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pp2a akt recruitment

Anastasia Sacharidou, Ken L Chambliss, Victoria Ulrich, Jane E Salmon, Yu-Min Shen, Joachim Herz, David Y Hui, Lance S Terada, Philip W Shaul, Chieko Mineo
In the antiphospholipid syndrome (APS), antiphospholipid antibody (aPL) recognition of β2 glycoprotein I promotes thrombosis, and preclinical studies indicate that this is due to endothelial nitric oxide synthase (eNOS) antagonism via apolipoprotein E receptor 2 (apoER2)-dependent processes. How apoER2 molecularly links these events is unknown. Here, we show that, in endothelial cells, the apoER2 cytoplasmic tail serves as a scaffold for aPL-induced assembly and activation of the heterotrimeric protein phosphatase 2A (PP2A)...
May 10, 2018: Blood
Deborah Denis, Cecile Rouleau, Brian S Schaffhausen
Middle T antigen (MT), the principal oncoprotein of murine polyomavirus, transforms by association with cellular proteins. Protein phosphatase 2A (PP2A), YAP, Src family tyrosine kinases, Shc, phosphatidylinositol 3-kinase (PI3K), and phospholipase C-γ1 (PLCγ1) have all been implicated in MT transformation. Mutant dl1015, with deletion of residues 338 to 347 in the C-terminal region, has been an enigma, because the basis for its transformation defect has not been apparent. This work probes the dl1015 region of MT...
January 15, 2017: Journal of Virology
H Liu, H Qiu, Y Song, Y Liu, H Wang, M Lu, M Deng, Y Gu, J Yin, K Luo, Z Zhang, X Jia, G Zheng, Z He
Triple-negative breast cancer (TNBC) is very aggressive and currently has no specific therapeutic targets; as a consequence, TNBC exhibits poor clinical outcome. In this study, we showed that cancerous inhibitor of protein phosphatase 2A (Cip2a) represents a promising target in TNBC because Cip2a was highly expressed in TNBC cells and tumor tissues, and its expression showed an inverse correlation with overall survival in patients with TNBC. We found that inhibition of Cip2a in TNBC cells induced cell cycle arrest at the G2/M phase, inhibited cell proliferation and delayed tumor growth in the xenograft model...
April 6, 2017: Oncogene
Dorien Haesen, Layka Abbasi Asbagh, Rita Derua, Antoine Hubert, Stefanie Schrauwen, Yana Hoorne, Frédéric Amant, Etienne Waelkens, Anna Sablina, Veerle Janssens
Somatic missense mutations in the Ser/Thr protein phosphatase 2A (PP2A) Aα scaffold subunit gene PPP2R1A are among the few genomic alterations that occur frequently in serous endometrial carcinoma (EC) and carcinosarcoma, two clinically aggressive subtypes of uterine cancer with few therapeutic options. Previous studies reported that cancer-associated Aα mutants exhibit defects in binding to other PP2A subunits and contribute to cancer development by a mechanism of haploinsufficiency. Here we report on the functional significance of the most recurrent PPP2R1A mutations in human EC, which cluster in Aα HEAT repeats 5 and 7...
October 1, 2016: Cancer Research
Tomonaga Ichikawa, Shingo Nakahata, Masahiro Fujii, Hidekatsu Iha, Kazuhiro Morishita
The activation of nuclear factor kappa B (NF-κB) signaling has a central role in the development of adult T-cell leukemia/lymphoma (ATL) and many other cancers. However, the activation mechanism of the NF-κB pathways remains poorly understood. Recently, we reported that N-myc downstream-regulated gene 2 (NDRG2) is a negative regulator of the phosphoinositide 3-kinase (PI3K)/AKT pathway by promoting the active dephosphorylated form of PTEN at its C-terminus via the recruitment of PP2A. Additionally, the down-regulation of NDRG2 expression promotes the inactive phosphorylated form of PTEN, which results in constitutively active PI3K/AKT signaling in various cancer cell types...
August 13, 2015: Scientific Reports
Shaoyong Lu, Rong Deng, Haiming Jiang, Huili Song, Shuai Li, Qiancheng Shen, Wenkang Huang, Ruth Nussinov, Jianxiu Yu, Jian Zhang
Kinases use ATP to phosphorylate substrates; recent findings underscore the additional regulatory roles of ATP. Here, we propose a mechanism for allosteric regulation of Akt1 kinase phosphorylation by ATP. Our 4.7-μs molecular dynamics simulations of Akt1 and its mutants in the ATP/ADP bound/unbound states revealed that ATP occupancy of the ATP-binding site stabilizes the closed conformation, allosterically protecting pT308 by restraining phosphatase access and key interconnected residues on the ATP→pT308 allosteric pathway...
September 1, 2015: Structure
Tomonaga Ichikawa, Shingo Nakahata, Tomohiro Tamura, Nawin Manachai, Kazuhiro Morishita
N-myc downstream-regulated gene 2 (NDRG2) is one of the important stress-inducible genes and plays a critical role in negatively regulating PI3K/AKT signaling during hypoxia and inflammation. Through recruitment of PP2A phosphatase, NDRG2 maintains the dephosphorylated status of PTEN to suppress excessive PI3K/AKT signaling, and loss of NDRG2 expression is frequently seen in various types of cancer with enhanced activation of PI3K/AKT signaling. Because NDRG2 is highly expressed in the nervous system, we investigated whether NDRG2 plays a functional role in the nervous system using Ndrg2-deficient mice...
October 2015: Cellular Signalling
E Bousquet, O Calvayrac, J Mazières, I Lajoie-Mazenc, N Boubekeur, G Favre, A Pradines
Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, which is mainly due to its high risk of metastatic dissemination. One critical point of this process is the ability of cancer cells to detach from the primary tumor and migrate through the extracellular matrix; however, the underlying molecular mechanisms are not yet fully understood. In the present study, we identified the small GTPase RhoB as a key regulator of bronchial cell morphology in a three-dimensional (3D) matrix...
April 7, 2016: Oncogene
Yue Zhou, Daying Wang, Xiufang Gao, Karsheng Lew, Arthur Mark Richards, Peipei Wang
Hydrogen sulfide (H2S) is known to have cardiac protective effects through Akt activation. Akt acts as a 'central sensor' for myocyte survival or death; its activity is regulated by multiple kinases including PI3K, mTORC2, PDK1 and phosphatases including PTEN, PP2A and PHLPPL. Based on the previous finding that PI3K inhibitor LY294002 abolishes H2S-induced Akt phosphorylation and cardioprotection, it is accepted that PI3K is the mediator of H2S-induced Akt phosphorylation. However, LY294002 inhibits both PI3K and mTOR, and PI3K only recruits Akt to the membrane where Akt is phosphorylated by Akt kinases...
2014: PloS One
Shingo Nakahata, Tomonaga Ichikawa, Phudit Maneesaay, Yusuke Saito, Kentaro Nagai, Tomohiro Tamura, Nawin Manachai, Norio Yamakawa, Makoto Hamasaki, Issay Kitabayashi, Yasuhito Arai, Yae Kanai, Tomohiko Taki, Takaya Abe, Hiroshi Kiyonari, Kazuya Shimoda, Koichi Ohshima, Akira Horii, Hiroshi Shima, Masafumi Taniwaki, Ryoji Yamaguchi, Kazuhiro Morishita
Constitutive phosphatidylinositol 3-kinase (PI3K)-AKT activation has a causal role in adult T-cell leukaemia-lymphoma (ATLL) and other cancers. ATLL cells do not harbour genetic alterations in PTEN and PI3KCA but express high levels of PTEN that is highly phosphorylated at its C-terminal tail. Here we report a mechanism for the N-myc downstream-regulated gene 2 (NDRG2)-dependent regulation of PTEN phosphatase activity via the dephosphorylation of PTEN at the Ser380, Thr382 and Thr383 cluster within the C-terminal tail...
February 26, 2014: Nature Communications
L M Harrison, S H Muller, D Spano
G protein-coupled receptors (GPCR) signal not only through heterotrimeric G proteins, but also through alternate pathways. Thus, dopamine D2 receptors in the striatum signal through Gαi/o and also by promoting formation of a multi-protein complex containing β-arrestin2, protein phosphatase 2A (PP2A), and Akt in order to dephosphorylate Akt. Lithium, on the other hand, disrupts this complex to increase Akt phosphorylation. Rhes is a striatally enriched GTP-binding protein that has been shown to inhibit dopamine receptor-mediated behavior and signaling through heterotrimeric G proteins...
April 16, 2013: Neuroscience
Ma Eugenia Díaz, Lorena González, Johanna G Miquet, Carolina S Martínez, Ana I Sotelo, Andrzej Bartke, Daniel Turyn
The epidermal growth factor (EGF) activates the phosphatidylinositol 3-kinase (PI3K)-Akt cascade among other signaling pathways. This route is involved in cell proliferation and survival, therefore, its dysregulation can promote cancer. Considering the relevance of the PI3K-Akt signaling in cell survival and in the pathogenesis of cancer, and that GH was reported to modulate EGFR expression and signaling, the objective of this study was to analyze the effects of increased GH levels on EGF-induced PI3K-Akt signaling...
February 2012: Cellular Signalling
Pascale G Charest, Zhouxin Shen, Ashley Lakoduk, Atsuo T Sasaki, Steven P Briggs, Richard A Firtel
Ras was found to regulate Dictyostelium chemotaxis, but the mechanisms that spatially and temporally control Ras activity during chemotaxis remain largely unknown. We report the discovery of a Ras signaling complex that includes the Ras guanine exchange factor (RasGEF) Aimless, RasGEFH, protein phosphatase 2A (PP2A), and a scaffold designated Sca1. The Sca1/RasGEF/PP2A complex is recruited to the plasma membrane in a chemoattractant- and F-actin-dependent manner and is enriched at the leading edge of chemotaxing cells where it regulates F-actin dynamics and signal relay by controlling the activation of RasC and the downstream target of rapamycin complex 2 (TORC2)-Akt/protein kinase B (PKB) pathway...
May 18, 2010: Developmental Cell
Michael J Van Kanegan, Stefan Strack
Nerve growth factor (NGF) is critical for the differentiation and maintenance of neurons in the peripheral and central nervous system. Sustained autophosphorylation of the TrkA receptor tyrosine kinase and long-lasting activation of downstream kinase cascades are hallmarks of NGF signaling, yet our knowledge of the molecular mechanisms underlying prolonged TrkA activity is incomplete. Protein phosphatase 2A (PP2A) is a heterotrimeric Ser/Thr phosphatase composed of a scaffolding, catalytic, and regulatory subunit (B, B', and B" gene families)...
February 2009: Molecular and Cellular Biology
Shirly Amar, Galit Shaltiel, Liad Mann, Alon Shamir, Brian Dean, Elizabeth Scarr, Yuly Bersudsky, R H Belmaker, Galila Agam
Par-4 has been suggested to mediate dopamine neurotransmission. Dopamine D2 receptor (DRD2) activation induces a signalling complex of AKT1, PP2A and beta-arrestin2 which dephosphorylates/inactivates AKT1 thereby activating GSK-3beta, transducing dopamine-dependent behaviour. DRD2 activation also results in down-regulation of PKA activity. Among other substrates PKA phosphorylates GSK-3beta. Prolonged DRD2 activation leads to its 'desensitization' which involves GRKs and beta-arrestins. beta-arrestin1 binds to phosphorylated receptors preventing further G-protein stimulation...
March 2008: International Journal of Neuropsychopharmacology
Lloyd C Trotman, Andrea Alimonti, Pier Paolo Scaglioni, Jason A Koutcher, Carlos Cordon-Cardo, Pier Paolo Pandolfi
The proto-oncogene AKT (also known as PKB) is activated in many human cancers, mostly owing to loss of the PTEN tumour suppressor. In such tumours, AKT becomes enriched at cell membranes where it is activated by phosphorylation. Yet many targets inhibited by phosphorylated AKT (for example, the FOXO transcription factors) are nuclear; it has remained unclear how relevant nuclear phosphorylated AKT (pAKT) function is for tumorigenesis. Here we show that the PMLtumour suppressor prevents cancer by inactivating pAKT inside the nucleus...
May 25, 2006: Nature
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