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Emilie Clement, Hiroyuki Inuzuka, Naoe T Nihira, Wenyi Wei, Alex Toker
The PI3K-AKT kinase signaling pathway is frequently deregulated in human cancers, particularly breast cancer, where amplification and somatic mutations of PIK3CA occur with high frequency in patients. Numerous small-molecule inhibitors targeting both PI3K and AKT are under clinical evaluation, but dose-limiting toxicities and the emergence of resistance limit therapeutic efficacy. Various resistance mechanisms to PI3K inhibitors have been identified, including de novo mutations, feedback activation of AKT, or cross-talk pathways...
March 13, 2018: Science Signaling
Mitsugu Shimobayashi, Verena Albert, Bettina Woelnerhanssen, Irina C Frei, Diana Weissenberger, Anne Christin Meyer-Gerspach, Nicolas Clement, Suzette Moes, Marco Colombi, Jerome A Meier, Marta M Swierczynska, Paul Jenö, Christoph Beglinger, Ralph Peterli, Michael N Hall
Obesity is a major risk factor for insulin resistance and type 2 diabetes. In adipose tissue, obesity-mediated insulin resistance correlates with the accumulation of proinflammatory macrophages and inflammation. However, the causal relationship of these events is unclear. Here, we report that obesity-induced insulin resistance in mice precedes macrophage accumulation and inflammation in adipose tissue. Using a mouse model that combines genetically induced, adipose-specific insulin resistance (mTORC2-knockout) and diet-induced obesity, we found that insulin resistance causes local accumulation of proinflammatory macrophages...
March 12, 2018: Journal of Clinical Investigation
Alberto M Martelli, Francesca Buontempo, James A McCubrey
Mechanistic target of rapamycin (mTOR) is the kinase subunit of two structurally and functionally distinct large multiprotein complexes, referred to as mTOR complex 1 (mTORC1) and mTORC2. mTORC1 and mTORC2 play key physiological roles as they control anabolic and catabolic processes in response to external cues in a variety of tissues and organs. However, mTORC1 and mTORC2 activities are deregulated in widespread human diseases, including cancer. Cancer cells take advantage of mTOR oncogenic signaling to drive their proliferation, survival, metabolic transformation, and metastatic potential...
March 15, 2018: Clinical Science (1979-)
Glenn R Bantug, Marco Fischer, Jasmin Grählert, Maria L Balmer, Gunhild Unterstab, Leyla Develioglu, Rebekah Steiner, Lianjun Zhang, Ana S H Costa, Patrick M Gubser, Anne-Valérie Burgener, Ursula Sauder, Jordan Löliger, Réka Belle, Sarah Dimeloe, Jonas Lötscher, Annaïse Jauch, Mike Recher, Gideon Hönger, Michael N Hall, Pedro Romero, Christian Frezza, Christoph Hess
Glycolysis is linked to the rapid response of memory CD8+ T cells, but the molecular and subcellular structural elements enabling enhanced glucose metabolism in nascent activated memory CD8+ T cells are unknown. We found that rapid activation of protein kinase B (PKB or AKT) by mammalian target of rapamycin complex 2 (mTORC2) led to inhibition of glycogen synthase kinase 3β (GSK3β) at mitochondria-endoplasmic reticulum (ER) junctions. This enabled recruitment of hexokinase I (HK-I) to the voltage-dependent anion channel (VDAC) on mitochondria...
March 1, 2018: Immunity
Shun Bai, Le Cheng, Yingwen Zhang, Chunsen Zhu, Zhiping Zhu, Ruping Zhu, C Yan Cheng, Lan Ye, Ke Zheng
STUDY QUESTION: What is the physiological role of Rictor in spermatogenic cells? SUMMARY ANSWER: Germline expression of Rictor regulates spermatogonial differentiation and has an essential role in coordinating germ cells and Sertoli cells in maintaining intact cell-cell adhesion dynamics and cytoskeleton-based architecture in the seminiferous epithelium. WHAT IS KNOWN ALREADY: The mechanistic target of rapamycin (mTOR) resides in its functions as the catalytic subunits of the structurally and functionally distinct mTORC1 and mTORC2 complexes...
February 6, 2018: Molecular Human Reproduction
Yujie Li, Sandra Finkbeiner, Athina Ganner, Julia Gerber, Marinella Klein, Manuel Grafe, Jakob Kandzia, Antje Thien, Kathrin Thedieck, Gerhard Breves, Thomas Jank, Ralf Baumeister, Gerd Walz, Elke Neumann-Haefelin
The mechanistic target of rapamycin (mTOR) kinase is central to metabolism and growth, and has a conserved role in aging. mTOR functions in two complexes, mTORC1 and mTORC2. In diverse eukaryotes, inhibition of mTORC1 signaling increases lifespan. mTORC1 transduces anabolic signals to stimulate protein synthesis and inhibits autophagy. In this study, we demonstrate that CGEF-1, the C. elegans homolog of the human guanine nucleotide exchange factor Dbl, is a novel binding partner of RHEB-1 and activator of mTORC1 signaling in C...
February 9, 2018: Oncotarget
Jérôme Hadjadj, Guillaume Canaud, Tristan Mirault, Maxime Samson, Patrick Bruneval, Alexis Régent, Claire Goulvestre, Véronique Witko-Sarsat, Nathalie Costedoat-Chalumeau, Loïc Guillevin, Luc Mouthon, Benjamin Terrier
Objectives: Takayasu arteritis (TA) and GCA are large-vessel vasculitides characterized by vascular remodelling involving endothelial cells (ECs) and vascular smooth muscle cells. Mammalian target of rapamycin (mTOR) pathway has been involved in vascular remodelling. We hypothesized that the mTOR pathway was involved in the pathogenesis of large-vessel vasculitis. Methods: We used IF analysis on aortic and temporal artery biopsies from patients with TA and GCA to assess the involvement of the mTOR pathway and searched for antibodies targeting ECs in serum by IIF and cellular ELISA...
February 27, 2018: Rheumatology
Dong-Qing Xu, Hidemi Toyoda, Xiao-Jun Yuan, Lei Qi, Vipin Shankar Chelakkot, Mari Morimoto, Ryo Hanaki, Kentarou Kihira, Hiroki Hori, Yoshihiro Komada, Masahiro Hirayama
Neuroblastoma (NB) is one of the most common solid tumors in children. High-risk NB remains lethal in about 50% of patients despite comprehensive and intensive treatments. Activation of PI3K/Akt/mTOR signaling pathway correlates with oncogenesis, poor prognosis and chemotherapy resistance in NB. Due to its central role in growth and metabolism, mTOR seems to be an important factor in NB, making it a possible target for NB. In this study, we investigated the effect of AZD8055, a potent dual mTORC1-mTORC2 inhibitor, in NB cell lines...
February 27, 2018: Experimental Cell Research
Sophie Laguesse, Nadege Morisot, Khanhky Phamluong, Samuel A Sakhai, Dorit Ron
Actin is highly enriched at dendritic spines, and actin remodeling plays an essential role in structural plasticity. The mammalian target of rapamycin complex 2 (mTORC2) is a regulator of actin polymerization. Here, we report that alcohol consumption increases F-actin content in the dorsomedial striatum (DMS) of mice, thereby altering dendritic spine morphology in a mechanism that requires mTORC2. Specifically, we found that excessive alcohol consumption increases mTORC2 activity in the DMS, and that knockdown of Rictor, an essential component of mTORC2 signaling, reduces actin polymerization, and attenuates the alcohol-dependent alterations in spine head size and the number of mushroom spines...
February 7, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Goro Kawasaki, Tomofumi Naruse, Kohei Furukawa, Masahiro Umeda
BACKGROUND/AIM: Mammalian target of rapamycin (mTOR) plays a critical role in the regulation of tumor cell motility, invasion and cancer cell metastasis. mTOR consists of two separate multi-protein complexes, mTOR complex (mTORC) 1 and mTORC2. MATERIALS AND METHODS: We investigated the expression levels of mTORC1 and mTORC2 immunohistochemically in oral squamous cell carcinoma (OSCC). RESULTS: mTORC1 and mTORC2 were more highly expressed in tumors than in normal oral mucosa...
March 2018: Anticancer Research
Yun Chen, Cheng-Hung Lee, Bor-Yuan Tseng, Ya-Hui Tsai, Huang-Wen Tsai, Chao-Ling Yao, Sheng-Hong Tseng
BACKGROUND/AIM: AZD8055 is an inhibitor of mammalian target of rapamycin (mTOR) that can suppress both mTOR complex 1 (mTORC1) and mTORC2. This study investigated the antitumor effects of AZD8055 on colon cancer. MATERIALS AND METHODS: The effects of AZD8055 on proliferation, apoptosis, and cell cycle of colon cancer cells, and tumor growth in a mouse colon cancer model were studied. RESULTS: AZD8055 significantly inhibited proliferation and induced apoptosis of colon cancer cells (p<0...
March 2018: Anticancer Research
Vladimir R Babaev, Jiansheng Huang, Lei Ding, Youmin Zhang, James M May, MacRae F Linton
Background: Rictor is an essential component of mammalian target of rapamycin (mTOR) complex 2 (mTORC2), a conserved serine/threonine kinase that may play a role in cell proliferation, survival and innate or adaptive immune responses. Genetic loss of Rictor inactivates mTORC2, which directly activates Akt S473 phosphorylation and promotes pro-survival cell signaling and proliferation. Methods and results: To study the role of mTORC2 signaling in monocytes and macrophages, we generated mice with myeloid lineage-specific Rictor deletion (M Rictor -/- )...
2018: Frontiers in Immunology
Philip H Iffland, Marianna Baybis, Allan E Barnes, Richard J Leventer, Paul J Lockhart, Peter B Crino
Mutations in DEPDC5 and NPRL3 subunits of GATOR1, a modulator of mechanistic target of rapamycin (mTOR), are linked to malformations of cortical development (MCD). Brain specimens from these individuals reveal abnormal cortical lamination, altered cell morphology, and hyperphosphorylation of ribosomal S6 protein (PS6), a marker for mTOR activation. While numerous studies have examined GATOR1 subunit function in non-neuronal cell lines, few have directly assessed loss of GATOR 1 subunit function in neuronal cell types...
February 23, 2018: Neurobiology of Disease
Ting Yuan, Blaz Lupse, Kathrin Maedler, Amin Ardestani
The mechanistic target of rapamycin (mTOR) signaling pathway is an evolutionary conserved pathway that senses signals from nutrients and growth factors to regulate cell growth, metabolism and survival. mTOR acts in two biochemically and functionally distinct complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), which differ in terms of regulatory mechanisms, substrate specificity and functional outputs. While mTORC1 signaling has been extensively studied in islet/ β-cell biology, recent findings demonstrate a distinct role for mTORC2 in the regulation of pancreatic β-cell function and mass...
February 23, 2018: Journal of Molecular Biology
Yi-Ping Jin, Nicole M Valenzuela, Xiaohai Zhang, Enrique Rozengurt, Elaine F Reed
Transplant recipients developing donor-specific HLA class II (HLA-II) Abs are at higher risk for Ab-mediated rejection (AMR) and transplant vasculopathy. To understand how HLA-II Abs cause AMR and transplant vasculopathy, we determined the signaling events triggered in vascular endothelial cells (EC) following Ab ligation of HLA-II molecules. HLA-II expression in EC was induced by adenoviral vector expression of CIITA or by pretreatment with TNF-α/IFN-γ. Ab ligation of class II stimulated EC proliferation and migration...
February 23, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Jordi Creus-Muncunill, Laura Rué, Rafael Alcalá-Vida, Raquel Badillos-Rodríguez, Joan Romaní-Aumedes, Sonia Marco, Jordi Alberch, Isabel Perez-Otaño, Cristina Malagelada, Esther Pérez-Navarro
Rictor associates with mTOR to form the mTORC2 complex, which activity regulates neuronal function and survival. Neurodegenerative diseases are characterized by the presence of neuronal dysfunction and cell death in specific brain regions such as for example Huntington's disease (HD), which is characterized by the loss of striatal projection neurons leading to motor dysfunction. Although HD is caused by the expression of mutant huntingtin, cell death occurs gradually suggesting that neurons have the capability to activate compensatory mechanisms to deal with neuronal dysfunction and later cell death...
February 19, 2018: Molecular Neurobiology
Ahlem Jebali, Nicolas Dumaz
The importance of the network defined by phosphatidylinositol-3-kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) downstream of Receptor Tyrosine Kinase (RTK) has been known for many years but the central role of RICTOR (rapamycin-insensitive companion of mTOR) in this pathway is only starting to emerge. RICTOR is critical for mTORC2 (the mammalian target of rapamycin complex 2) kinase activity and as such plays a key role downstream of RTK. Alterations of RICTOR have been identified in a number of cancer cell types and its involvement in tumorigenesis has begun to be unraveled recently...
February 19, 2018: Molecular Cancer
Rossina Novas, Magdalena Cardenas-Rodriguez, Paola Lepanto, Matías Fabregat, Magela Rodao, María Inés Fariello, Mauricio Ramos, Camila Davison, Gabriela Casanova, Lucía Alfaya, Federico Lecumberry, Gualberto González-Sapienza, Florencia Irigoín, Jose L Badano
Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinal degeneration, obesity, polydactyly, renal disease and mental retardation. CCDC28B is a BBS-associated protein that we have previously shown plays a role in cilia length regulation whereby its depletion results in shortened cilia both in cells and Danio rerio (zebrafish). At least part of that role is achieved by its interaction with the mTORC2 component SIN1, but the mechanistic details of this interaction and/or additional functions that CCDC28B might play in the context of cilia remain poorly understood...
February 14, 2018: Scientific Reports
Vipin Mohan Dan, Balaji Muralikrishnan, Rahul Sanawar, Vinodh J S, Bhushan Bapusaheb Burkul, Kalanghad Puthankalam Srinivas, Asha Lekshmi, N S Pradeep, Syed G Dastager, B Santhakumari, Thankayyan R Santhoshkumar, R Ajay Kumar, Madhavan Radhakrishna Pillai
In cervical cancer, the association between HPV infection and dysregulation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway (PI3K/AKT/mTOR pathway) places mTOR as an attractive therapeutic target. The failure of current treatment modalities in advanced stages of this cancer and drawbacks of already available mTOR inhibitors demand for novel drug candidates. In the present study we identified the presence of a mTOR inhibitor in an active fraction of the ethyl acetate extract of Streptomyces sp OA293...
February 12, 2018: Scientific Reports
Xujun Hu, Zirui Wang, Meikai Chen, Xuerong Chen, Wenqing Liang
mTOR over-activation is important for human osteosarcoma (OS) tumorigenesis and progression. RES-529 is a mTORC1/2 dual inhibitor. Here, our results show that RES-529 inhibited viability, cell cycle progression and proliferation of the established (U2OS line) and primary human OS cells. RES-529 induced apoptosis activation in OS cells. It was yet non-cytotoxic to OB-6 osteoblastic cells and the primary human osteoblasts. RES-529 disrupted assembling of mTORC1 (mTOR-Raptor association) and mTORC2 (mTOR-Rictor-mLST8 association) in human OS cells, blocking mTORC1/2 activation...
February 9, 2018: Biochemical and Biophysical Research Communications
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