Kinase Family PIKK
PIKK, despite the name (Phosphatidyl inositol 3’ kinase-related kinases) are eukaryotic protein kinases that function largely in DNA repair and nutrient sensing.
All PIKK have a PKL-fold kinase domain that is much more closely related to the PIK domain of phosphatidyl inositol kinases than to the typical ePK protein kinase domain. This kinase domain is flanked by a FAT domain on the N-terminal side and a FATC domain  on the C-terminal side. Most PIKKs have a large N-termainal extension beyond that, containing a large number of divergent HEAT repeats and are usually 3-4,000 AA long.
Subfamilies and Evolution
Most PIKKs are found throughout all eukaryotes, usually with one copy per genome. The ATM and ATR kinases participated in single-strand DNA break repair, while DNAPK has a similar role in double-stranded break repair. TOR has a very different role, as a major hub for sensing and acting on nutrient stress. SMG1 is involved in nonsense-mediated decay, while TRRAP, a pseudokinase, functions as a cell cycle checkpoint. Multiple copies of TOR-like proteins are seen in many protist lineges, and DNAPK is one of the most frequently lost of kinases.
Lipid Kinase relevance?
Although PIKKs are clearly related to PIK kinases, they appear not have lipid substrates. A single report indicated that TOR might have PI4K kinase activity , but this has not been replicated or generally accepted. The kinase activity was not effected by the TOR inhibitor, rapamycin, suggesting that the activity may have been from a contaminating lipid kinase. By contrast, PIK kinases have shown several scattered reports of protein kinase activity, suggesting that the difference between the two activities may be relatively easy to surmount.
- Bosotti R, Isacchi A, and Sonnhammer EL. FAT: a novel domain in PIK-related kinases. Trends Biochem Sci. 2000 May;25(5):225-7.
- Sabatini DM, Pierchala BA, Barrow RK, Schell MJ, and Snyder SH. The rapamycin and FKBP12 target (RAFT) displays phosphatidylinositol 4-kinase activity. J Biol Chem. 1995 Sep 8;270(36):20875-8.