Abstract
Phosphatidylinositol 3-kinase-related kinases (PIKKs) play vital roles in the regulation of cell growth, proliferation, survival, and consequently metabolism, as well as in the cellular response to stresses such as ionizing radiation or redox changes. In humans six family members are known to date, namely mammalian/mechanistic target of rapamycin (mTOR), ataxia-telangiectasia mutated (ATM), ataxia- and Rad3-related (ATR), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), suppressor of morphogenesis in genitalia-1 (SMG-1), and transformation/transcription domain-associated protein (TRRAP). All fulfill rather diverse functions and most of them have been detected in different cellular compartments including various cellular membranes. It has been suggested that the regulation of the localization of signaling proteins allows for generating a locally specific output. Moreover, spatial partitioning is expected to improve the reliability of biochemical signaling. Since these assumptions may also be true for the regulation of PIKK function, the current knowledge about the regulation of the localization of PIKKs at different cellular (membrane) compartments by a network of interactions is reviewed. Membrane targeting can involve direct lipid-/membrane interactions as well as interactions with membrane-anchored regulatory proteins, such as, for example, small GTPases, or a combination of both.
Highlights
The family of phosphatidylinositol 3-kinase-related kinases (PIKKs) controls a multitude of cellular signaling branches (Figure 1) in response to different stresses and the availability of nutrients [1,2,3]
Since regulation of the cellular localization of Phosphatidylinositol 3-kinase-related kinases (PIKKs) may generally allow a locally specific action in response to ionizing radiation (IR) and other cellular stress factors and signals, we review in the following the significant existing knowledge about the network of interactions mediating the localization of mechanistic target of rapamycin (mTOR)
Besides the mentioned mTOR localization and activation places, signaling to mTOR Complex 1 (mTORC1) may further occur from the peroxisome to which Ras homolog enriched in the brain (Rheb) but not the tuberous sclerosis complex (TSC) complex or Target of Rapamycin (TOR) have been localized [144]; this potential activation route remains to be confirmed
Summary
The family of phosphatidylinositol 3-kinase-related kinases (PIKKs) controls a multitude of cellular signaling branches (Figure 1) in response to different stresses and the availability of nutrients [1,2,3]. Based on a recent review about the structural similarities of PIKKs, DNA-PKcs, SMG-1, and TRRAP may contain an FRB (FKBP12-rapamycin-binding)-like domain between the FAT and the kinase domains [51]. The FATC domains of ATM, DNA-PKcs, and ATR have been proposed to mediate protein–protein interactions [2,55,56] Those of all human PIKKs may further function as conditional membrane anchors [57]. For the FRB domain additional structures alone or in complex with small molecules (e.g., [77,78,79]) and in complex with the FKBP12-like domains of FKBP51 and 52 and rapamycin [80], as well as a structural model for the HEAT repeat region [49], have been published.In the following paragraphs these interactions are described in more detail and complement the review of the localization of TOR in mammalian and yeast cells by Betz and Hall from 2013 [81]
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