Emerging common themes in regulation of PIKKs and PI3Ks

• Published in: The EMBO journal Vol. 28; no. 20; pp. 3067 - 3073
• Main Authors: Lempiäinen, Harri, Halazonetis, Thanos D
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 21.10.2009; Blackwell Publishing Ltd; Nature Publishing Group
• Subjects: Animals; Ataxia Telangiectasia Mutated Proteins; ATM; ATR; Binding sites; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Cycle Proteins - physiology; DNA damage; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; DNA-PK; EMBO Member's Review; Gene Expression Regulation, Enzymologic; Humans; Kinases; Molecular biology; Molecular structure; Phosphatidylinositol 3-Kinases - chemistry; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; PI3K; PIKK; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases - chemistry; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Protein-Serine-Threonine Kinases - physiology; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumor Suppressor Proteins - physiology
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2009.281

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.