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https://www.readbyqxmd.com/read/29184034/mek-inhibitor-trametinib-does-not-prevent-the-growth-of-anaplastic-lymphoma-kinase-alk-addicted-neuroblastomas
#1
Ganesh Umapathy, Jikui Guan, Dan E Gustafsson, Niloufar Javanmardi, Diana Cervantes-Madrid, Anna Djos, Tommy Martinsson, Ruth H Palmer, Bengt Hallberg
Activation of the RAS-RAF-MEK-ERK signaling pathway is implicated in driving the initiation and progression of multiple cancers. Several inhibitors targeting the RAS-MAPK pathway are clinically approved as single- or polyagent therapies for patients with specific types of cancer. One example is the MEK inhibitor trametinib, which is included as a rational polytherapy strategy for treating EML4-ALK-positive, EGFR-activated, or KRAS-mutant lung cancers and neuroblastomas that also contain activating mutations in the RAS-MAPK pathway...
November 28, 2017: Science Signaling
https://www.readbyqxmd.com/read/29156676/uncoupling-torc2-from-agc-kinases-inhibits-tumour-growth
#2
Angus J M Cameron, Selvaraju Veeriah, Jacqueline J T Marshall, Elizabeth R Murray, Banafshé Larijani, Peter J Parker
Mammalian target of rapamycin (mTOR) is a central regulator of growth and metabolism. mTOR resides in two distinct multi-protein complexes - mTORC1 and mTORC2 - with distinct upstream regulators and downstream targets. While it is possible to specifically inhibit mTORC1 with rapamycin, or inhibit both mTOR complexes together with ATP pocket directed mTOR kinase inhibitors, it is not possible to assess the specific roles for mTORC2 pharmacologically. To overcome this, we have developed a novel, inducible, dominant negative system for disrupting substrate recruitment to mTORC2...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29104218/evolutionary-conservation-of-the-components-in-the-tor-signaling-pathways
#3
REVIEW
Hisashi Tatebe, Kazuhiro Shiozaki
Target of rapamycin (TOR) is an evolutionarily conserved protein kinase that controls multiple cellular processes upon various intracellular and extracellular stimuli. Since its first discovery, extensive studies have been conducted both in yeast and animal species including humans. Those studies have revealed that TOR forms two structurally and physiologically distinct protein complexes; TOR complex 1 (TORC1) is ubiquitous among eukaryotes including animals, yeast, protozoa, and plants, while TOR complex 2 (TORC2) is conserved in diverse eukaryotic species other than plants...
November 1, 2017: Biomolecules
https://www.readbyqxmd.com/read/28934384/short-syndrome-due-to-a-novel-de-novo-mutation-in-prkce-protein-kinase-c%C3%A9-impairing-torc2-dependent-akt-activation
#4
Diana Alcantara, Frances Elmslie, Martine Tetreault, Eric Bareke, Taila Hartley, Jacek Majewski, Kym Boycott, A Micheil Innes, David A Dyment, Mark O'Driscoll
SHORT syndrome is a rare, recognizable syndrome resulting from heterozygous mutations in PIK3R1 encoding a regulatory subunit of phosphoinositide-3-kinase (PI3K). The condition is characterized by short stature, intrauterine growth restriction, lipoatrophy and a facial gestalt involving a triangular face, deep set eyes, low hanging columella and small chin. PIK3R1 mutations in SHORT syndrome result in reduced signaling through the PI3K-AKT-mTOR pathway. We performed whole exome sequencing for an individual with clinical features of SHORT syndrome but negative for PIK3R1 mutation and her parents...
October 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28751630/the-effect-of-sin1-and-microtubules-on-insulin-induced-pkc-%C3%AE-activation
#5
Xiang Yingying, Wang Caijuan, Yue Yenan, Tang Yuqin, Cai Xueqin, Wu Zhongming
BACKGROUND Protein kinase C zeta (PKC ζ) plays an important role in insulin induced glycometabolism and insulin receptor (IR) associated signaling pathways. The full activation of PKC ζ depends on its translocation from cytosol to membrane and phosphorylation at Thr410. However, the mechanism of PKC ζ activation remains elusive. In this study, the effect of SIN1 and microtubules on insulin-induced PKC ζ activation was investigated. MATERIAL AND METHODS HepG2 cells were stimulated with insulin for co-immunoprecipitation (co-IP) assay...
July 28, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/28738898/silicanin-1-is-a-conserved-diatom-membrane-protein-involved-in-silica-biomineralization
#6
Alexander Kotzsch, Philip Gröger, Damian Pawolski, Paul H H Bomans, Nico A J M Sommerdijk, Michael Schlierf, Nils Kröger
BACKGROUND: Biological mineral formation (biomineralization) proceeds in specialized compartments often bounded by a lipid bilayer membrane. Currently, the role of membranes in biomineralization is hardly understood. RESULTS: Investigating biomineralization of SiO2 (silica) in diatoms we identified Silicanin-1 (Sin1) as a conserved diatom membrane protein present in silica deposition vesicles (SDVs) of Thalassiosira pseudonana. Fluorescence microscopy of GFP-tagged Sin1 enabled, for the first time, to follow the intracellular locations of a biomineralization protein during silica biogenesis in vivo...
July 24, 2017: BMC Biology
https://www.readbyqxmd.com/read/28692058/tumor-suppressor-pdcd4-attenuates-sin1-translation-to-inhibit-invasion-in-colon-carcinoma
#7
Q Wang, J Zhu, Y-W Wang, Y Dai, Y-L Wang, C Wang, J Liu, A Baker, N H Colburn, H-S Yang
Programmed cell death 4 (Pdcd4), a tumor invasion suppressor, is frequently downregulated in colorectal cancer and other cancers. In this study, we find that loss of Pdcd4 increases the activity of mammalian target of rapamycin complex 2 (mTORC2) and thereby upregulates Snail expression. Examining the components of mTORC2 showed that Pdcd4 knockdown increased the protein but not mRNA level of stress-activated-protein kinase interacting protein 1 (Sin1), which resulted from enhanced Sin1 translation. To understand how Pdcd4 regulates Sin1 translation, the SIN1 5' untranslated region (5'UTR) was fused with luciferase reporter and named as 5'Sin1-Luc...
November 9, 2017: Oncogene
https://www.readbyqxmd.com/read/28489822/traf2-and-otud7b-govern-a-ubiquitin-dependent-switch-that-regulates-mtorc2-signalling
#8
Bin Wang, Zuliang Jie, Donghyun Joo, Alban Ordureau, Pengda Liu, Wenjian Gan, Jianping Guo, Jinfang Zhang, Brian J North, Xiangpeng Dai, Xuhong Cheng, Xiuwu Bian, Lingqiang Zhang, J Wade Harper, Shao-Cong Sun, Wenyi Wei
The mechanistic target of rapamycin (mTOR) has a key role in the integration of various physiological stimuli to regulate several cell growth and metabolic pathways. mTOR primarily functions as a catalytic subunit in two structurally related but functionally distinct multi-component kinase complexes, mTOR complex 1 (mTORC1) and mTORC2 (refs 1, 2). Dysregulation of mTOR signalling is associated with a variety of human diseases, including metabolic disorders and cancer. Thus, both mTORC1 and mTORC2 kinase activity is tightly controlled in cells...
May 18, 2017: Nature
https://www.readbyqxmd.com/read/28467426/pkb%C3%AE-akt3-loss-of-function-causes-learning-and-memory-deficits-and-deregulation-of-akt-mtorc2-signaling-relevance-for-schizophrenia
#9
Kristy R Howell, Kirsten Floyd, Amanda J Law
Psychiatric genetic studies have identified genome-wide significant loci for schizophrenia. The AKT3/1q44 locus is a principal risk region and gene-network analyses identify AKT3 polymorphisms as a constituent of several neurobiological pathways relevant to psychiatric risk; the neurobiological mechanisms remain unknown. AKT3 shows prenatal enrichment during human neocortical development and recurrent copy number variations involving the 1q43-44 locus are associated with cortical malformations and intellectual disability, implicating an essential role in early brain development...
2017: PloS One
https://www.readbyqxmd.com/read/28453552/specific-blockade-of-rictor-mtor-association-inhibits-mtorc2-activity-and-is-cytotoxic-in-glioblastoma
#10
Angelica Benavides-Serrato, Jihye Lee, Brent Holmes, Kenna A Landon, Tariq Bashir, Michael E Jung, Alan Lichtenstein, Joseph Gera
A small molecule which specifically blocks the interaction of Rictor and mTOR was identified utilizing a high-throughput yeast two-hybrid screen and evaluated as a potential inhibitor of mTORC2 activity in glioblastoma multiforme (GBM). In vitro, CID613034 inhibited mTORC2 kinase activity at submicromolar concentrations and in cellular assays specifically inhibited phosphorylation of mTORC2 substrates, including AKT (Ser-473), NDRG1 (Thr-346) and PKCα (Ser-657), while having no appreciable effects on the phosphorylation status of the mTORC1 substrate S6K (Thr-389) or mTORC1-dependent negative feedback loops...
2017: PloS One
https://www.readbyqxmd.com/read/28264193/substrate-specificity-of-tor-complex-2-is-determined-by-a-ubiquitin-fold-domain-of-the-sin1-subunit
#11
Hisashi Tatebe, Shinichi Murayama, Toshiya Yonekura, Tomoyuki Hatano, David Richter, Tomomi Furuya, Saori Kataoka, Kyoko Furuita, Chojiro Kojima, Kazuhiro Shiozaki
The target of rapamycin (TOR) protein kinase forms multi-subunit TOR complex 1 (TORC1) and TOR complex 2 (TORC2), which exhibit distinct substrate specificities. Sin1 is one of the TORC2-specific subunit essential for phosphorylation and activation of certain AGC-family kinases. Here, we show that Sin1 is dispensable for the catalytic activity of TORC2, but its conserved region in the middle (Sin1CRIM) forms a discrete domain that specifically binds the TORC2 substrate kinases. Sin1CRIM fused to a different TORC2 subunit can recruit the TORC2 substrate Gad8 for phosphorylation even in the sin1 null mutant of fission yeast...
March 7, 2017: ELife
https://www.readbyqxmd.com/read/28174303/central-regulatory-role-for-sin1-in-interferon-%C3%AE-ifn%C3%AE-signaling-and-generation-of-biological-responses
#12
Barbara Kroczynska, Gavin T Blyth, Robert L Rafidi, Beata Majchrzak-Kita, Lucy Xu, Diana Saleiro, Ewa M Kosciuczuk, Jacek Jemielity, Bing Su, Jessica K Altman, Elizabeth A Eklund, Eleanor N Fish, Leonidas C Platanias
The precise signaling mechanisms by which type II IFN receptors control expression of unique genes to induce biological responses remain to be established. We provide evidence that Sin1, a known element of the mammalian target of rapamycin complex 2 (mTORC2), is required for IFNγ-induced phosphorylation and activation of AKT and that such activation mediates downstream regulation of mTORC1 and its effectors. These events play important roles in the assembly of the eukaryotic translation initiation factor 4F (eIF4F) and mRNA translation of IFN-stimulated genes...
March 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28143890/localization-of-mtorc2-activity-inside-cells
#13
Michael Ebner, Benjamin Sinkovics, Magdalena Szczygieł, Daniela Wolfschoon Ribeiro, Ivan Yudushkin
Activation of protein kinase Akt via its direct phosphorylation by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) couples extracellular growth and survival cues with pathways controlling cell growth and proliferation, yet how growth factors target the activity of mTORC2 toward Akt is unknown. In this study, we examine the localization of the obligate mTORC2 component, mSin1, inside cells and report the development of a reporter to examine intracellular localization and regulation by growth factors of the endogenous mTORC2 activity...
February 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28036153/semiquantifiable-angiogenesis-parameters-in-association-with-the-malignant-transformation-of-oral-leukoplakia
#14
Daniel G E Thiem, Schamiem Schneider, Narayan T Venkatraman, Vinay V Kumar, Jürgen Brieger, Bernhard Frerich, Peer W Kämmerer
BACKGROUND: Aim of the study was to assess the role of angiogenesis in the process of malignant transformation of clinical diagnosed oral leucoplakia (OL). MATERIALS AND METHODS: A total of 131 histological preparations [oral leukoplakia/hyperkeratosis without dysplasia (OL; n = 49), oral leukoplakia/hyperkeratosis with mild dysplasia (OL-SIN1; n = 33), with moderate dysplasia (OL-SIN2; n = 13) and leukoplakia-derived oral squamous cell carcinoma (OL-OSCC; n = 36)] were evaluated for microvessel density (MVD), vessel diameter as well as for vascular endothelial growth factor (VEGF-A) expression...
October 2017: Journal of Oral Pathology & Medicine
https://www.readbyqxmd.com/read/27993679/epigenetic-activation-of-sin1-promotes-nsclc-cell-proliferation-and-metastasis-by-affecting-the-epithelial-mesenchymal-transition
#15
Zhongwu Hu, Yaqin Wang, Yuemei Wang, Bao Zang, Hongxia Hui, Zhenbing You, Xiaowei Wang
Stress-activated protein kinase (SAPK) interacting protein 1 (SIN1) is an essential component of mTORC2. Previous studies have shown that SIN1 is a key regulator of Akt pathway which plays an important role in various pathological conditions including cancer. While its effects and mechanisms on the progression of NSCLC remain unknown. In this study, we report that SIN1 is able to promote the growth and migration of NSCLC cells both in vitro and in vivo. Overexpression of SIN1 promoted A549 and H1299 cells proliferation by both MTT and colony formation assays...
January 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27986865/cross-talks-via-mtorc2-can-explain-enhanced-activation-in-response-to-insulin-in-diabetic-patients
#16
Rasmus Magnusson, Mika Gustafsson, Gunnar Cedersund, Peter Strålfors, Elin Nyman
The molecular mechanisms of insulin resistance in Type 2 diabetes have been extensively studied in primary human adipocytes, and mathematical modelling has clarified the central role of attenuation of mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activity in the diabetic state. Attenuation of mTORC1 in diabetes quells insulin-signalling network-wide, except for the mTOR in complex 2 (mTORC2)-catalysed phosphorylation of protein kinase B (PKB) at Ser(473) (PKB-S473P), which is increased. This unique increase could potentially be explained by feedback and interbranch cross-talk signals...
February 28, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/27894090/gremlin-promotes-retinal-pigmentation-epithelial-rpe-cell-proliferation-migration-and-vegf-production-via-activating-vegfr2-akt-mtorc2-signaling
#17
Yuan Liu, Zhijun Chen, Haixia Cheng, Juan Chen, Jing Qian
Retinopathy of prematurity (ROP) is characterized by late-phase pathologic retinal vasoproliferation. Gremlin is a novel vascular endothelial growth factors (VEGF) receptor 2 (VEGFR2) agonist and promotes angiogenic response. We demonstrated that gremlin expression was significantly increased in retinas of ROP model mice, which was correlated with VEGF upregulation. In retinal pigmentation epithelial (RPE) cells, gremlin activated VEGFR2-Akt-mTORC2 (mammalian target of rapamycin complex 2) signaling, and promoted cell proliferation, migration and VEGF production...
January 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/27780891/sin1-promotes-the-proliferation-and-migration-of-breast-cancer-cells-by-akt-activation
#18
Deqiang Wang, Ping Wu, Hui Wang, Lei Zhu, Wei Zhao, Yuqin Lu
Stress-activated protein kinase (SAPK) interacting protein 1 (SIN1) is an essential TORC2 component and a key regulator of Akt pathway that plays an important role in various pathological conditions including cancer. Whereas its functional role in breast cancer has not been well characterized. In the present study, SIN1 is associated with the progression and survival of breast cancer patients, as well as human breast cancer cell proliferation and migration. SIN1 mRNA level was significantly up-regulated in human breast cancer samples compared with their corresponding paracancerous histological normal tissues...
December 2016: Bioscience Reports
https://www.readbyqxmd.com/read/27412013/over-expression-of-dna-pkcs-in-renal-cell-carcinoma-regulates-mtorc2-activation-hif-2%C3%AE-expression-and-cell-proliferation
#19
Bing Zheng, Jia-Hui Mao, Xiao-Qing Li, Lin Qian, Hua Zhu, Dong-Hua Gu, Xiao-Dong Pan
Here, we demonstrated that DNA-PKcs is over-expressed in multiple human renal cell carcinoma (RCC) tissues and in primary/established human RCCs. Pharmacological or genetic inhibition of DNA-PKcs suppressed proliferation of RCC cells. DNA-PKcs was in the complex of mTOR and SIN1, mediating mTORC2 activation and HIF-2α expression in RCC cells. Inhibiting or silencing DNA-PKcs suppressed AKT Ser-473 phosphorylation and HIF-2α expression. In vivo, DNA-PKcs knockdown or oral administration of the DNA-PKcs inhibitor NU-7441 inhibited AKT Ser-473 phosphorylation, HIF-2α expression and 786-0 RCC xenograft growth in nude mice...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27237051/inhibition-of-rb-phosphorylation-leads-to-mtorc2-mediated-activation-of-akt
#20
Jinfang Zhang, Kai Xu, Pengda Liu, Yan Geng, Bin Wang, Wenjian Gan, Jianping Guo, Fei Wu, Y Rebecca Chin, Christian Berrios, Evan C Lien, Alex Toker, James A DeCaprio, Piotr Sicinski, Wenyi Wei
The retinoblastoma (Rb) protein exerts its tumor suppressor function primarily by inhibiting the E2F family of transcription factors that govern cell-cycle progression. However, it remains largely elusive whether the hyper-phosphorylated, non-E2F1-interacting form of Rb has any physiological role. Here we report that hyper-phosphorylated Rb directly binds to and suppresses the function of mTORC2 but not mTORC1. Mechanistically, Rb, but not p107 or p130, interacts with Sin1 and blocks the access of Akt to mTORC2, leading to attenuated Akt activation and increased sensitivity to chemotherapeutic drugs...
June 16, 2016: Molecular Cell
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