<scp>PIKK</scp>ing a way to regulate inflammation

Quek, Hazel; Lim, Yi Chieh; Lavin, Martin F.; Roberts, Tara L.

doi:10.1111/imcb.1001

Cited by 13 publications

(13 citation statements)

References 105 publications

(233 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Dysregulation of mTORC1 [4], mTORC2 [126], and other PIKKs [127] is well known to be associated with various diseases. As our understanding of the molecular mechanisms governing the function of these big complexes develops, this knowledge could contribute to emerging therapies.…”

Section: Perspectivesmentioning

confidence: 99%

Structural Insights into TOR Signaling

Tafur

Kefauver

Loewith

2020

Genes

View full text Add to dashboard Cite

The Target of Rapamycin (TOR) is a highly conserved serine/threonine protein kinase that performs essential roles in the control of cellular growth and metabolism. TOR acts in two distinct multiprotein complexes, TORC1 and TORC2 (mTORC1 and mTORC2 in humans), which maintain different aspects of cellular homeostasis and orchestrate the cellular responses to diverse environmental challenges. Interest in understanding TOR signaling is further motivated by observations that link aberrant TOR signaling to a variety of diseases, ranging from epilepsy to cancer. In the last few years, driven in large part by recent advances in cryo-electron microscopy, there has been an explosion of available structures of (m)TORC1 and its regulators, as well as several (m)TORC2 structures, derived from both yeast and mammals. In this review, we highlight and summarize the main findings from these reports and discuss both the fascinating and unexpected molecular biology revealed and how this knowledge will potentially contribute to new therapeutic strategies to manipulate signaling through these clinically relevant pathways.

show abstract

Section: Perspectivesmentioning

confidence: 99%

Structural Insights into TOR Signaling

Tafur

Kefauver

Loewith

2020

Genes

View full text Add to dashboard Cite

show abstract

“…It has been proposed that targeted membrane localization allows spatial separation of individual signaling branches of large signaling networks, thereby potentially improving the reliability of biochemical signaling processes (19). Because PIKKs generally participate in a multitude of signaling pathways in response to ionizing radiation and other stress factors or metabolic signals (2,5,7,16,20,21), their localization may also determine the specific signaling output (22). ATM has been found to localize and function not only in the nucleus but also in the cytoplasm (12).…”

mentioning

confidence: 99%

NMR– and MD simulation–based structural characterization of the membrane-associating FATC domain of ataxia telangiectasia mutated

Rahim

Cherniavskyi

Tieleman

et al. 2019

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Wolfgang Peti The Ser/Thr protein kinase ataxia telangiectasia mutated (ATM) plays an important role in the DNA damage response, signaling in response to redox signals, the control of metabolic processes, and mitochondrial homeostasis. ATM localizes to the nucleus and at the plasma membrane, mitochondria, peroxisomes, and other cytoplasmic vesicular structures. It has been shown that the C-terminal FATC domain of human ATM (hAT-Mfatc) can interact with a range of membrane mimetics and may thereby act as a membrane-anchoring unit. Here, NMR structural and 15 N relaxation data, NMR data using spin-labeled micelles, and MD simulations of micelle-associated hATMfatc revealed that it binds the micelle by a dynamic assembly of three helices with many residues of hATMfatc located in the headgroup region. We observed that none of the three helices penetrates the micelle deeply or makes significant tertiary contacts to the other helices. NMR-monitored interaction experiments with hATMfatc variants in which two conserved aromatic residues (Phe 3049 and Trp 3052) were either individually or both replaced by alanine disclosed that the double substitution does not abrogate the interaction with micelles and bicelles at the high concentrations at which these aggregates are typically used, but impairs interactions with small unilamellar vesicles, usually used at much lower lipid concentrations and considered a better mimetic for natural membranes. We conclude that the observed dynamic structure of micelle-associated hATMfatc may enable it to interact with differently composed membranes or membrane-associated interaction partners and thereby regulate ATM's kinase activity. Moreover, the FATC domain of ATM may function as a membrane-anchoring unit for other biomolecules. Ataxia telangiectasia mutated (ATM) 4 belongs to the family of phosphatidylinositol 3-kinase-related kinases (PIKKs) that phosphorylate Ser/Thr residues of proteins regulating processes such as DNA repair, cell cycle progression, cellular senescence, apoptosis, and metabolic processes (1-4). Recently, it was found out that PIKKs also play a role in signaling in response to virus infections and during inflammation (5, 6). The function of ATM and of the related mammalian/mechanistic target of rapamycin (mTOR), a central controller of cell growth and metabolism in all eukaryotes that also has links to DNA repair signaling (7, 8), has further been related to redox signaling (9-12). Whereas the mTOR pathway negatively controls ATM (13), ATM inactivates mTORC1 in response to reactive oxygen species to induce autophagy (12), based on additional data, specifically that of peroxisomes (14). ATM also down-regulates mTORC1 under hypoxic conditions (11). Other studies indicate that ATM plays direct roles in modulating mitochondrial homeostasis (15). Activation of ATM by oxidation and other factors has been reviewed (16). Inactivation of ATM leads to ataxia-telangiectasia (A-T) disease and more generally plays a role in neuronal development and neurodegeneration (17)...

show abstract

“…also interacts with ATM to stimulate cell cycle arrest in response to radiation induced double strand breaks [41] via AKT activation [42]. High TELO2 expression activity has been identified to be correlated with cell protection when exposed to high radiation doses [42]; conversely, TELO2 overexpression can trigger inflammation by influencing PIKKs (via mTORC1 binding [43]) while responding to DNA damage [44]. PARD6G was found to have opposite direction of expression in prostate and whole-blood tissue, which could be attributed to tissue specific differences.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomics & copy number variation of radiotoxicity points to altered mitochondrial and DNA repair mechanisms

Pathak¹,

Polimanti²,

Silzer³

et al. 2020

Preprint

View full text Add to dashboard Cite

Proctitis is an inflammation of the rectum and may be induced by radiation treatment for cancer. We investigated proctitis as a radiotoxic endpoint in prostate cancer patients who received radiotherapy (n=222). We analyzed the copy number variation and SNP-derived transcriptomic profiles of whole-blood and prostate tissue associated with proctitis. The SNP and copy number data were genotyped on Affymetrix® Genome-wide Human SNP Array 6.0. Following QC measures, the genotypes were used to obtain gene expression by leveraging GTEx, a reference dataset for gene expression association based on genotype and RNA-seq information for prostate (n= 132) and whole-blood tissue (n=369). In prostate tissue, 62 genes were significantly associated with proctitis, and 98 genes in whole-blood tissue. Six genes - CABLES2, ATP6AP1L, IFIT5, ATRIP, TELO2 , and PARD6G were common to both tissues. The copy number analysis identified seven regions associated with proctitis, one of which ( ALG1L2) was also associated with proctitis based on transcriptomic profiles in the whole-blood tissue. The genes identified via transcriptomics and copy number variation association were further investigated for enriched pathways and gene ontology. Some of the enriched processes were DNA repair, mitochondrial apoptosis regulation, cell-to-cell signaling interaction processes for renal and urological system, and organismal injury.

show abstract

PIKKing a way to regulate inflammation

Cited by 13 publications

References 105 publications

Structural Insights into TOR Signaling

Structural Insights into TOR Signaling

NMR– and MD simulation–based structural characterization of the membrane-associating FATC domain of ataxia telangiectasia mutated

Transcriptomics & copy number variation of radiotoxicity points to altered mitochondrial and DNA repair mechanisms

Contact Info

Product

Resources

About

PIKKing a way to regulate inflammation

Cited by 13 publications

References 105 publications

Structural Insights into TOR Signaling

Structural Insights into TOR Signaling

NMR– and MD simulation–based structural characterization of the membrane-associating FATC domain of ataxia telangiectasia mutated

Transcriptomics &amp; copy number variation of radiotoxicity points to altered mitochondrial and DNA repair mechanisms

Contact Info

Product

Resources

About

Transcriptomics & copy number variation of radiotoxicity points to altered mitochondrial and DNA repair mechanisms