoptosis and growth, but other signalling pathways are also known to be regulated by PI3K activity and might be involved in PI3K-mediated tumorigenesis.

  • The available clinical evidence of PI3K-pathway deregulation in various cancers and the identification of downstream kinases that are involved in mediating the effects of PI3K (AKT, mTOR, PDK1 and ILK) provide potential targets for the development of small-molecule therapies.

  • The importance of lipid–protein interaction domains (such as the PH domains of AKT and PDK1) for the activation of PI3K targets provides another potential strategy for developing targeted therapies.

Abstract

One signal that is overactivated in a wide range of tumour types is the production of a phospholipid, phosphatidylinositol (3,4,5) trisphosphate, by phosphatidylinositol 3-kinase (PI3K). This lipid and the protein kinase that is activated by it — AKT — trigger a cascade of responses, from cell growth and proliferation to survival and motility, that drive tumour progression. Small-molecule therapeutics that block PI3K signalling might deal a severe blow to cancer cells by blocking many aspects of the tumour-cell phenotype.

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Figure 1: Minding your Ps: the PtdIns(4,5)P2–PtdIns(3,4,5)P3 cycle.
Figure 2: Model of PI3K activation.
Figure 3: Regulation of AKT activity.
Figure 4: PI3K signalling: the big picture.

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Acknowledgements

We apologize to those authors whose work is not cited owing to space constraints. C.L.S. is a Doris Duke Distinguished Clinical Scientist and receives research support from the National Cancer Institute, Department of Defense, Leukemia and Lymphoma Society and CapCURE.

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DATABASES

Cancer.gov

breast cancer

chronic myelogenous leukaemia

colon cancer

endometrial cancer

gastrointestinal stromal tumours

liver cancer

ovarian cancer

pancreatic cancer

prostate cancer

thyroid cancer

LocusLink

4E-BP1

ABL

AKT

AKT1

AKT2

AKT3

ARAP3

ARF6

ATM

ATR

BAD

BCL-XL

BCR

BIM

caspase-9

CDC42

CTMP

cyclin D1

EGFR

ERBB2

FAK

FAS ligand

FKHR

GSK3β

HIF-1α

IGF1

IκB

IKK

ILK

IRS1

IRS2

KIP1

c-KIT

MAPKs

MDM2

mTOR

NF-κB

p110 catalytic subunit

p53

p65

p85

p85α

PCNA

PDK1

PDK2

PI3K

platelet-derived growth-factor receptor

PREX1

PTEN

RAC1

RAS

RSK

SGK

SHIP1

SHIP2

SRC

TCL1

VAV1

VEGF

WAF1

InterPro

C2 domain

pleckstrin-homology domain

SH2 domain

SH3 domain

Medscape DrugInfo

Gleevec

Herceptin

paclitaxel

Glossary

POLYOMAVIRUS MIDDLE T ANTIGEN

A membrane-bound peptide that is produced during the lytic phase of polyomavirus infections. It helps to drive oncogenic signalling by recruiting a multimolecular signalling complex to the plasma membrane.

SH2 DOMAIN

(SRC homology 2 domain). A protein motif that recognizes and binds tyrosine-phosphorylated sequences, and thereby has a key role in relaying cascades of signal transduction.

INSULIN RECEPTOR SUBSTRATES

Adaptor proteins that bind the activated insulin receptor and recruit downstream signalling molecules.

SH3 DOMAIN

(SRC homology 3 domain). A protein sequence of 50 amino acids that recognizes and binds sequences that are rich in proline.

BCR-HOMOLOGY DOMAIN

(Breakpoint cluster region homology domain). A protein–protein interaction motif that is homologous to a region of the BCR gene, which is the fusion partner for the ABL tyrosine kinase in chronic myeloid leukaemia cells.

COWDEN'S DISEASE

A hereditary predisposition to tumours — especially hamartomas of the skin, mucous membranes, breast and thyroid — that is caused by PTEN mutations.

DOMINANT NEGATIVE

A defective protein that retains interaction capabilities and so distorts or competes with normal proteins.

BCL2 FAMILY

A family of proteins that determine whether or not a cell commits apoptosis by regulating the exit of cytochrome c from mitochondria. The family comprises both pro-apoptotic and anti-apoptotic members.

E3 UBIQUITIN LIGASE

The third enzyme in a series — the first two are designated E1 and E2 — that is responsible for ubiquitylating target proteins. E3 enzymes provide platforms for binding E2 enzymes and specific substrates, thereby coordinating ubiquitylation of the selected substrates.

EPISTASIS

The masking of a phenotype that is caused by a mutation in one gene, by a mutation in another gene. Epistasis analysis can be used to dissect the order in which genes in a genetic pathway act.

KNUDSON'S TWO-HIT MODEL

In 1971, Alfred Knudson proposed that two successive genetic 'hits', one in each allele of a tumour-suppressor gene, are required to turn a normal cell into a tumour cell, and that one hit was inherited in familial cancers, leading to earlier onset of disease.

PHARMACOKINETICS

The study of the time course of a drug and its metabolites in the body after administration by any route.

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Vivanco, I., Sawyers, C. The phosphatidylinositol 3-Kinase–AKT pathway in human cancer. Nat Rev Cancer 2, 489–501 (2002). https://doi.org/10.1038/nrc839

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