Phosphatidylinositol 3-kinase-related kinases (PIKKs) are a family of Ser/Thr-protein kinases with sequence similarity to phosphatidylinositol-3 kinases (PI3Ks). Members of the phosphatidylinositol-3 kinase family can produce phospholipids after activation by growth factors and other factors. As a second messenger, they bind and activate different target cells, forming a complex signal cascade. It plays a central role in chemotaxis, survival, protein transportation, and glucose metabolism. Based on the detailed classification and structural characteristics of phosphatidylinositol-3 kinase family members, the phosphatidylinositol-3 kinase-dependent signaling pathway and its related functions are introduced.

Figure 1. Phosphatidylinositol-4,5-bisphosphate 3-kinase.

Examples of PIKK family kinases

ATM

ATM serine/threonine kinase (symbol ATM) is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks. It phosphorylates several key proteins that initiate the activation of DNA damage checkpoints, causing cell cycle arrest, DNA repair, or apoptosis. Several of these targets, including p53, CHK2, BRCA1, NBS1, and H2AX are tumor suppressors. Activation of ATM after DSB requires a functional MRN complex. The complex functions upstream of ATM in mammalian cells and induces conformational changes, thereby promoting an increased affinity of ATM to its substrates such as CHK2 and p53. There are inactive ATMs in units without DSB, these monomers are dimers or multimers. When DNA is damaged, ATM is autophosphorylated at residue Ser1981. This phosphorylation promotes dissociation of the ATM dimer and subsequently releases the active ATM monomer. The normal activity of ATM kinase requires further autophosphorylation (residues Ser367 and Ser1893). Activation of ATM by the MRN complex requires at least two steps, namely, recruitment of ATM to the DSB end via a mediator that binds MRE11's DNA damage checkpoint protein 1 (MDC1), and subsequent stimulation of kinase activity with NBS1 C. -end. The three domains FAT, PRD and FATC are involved in regulating the activity of the KD kinase domain. The FAT domain interacts with the KD domain of the ATM to stabilize the C-terminal region of the ATM itself. The FATC domain is critical for kinase activity and is highly sensitive to mutagenesis. It mediates protein-protein interactions, such as histone acetyltransferase TIP60 (HIV-1 Tat interacting protein 60 kDa), which acetylates ATM on residue Lys3016. Acetylation occurs in the C-terminal half of the PRD domain and is required for ATM kinase activation and its conversion to monomers. Although the deletion of the entire PRD domain eliminates ATM kinase activity, specific small deletions have no effect.

mTOR

Mammalian target of rapamycin (mTOR) is an important regulator of cell growth and proliferation. Numerous studies have shown that the abnormal regulation of mTOR signaling pathway is closely related to cell proliferation. mTOR is linked to other proteins and serves as the core component of two different protein complexes, mTOR complex 1 and mTOR complex 2, which regulate different cellular processes. In particular, mTOR, as the core component of these two complexes, acts as a serine / threonine protein kinase, regulating cell growth, cell proliferation, cell movement, cell survival, protein synthesis, autophagy and transcription. As a core component of mTORC2, mTOR also functions as a tyrosine protein kinase and promotes the activation of insulin receptors and insulin-like growth factor 1 receptors. mTORC2 is also involved in the control and maintenance of actin cytoskeleton.

Figure 2. Structure of the mTOR protein.

ATR

ATR is a serine/threonine-specific protein kinase that is involved in sensing DNA damage and activating DNA damage checkpoints, resulting in cell cycle arrest. ATR is activated in response to persistent single-stranded DNA, a common intermediate formed during the detection and repair of DNA damage. Single-stranded DNA occurs at stalled replication forks and acts as an intermediate in DNA repair pathways such as nucleotide excision repair and homologous recombination repair. ATR, together with a chaperone protein called ATRIP, recognizes single-stranded DNA wrapped in RPA. Once ATR is activated, it phosphorylates Chk1, thereby initiating a signal transduction cascade, which eventually leads to cell cycle arrest. In addition to its role in activating DNA damage checkpoints, ATR is thought to play a role in undisturbed DNA replication

References

1. Cimprich KA; et al. cDNA cloning and gene mapping of a candidate human cell cycle checkpoint protein. Proceedings of the National Academy of Sciences of the United States of America. 1996,93 (7): 2850-5.
2. Sabers CJ1; et al. Isolation of a Protein Target of the FKBP12-Rapamycin Complex in Mammalian Cells. J Biol Chem. 1995, 270(2):815-22