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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
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
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
D Thiem, S Schneider, Narayan T V, V V Kumar, J Brieger, B Frerich, P W Kämmerer
BACKGROUND: Aim of the study was to assess the role of angiogenesis in the process of malignant transformation of clinical diagnosed oral leukoplakia (OL). MATERIALS AND METHODS: 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...
December 30, 2016: Journal of Oral Pathology & Medicine
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
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
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
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
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
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
Ankita Khanna, Pouya Lotfi, Anita J Chavan, Nieves M Montaño, Parvin Bolourani, Gerald Weeks, Zhouxin Shen, Steven P Briggs, Henderikus Pots, Peter J M Van Haastert, Arjan Kortholt, Pascale G Charest
Target of Rapamycin Complex 2 (TORC2) has conserved roles in regulating cytoskeleton dynamics and cell migration and has been linked to cancer metastasis. However, little is known about the mechanisms regulating TORC2 activity and function in any system. In Dictyostelium, TORC2 functions at the front of migrating cells downstream of the Ras protein RasC, controlling F-actin dynamics and cAMP production. Here, we report the identification of the small GTPase Rap1 as a conserved binding partner of the TORC2 component RIP3/SIN1, and that Rap1 positively regulates the RasC-mediated activation of TORC2 in Dictyostelium...
May 13, 2016: Scientific Reports
Florence A Giger, Julien G Dumortier, Nicolas B David
Cell migration is key to many physiological and pathological conditions, including cancer metastasis. The cellular and molecular bases of cell migration have been thoroughly analyzed in vitro. However, in vivo cell migration somehow differs from in vitro migration, and has proven more difficult to analyze, being less accessible to direct observation and manipulation. This protocol uses the migration of the prospective prechordal plate in the early zebrafish embryo as a model system to study the function of candidate genes in cell migration...
2016: Journal of Visualized Experiments: JoVE
C S Lyu, Y L Zhang, J H Lang
OBJECTIVE: To investigate the efficiency of biological function of AT rich interaction domain 1A (ARID1A) gene silenced by small interfering RNA (siRNA) on ovarian clear cell carcinoma ES2 cell line. METHODS: (1) The three pairs ARID1A gene siRNA interference fragments siN1 (ARID1A-705), siN2 (ARID1A-1513), siN3 (ARID1A-2282) and one pair negative control were respectively designed, and transfected into ES2 cells by RNA interference max reagent transiently. Reverse transcription (RT)-PCR and western blot methods were used to detect the expression of ARID1A mRNA and protein in ES2 cells transfected with interference fragments respectively...
March 2016: Zhonghua Fu Chan Ke za Zhi
Han C Dan, Ricardo J Antonia, Albert S Baldwin
The ser-thr Akt plays a critical role in the regulation of cell survival, cell growth and proliferation, as well as energy metabolism and is dysregulated in many cancers. The regulation of Akt activity depends on the phosphorylation at two sites: (i) Thr308 in the activation loop by phosphoinositide-dependent kinase-1 (PDK1) and (ii) Ser473 hydrophobic motif at the carboxyl terminus by a second activity termed PDK2, which is the mTORC2 complex composed of mTOR, rictor, and Sin1. Previously we demonstrated that IKKα, a component of the IKK complex that controls NF-κB activation, participates in the Akt-dependent regulation of mTORC1...
April 19, 2016: Oncotarget
Yancun Yin, Hui Hua, Minjing Li, Shu Liu, Qingbin Kong, Ting Shao, Jiao Wang, Yuanming Luo, Qian Wang, Ting Luo, Yangfu Jiang
Mammalian target of rapamycin (mTOR) is a core component of raptor-mTOR (mTORC1) and rictor-mTOR (mTORC2) complexes that control diverse cellular processes. Both mTORC1 and mTORC2 regulate several elements downstream of type I insulin-like growth factor receptor (IGF-IR) and insulin receptor (InsR). However, it is unknown whether and how mTOR regulates IGF-IR and InsR themselves. Here we show that mTOR possesses unexpected tyrosine kinase activity and activates IGF-IR/InsR. Rapamycin induces the tyrosine phosphorylation and activation of IGF-IR/InsR, which is largely dependent on rictor and mTOR...
January 2016: Cell Research
Hadara Rubinfeld, Ortal Cohen, Adi Kammer, Guang Yang, Zvi R Cohen, Moshe Hadani, Ilan Shimon
BACKGROUND: Despite the success in treating some cancers, the efficacy of the mTOR inhibitors rapalogs as anti-cancer therapeutics has been limited. AIMS: We undertook to examine the effects of Torin1, a second-generation selective ATP-competitive mTOR inhibitor, in non-functioning pituitary tumor cells. During characterization of the molecular mechanisms that mediate Torin1 actions, there seemed to be a rationale for combining it with rapalogs. METHODS: Proliferation assays, flow cytometry and Western blotting were applied to assess the effects of Torin1, RAD001 and their combination on an MtT/E pituitary cell line and human-derived non-functioning pituitary tumor cells...
2016: Neuroendocrinology
Hai-Xin Yuan, Kun-Liang Guan
The mTOR complex 2, mTORC2, is a critical downstream effector of PI3K that stimulates AGC kinase members, including AKT, PKC, and SGK. Liu and colleagues reported that the pleckstrin homology domain of SIN1, an essential component of mTORC2, directly binds the PI3K product PtdIns(3,4,5)P3 to promote mTORC2 kinase activation and membrane localization, thereby revealing a mechanistic link between PI3K and mTORC2. Cancer Discov; 5(11); 1127-9. ©2015 AACR.See related article by Liu and colleagues, p. 1194.
November 2015: Cancer Discovery
Pengda Liu, Wenjian Gan, Y Rebecca Chin, Kohei Ogura, Jianping Guo, Jinfang Zhang, Bin Wang, John Blenis, Lewis C Cantley, Alex Toker, Bing Su, Wenyi Wei
UNLABELLED: mTOR serves as a central regulator of cell growth and metabolism by forming two distinct complexes, mTORC1 and mTORC2. Although mechanisms of mTORC1 activation by growth factors and amino acids have been extensively studied, the upstream regulatory mechanisms leading to mTORC2 activation remain largely elusive. Here, we report that the pleckstrin homology (PH) domain of SIN1, an essential and unique component of mTORC2, interacts with the mTOR kinase domain to suppress mTOR activity...
November 2015: Cancer Discovery
Yuanyang Yuan, Bangfen Pan, Haipeng Sun, Guoqiang Chen, Bing Su, Ying Huang
Sin1 or MAPKAP1 is a key component of mTORC2 signaling complex which is necessary for AKT phosphorylation at the S473 and T450 sites, and also for AKT downstream signaling as well. A number of Sin1 splicing variants have been reported that can produce different Sin1 isoforms due to exon skipping or alternative transcription initiation. In this report, we characterized four Sin1 isoforms, including a novel Sin1 isoform due to alternative 3' termination of the exon 9a, termed Sin1γ. Sin1γ expression can be detected in multiple adult mouse tissues, and it encodes a C-terminal truncated protein comparing to the full length Sin1β isoform...
2015: PloS One
Guang Yang, Danielle S Murashige, Sean J Humphrey, David E James
The mechanistic target of rapamycin complex 2 (mTORC2) regulates cell survival and cytoskeletal organization by phosphorylating its AGC kinase substrates; however, little is known about the regulation of mTORC2 itself. It was previously reported that Akt phosphorylates the mTORC2 subunit SIN1 at T86, activating mTORC2 through a positive feedback loop, though another study reported that S6K phosphorylates SIN1 at the same site, inhibiting mTORC2 activity. We performed extensive analysis of SIN1 phosphorylation upon inhibition of Akt, S6K, and mTOR under diverse cellular contexts, and we found that, in all cell lines and conditions studied, Akt is the major kinase responsible for SIN1 phosphorylation...
August 11, 2015: Cell Reports
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