1.
Protein Phosphorylation Signaling Cascades in Autism: The Role of mTOR Pathway.
Boksha, IS, Prokhorova, TA, Tereshkina, EB, Savushkina, OK, Burbaeva, GS
Biochemistry. Biokhimiia. 2021;(5):577-596
Abstract
The mammalian target of rapamycin (mTOR) signaling pathway is a central regulator of cell metabolism, growth, and survival in response to hormones, growth factors, nutrients, and stress-induced signals. In this review, we analyzed the studies on the molecular abnormalities of the mTOR-associated signaling cascades in autism spectrum disorders (ASDs) and outlined the prospects for the pathogenicity-targeting pharmacotherapeutic approaches to ASDs, in particular syndromic ASDs. Based on available experimental and clinical data, we suggest that very early detection of molecular abnormalities in the ASD risk groups can be facilitated by using peripheral blood platelets. Also, identification of the time window of critical dysregulations in the described pathways in the ASD risk groups might suggest further research directions leading to more efficacious pharmacotherapeutic interventions in ASDs.
2.
Sensing of nutrients and microbes in the gut.
Bishu, S
Current opinion in gastroenterology. 2016;(2):86-95
Abstract
PURPOSE OF REVIEW Sensing of nutrients and microbes in the gut are fundamental processes necessary for life. This review aims to provide an overview of the basic background and new data on cellular nutrient, energy, and microbe sensors. RECENT FINDINGS The nutrient sensors 5' adenosine monophosphate-activated protein kinase, activating transcription factor 4 and mechanistic target of rapamycin (mTOR) are critical in control of the cell cycle. Recent data demonstrate their role in metabolic syndrome, in cell growth, and as therapeutic targets. Regulation of mTOR by the amino acids is the subject of intense investigation. Recent studies have further elucidated the exact mechanism of amino acid-dependent mTOR regulation. Pathogen recognition receptors (PRRs) are receptors that recognize conserved microbial molecules. New data demonstrate how lymphocyte-specific PRRs are necessary to maintain homeostasis. Moreover, new studies explore the role of PRRs in controlling the gut bacterial and fungal microbiome. SUMMARY Nutrient sensing molecules are central to cell growth and metabolism and are implicated in cancer and the metabolic syndrome. Regulation of nutrient sensors is complex, and may be amenable to therapeutic targeting. Microbial sensors play critical roles in homeostasis and maintenance of the gut fungal and bacterial microbiome.
3.
De novo RRAGC mutation activates mTORC1 signaling in syndromic fetal dilated cardiomyopathy.
Long, PA, Zimmermann, MT, Kim, M, Evans, JM, Xu, X, Olson, TM
Human genetics. 2016;(8):909-917
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Abstract
Idiopathic dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder with variable age-dependent penetrance. We sought to identify the genetic underpinnings of syndromic, sporadic DCM in a newborn female diagnosed in utero. Postnatal evaluation revealed ventricular dilation and systolic dysfunction, bilateral cataracts, and mild facial dysmorphisms. Comprehensive metabolic and genetic testing, including chromosomal microarray, mitochondrial DNA and targeted RASopathy gene sequencing, and clinical whole exome sequencing for known cardiomyopathy genes was non-diagnostic. Following exclusion of asymptomatic DCM in the parents, trio-based whole exome sequencing was carried out on a research basis, filtering for rare, predicted deleterious de novo and recessive variants. An unreported de novo S75Y mutation was discovered in RRAGC, encoding Ras-related GTP binding C, an essential GTPase in nutrient-activated mechanistic target of rapamycin complex 1 (mTORC1) signaling. In silico protein modeling and molecular dynamics simulation predicted the mutation to disrupt ligand interactions and increase the GDP-bound state. Overexpression of RagC(S75Y) rendered AD293 cells partially insensitive to amino acid deprivation, resulting in increased mTORC1 signaling compared to wild-type RagC. These findings implicate mTORC1 dysregulation through a gain-of-function mutation in RagC as a novel molecular basis for syndromic forms of pediatric heart failure, and expand genotype-phenotype correlation in RASopathy-related syndromes.
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The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling.
van Veelen, W, Korsse, SE, van de Laar, L, Peppelenbosch, MP
Oncogene. 2011;(20):2289-303
Abstract
The liver kinase B1 (LKB1)/adenosine mono-phosphate-activated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the Peutz-Jeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general.