Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2009 Oct 21;28(20):3067-73.
doi: 10.1038/emboj.2009.281. Epub 2009 Sep 24.

Emerging common themes in regulation of PIKKs and PI3Ks

Harri Lempiäinen  1 , Thanos D Halazonetis
Affiliations
Review

Emerging common themes in regulation of PIKKs and PI3Ks

Harri Lempiäinen et al. EMBO J. .

Abstract

Phosphatidylinositol-3 kinase-related kinases (PIKKs) comprise a family of protein kinases that respond to various stresses, including DNA damage, blocks in DNA replication, availability of nutrients and errors in mRNA splicing. PIKKs are characterized by the presence of a conserved kinase domain (KD), whose activity is regulated by two C-terminal regions, referred to as PIKK-regulatory domain (PRD) and FRAP-ATM-TRRAP-C-terminal (FATC), respectively. Here, we review functional and structural data that implicate the PRD and FATC domains in regulation of PIKK activity, drawing parallels to phosphatidylinositol-3 kinases (PI3K), lipid kinases that have sequence similarity to PIKKs. The PI3K C-terminus, which we propose to be equivalent to the PRD and FATC domains of PIKKs, is in close proximity to the activation loop of the KD, suggesting that in PIKKs, the PRD and FATC domains may regulate kinase activity by targeting the activation loop.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Domain structure and alignment of PIKKs and PI3Ks. (A) Schematic presentation of the known protein domains of selected PIKKs and PI3Ks. All the kinases shown are human, except for mTOR, which is of rat origin, and Mec1 and Tor1, which are S. cerevisiae proteins. PI3Kα and PI3Kγ refer to the PI3K catalytic subunits p110α and p110γ, respectively. The abbreviations of the domains are mentioned in the text. (B, C) Amino-acid alignment of the PRD (B) and FATC (C) domains of selected PIKKs to the C-terminal α-helices of the PI3K catalytic subunits p110α and p110γ. The boundaries of helices αK11, αK12 and αK13 of p110γ are shown below its sequence. Regions of homology are coloured green (four or more identical residues at that position) and yellow (five or more similar residues at that position). Residues, whose substitution decreases kinase activity, are coloured red; residues, whose substitution does not affect or enhances kinase activity, are coloured blue; residues of ATM targeted naturally by mutations in ataxia-telangiectasia patients are coloured orange. Residue numbers for each protein are indicated in parentheses.
Figure 2
Figure 2
Superimposition of the FATC domain of S. cerevisiae Tor1 (PDB file 1w1n) and of helices αK12 and αK13 of the PI3K catalytic subunit p110γ (PDB file 1e8x) on the three-dimensional structure of the helical and kinase domains (KDs) of the PI3K catalytic subunit p110α (PDB file 2rd0), according to the alignment shown in Figure 1B. The p110α helical (HEL) and KDs are coloured green and blue, respectively. The activation loop is coloured red; the red spheres mark the boundaries of the part of the activation loop, whose structure was not determined. The ATP, from the p110γ structure, is coloured orange. Helices αK11 and αK12 of p110α are coloured purple and bright yellow, respectively. Helix αK13 of p110α was not resolved in the electron density map and is not shown. Helices αK12 and αK13 of p110γ are coloured dark yellow, as are the side chains of the p110γ residues Trp1080 (W80), Trp1086 (W86) and Phe1087 (F87). The FATC domain of Tor1 is coloured light purple, as are the side chains of its residues Trp2466 (W66), Phe2469 (F69) and Trp2470 (W70). Note that residues 2465–2470 of Tor1 were modelled according to the p110γ structure, as described in the text. Residues of p110α targeted by cancer-associated mutations map to the N-terminus of the helical domain (E542, Glu542; E545, Glu545; Q546, Gln546) and to helix αK12 (M43, Met1043; H47, His1047). PI3Kα and PI3Kγ refer to the PI3K catalytic subunits p110α and p110γ, respectively.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Adami A, Garcia-Alvarez B, Arias-Palomo E, Barford D, Llorca O (2007) Structure of TOR and its complex with KOG1. Mol Cell 27: 509–516 - PubMed
    1. Bader AG, Kang S, Vogt PK (2006) Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc Natl Acad Sci USA 103: 1475–1479 - PMC - PubMed
    1. Ball HL, Myers JS, Cortez D (2005) ATRIP binding to replication protein A-single-stranded DNA promotes ATR-ATRIP localization but is dispensable for Chk1 phosphorylation. Mol Biol Cell 16: 2372–2381 - PMC - PubMed
    1. Bosotti R, Isacchi A, Sonnhammer EL (2000) FAT: a novel domain in PIK-related kinases. Trends Biochem Sci 25: 225–227 - PubMed
    1. Brunn GJ, Fadden P, Haystead TA, Lawrence JC Jr (1997) The mammalian target of rapamycin phosphorylates sites having a (Ser/Thr)-Pro motif and is activated by antibodies to a region near its COOH terminus. J Biol Chem 272: 32547–32550 - PubMed

Publication types

MeSH terms

Substances