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  • Review Article
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PKB/AKT: functional insights from genetic models

Nature Reviews Molecular Cell Biology volume 2, pages 760–768 (2001)Cite this article

Key Points

  • Since its discovery 10 years ago, studies have shown that PKB, also known as AKT, is an important enzyme in mediating the pro-survival signals of PI3K.

  • Activation of PKB/AKT is complex and tightly controlled by the activities of upstream protein kinases such as PDK1, which targets the T-loop in the protein. A hypothesized kinase, called PDK2, has also been implicated in PKB/AKT activation. Candidates for this kinase include MAPK-activated protein kinase 2 (MAPKAP-K2), Rsk (MAPKAP-K1) and integrin-linked kinase (ILK).

  • Identifying PKB/AKT substrates has been fundamental to understanding how the kinase impacts on insulin signalling, cell growth and apoptosis. PKB/AKT has been found to interact with factors, including the Forkhead family of transcription factors and GSK3, which indicates PKB/AKT might have several inputs into the control of the cell cycle.

  • PKB/AKT activation cooperates with other genes in promoting cancer and inflammation. PTEN is a tumour suppressor that acts to inactivate PKB/AKT, as well as other PI3K-activated targets. Small molecule drugs that inhibit PKB/AKT may have therapeutic potential in cancer treatment.

  • A relative of PKB/AKT, termed SGK/CISK, might cooperate with PKB in overlapping or distinct physiological functions. The difficulty will be to resolve the true functions of PKB/AKT and those of SGK/CISK, as it could be that SGK/CISK is responsible for some of the functions originally attributed to PKB/AKT.

Abstract

Since its discovery 10 years ago, the potential functions of protein kinase B (PKB)/AKT have been catalogued with increasing efficiency. The physiological relevance of some of the proposed mechanisms by which PKB/AKT mediates many of its effects has been questioned, and recent work using new reagents and approaches has revealed some cracks in our understanding of this important molecule, and also hinted that these effects may involve other players.

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Figure 1: Activation of PKB/AKT and its targets.
Figure 2: Sequence alignment and structural topology of human PKBα, β and γ (AKT1, 2 and 3), human SGK1 and SGK3, and mouse CISK.
Figure 3: Two models for PKB/AKT activation.
Figure 4: Putative PKB/AKT substrates.
Figure 5: ATP binding site similarity among PKB/AKT isoforms.

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Acknowledgements

M. P. Scheid is supported by a Canadian Institute for Health Research fellowship. J. R.Woodgett is supported by grants from the National Cancer Institute, Canadian Institute for Health Research, and an International Scholarship from the Howard Hughes Medical Institute. We thank Armen Manoukian for the Drosophila genetics figure.

Author information

Authors and Affiliations

  1. Ontario Cancer Institute, 610 University Avenue, Toronto, M5G 2M9, Ontario, Canada

    Michael P. Scheid & James R. Woodgett

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  1. Michael P. Scheid
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Correspondence to James R. Woodgett.

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DATABASES

LocusLink:

AFX

BRCA1

CDK2

CDK4

cyclin D1

FKHRL1

eNOS

ILK

MAPKAP-K2

mTOR

p21Cip1

p27Kip1

PDK1

PKB/AKT

PTEN

SGK

v-AKT

 SGD:

Ykr2

Ypk1

 Swiss-Prot:

PH domain

SH2

SH3

FURTHER INFORMATION

Scansite

James Woodgett's lab

Glossary

PLECKSTRIN HOMOLOGY DOMAIN

Pleckstrin is a protein of unknown function originally identified in platelets. It is a principal substrate of protein kinase C. Pleckstrin-homology domains are sequences of about 100 amino acids that are present in many signalling molecules.

METAZOANS

Refers to the kingdom Animalia (animals) that consists of roughly 35 phyla of multicellular organisms.

AGC CLASS OF PROTEIN KINASES

A broad family of sequence-related serine/threonine kinases (there are nine subgroups) that includes cAMP-dependent and cGMP-dependent protein kinases, and protein kinase C.

T-LOOP

A short peptide loop that is present in protein kinases located between subdomains VII and VIII, the conformation of which might be altered by phosphorylation to increase or decrease catalytic activity.

ACTIVATION LOOP

See T-loop.

PHOSPHOSPECIFIC ANTIBODY

An antibody that binds only the phosphorylated form of a protein or peptide.

CONSENSUS SITE

A common amino-acid sequence preference that surrounds a phosphoacceptor site, which typifies the specificity of a given protein kinase.

DEGENERATE PEPTIDE PHOSPHORYLATION SCREENS

A method whereby a library of randomly generated peptides are phosphorylated by a kinase and sorted to determine the optimal consensus site.

PHOSPHOACCEPTOR

A serine, threonine or tyrosine residue that can be modified by phosphorylation.

GERM LINE

The cell lineage that contributes to the formation of gametes.

MYRISTOYLATION

A covalent attachment of a hydrophobic myristoyl group to the amino-terminal glycine residue of a nascent polypeptide.

ECTOPIC APOPTOSIS

An unscheduled induction of programmed cell death in cells that are not normally fated to die.

TRANSHETEROZYGOUS SCREEN

A genetic cross between a strain that has only one copy of a particular gene and a library of mutants with a phenotype that is being observed only when library mutants are on the same pathway as the gene of interest.

HAPLO-INSUFFICIENT

A phenotype that arises in diploid organisms owing to the loss of one functional copy of a gene.

MASTER SWITCH TRANSCRIPTIONAL REGULATOR

A protein that controls the fate of a cohort of cells by inducing genes that trigger differentiation into a particular cell type.

ANTIGEN?MHC

The correct presentation of short peptide antigens on the surface of cells that trigger specific T cells to become activated.

CD4/CD8 DOUBLE POSITIVE THYMOCYTE

An immature developing T cell undergoing positive and negative selection on the basis of its T-cell-receptor specificity.

DOMINANT-NEGATIVE

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

PHOX HOMOLOGY (PX) DOMAIN

A domain that is similar in function to PH domains, they have an affinity for certain phosphorylated phospholipids.

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Scheid, M., Woodgett, J. PKB/AKT: functional insights from genetic models. Nat Rev Mol Cell Biol 2, 760–768 (2001). https://doi.org/10.1038/35096067

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