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https://www.readbyqxmd.com/read/29138862/liver-kinase%C3%A2-b1-restoration-promotes-exosome-secretion-and-motility-of-lung-cancer-cells
#1
Cheng Zhang, Xiang Xiao, Minyi Chen, Hitham Aldharee, Yanfang Chen, Weiwen Long
Liver kinase B1 (LKB1) regulates a variety of cellular functions, including cell polarity, energy metabolism and cell growth, by targeting multiple signaling pathways such as AMPK/mTOR and p53. LKB1 functions as a tumor suppressor in sporadic cancers including lung cancer. Extracellular vesicles such as exosomes secreted by cancer cells modulate the tumor microenvironment and progression by targeting both tumor cells (autocrine actions) and other types of cells associated with tumors (paracrine actions). While the roles of LKB1 in cellular signaling in general is well-studied, its specific role in exosome-mediated signaling remains to be explored...
November 9, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29133590/genotoxic-damage-activates-the-ampk-%C3%AE-1-isoform-in-the-nucleus-via-ca2-camkk2-signaling-to-enhance-tumor-cell-survival
#2
Diana Vara Ciruelos, Madhumita Dandapani, Alexander Gray, Ejaife O Egbani, A Mark Evans, D Grahame Hardie
Many genotoxic cancer treatments activate AMP-activated protein kinase (AMPK), but the mechanisms of AMPK activation in response to DNA damage, and its downstream consequences, have been unclear. In this study, etoposide activates the α1 but not the α2 isoform of AMPK, primarily within the nucleus. AMPK activation is independent of ataxia-telangiectasia mutated (ATM), a DNA damage-activated kinase, and the principal upstream kinase for AMPK, LKB1, but correlates with increased nuclear Ca2+ and requires the Ca2+/calmodulin-dependent kinase, CaMKK2...
November 13, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29118262/stress-hormones-promote-egfr-inhibitor-resistance-in-nsclc-implications-for-combinations-with-%C3%AE-blockers
#3
Monique B Nilsson, Huiying Sun, Lixia Diao, Pan Tong, Diane Liu, Lerong Li, Youhong Fan, Alissa Poteete, Seung-Oe Lim, Kathryn Howells, Vincent Haddad, Daniel Gomez, Hai Tran, Guillermo Armaiz Pena, Lecia V Sequist, James C Yang, Jing Wang, Edward S Kim, Roy Herbst, J Jack Lee, Waun Ki Hong, Ignacio Wistuba, Mien-Chie Hung, Anil K Sood, John V Heymach
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance mediated by T790M-independent mechanisms remains a major challenge in the treatment of non-small cell lung cancer (NSCLC). We identified a targetable mechanism of EGFR inhibitor resistance whereby stress hormones activate β2-adrenergic receptors (β2-ARs) on NSCLC cells, which cooperatively signal with mutant EGFR, resulting in the inactivation of the tumor suppressor, liver kinase B1 (LKB1), and subsequently induce interleukin-6 (IL-6) expression...
November 8, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29109251/metabolic-control-of-regulatory-t-cell-treg-survival-and-function-by-lkb1
#4
Nanhai He, Weiwei Fan, Brian Henriquez, Ruth T Yu, Annette R Atkins, Christopher Liddle, Ye Zheng, Michael Downes, Ronald M Evans
The metabolic programs of functionally distinct T cell subsets are tailored to their immunologic activities. While quiescent T cells use oxidative phosphorylation (OXPHOS) for energy production, and effector T cells (Teffs) rely on glycolysis for proliferation, the distinct metabolic features of regulatory T cells (Tregs) are less well established. Here we show that the metabolic sensor LKB1 is critical to maintain cellular metabolism and energy homeostasis in Tregs. Treg-specific deletion of Lkb1 in mice causes loss of Treg number and function, leading to a fatal, early-onset autoimmune disorder...
November 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29106388/calcium-signalling-links-myc-to-nuak1
#5
T Monteverde, J Tait-Mulder, A Hedley, J R Knight, O J Sansom, D J Murphy
NUAK1 is a member of the AMPK-related family of kinases. Recent evidence suggests that NUAK1 is an important regulator of cell adhesion and migration, cellular and organismal metabolism, and regulation of TAU stability. As such, NUAK1 may play key roles in multiple diseases ranging from neurodegeneration to diabetes and metastatic cancer. Previous work revealed a crucial role for NUAK1 in supporting viability of tumour cells specifically when MYC is overexpressed. This role is surprising, given that NUAK1 is activated by the tumour suppressor LKB1...
November 6, 2017: Oncogene
https://www.readbyqxmd.com/read/29089450/mark3-mediated-phosphorylation-of-arhgef2-couples-microtubules-to-the-actin-cytoskeleton-to-establish-cell-polarity
#6
María-José Sandí, Christopher B Marshall, Marc Balan, Étienne Coyaud, Ming Zhou, Daniel M Monson, Noboru Ishiyama, Arun A Chandrakumar, José La Rose, Amber L Couzens, Anne-Claude Gingras, Brian Raught, Wei Xu, Mitsuhiko Ikura, Deborah K Morrison, Robert Rottapel
The PAR-1-MARK pathway controls cell polarity through the phosphorylation of microtubule-associated proteins. Rho-Rac guanine nucleotide exchange factor 2 (ARHGEF2), which activates Ras homolog family member A (RHOA), is anchored to the microtubule network and sequestered in an inhibited state through binding to dynein light chain Tctex-1 type 1 (DYNLT1). We showed in mammalian cells that liver kinase B1 (LKB1) activated the microtubule affinity-regulating kinase 3 (MARK3), which in turn phosphorylated ARHGEF2 at Ser(151) This modification disrupted the interaction between ARHGEF2 and DYNLT1 by generating a 14-3-3 binding site in ARHGEF2, thus causing ARHGEF2 to dissociate from microtubules...
October 31, 2017: Science Signaling
https://www.readbyqxmd.com/read/29084199/class-iii-phosphatidylinositol-3-oh-kinase-controls-epithelial-integrity-through-endosomal-lkb1-regulation
#7
Fergal O'Farrell, Viola Hélène Lobert, Marte Sneeggen, Ashish Jain, Nadja Sandra Katheder, Eva Maria Wenzel, Sebastian Wolfgang Schultz, Kia Wee Tan, Andreas Brech, Harald Stenmark, Tor Erik Rusten
The molecular mechanisms underlying the interdependence between intracellular trafficking and epithelial cell polarity are poorly understood. Here we show that inactivation of class III phosphatidylinositol-3-OH kinase (CIII-PI3K), which produces phosphatidylinositol-3-phosphate (PtdIns3P) on endosomes, disrupts epithelial organization. This is caused by dysregulation of endosomally localized Liver Kinase B1 (LKB1, also known as STK11), which shows delocalized and increased activity accompanied by dysplasia-like growth and invasive behaviour of cells provoked by JNK pathway activation...
October 30, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/29050265/reactive-oxygen-species-dependent-phosphorylation-of-the-liver-kinase-b1-amp-activated-protein-kinase-acetyl-coa-carboxylase-signaling-is-critically-involved-in-apoptotic-effect-of-lambertianic-acid-in-hepatocellular-carcinoma-cells
#8
Arong Jeong, Ju-Ha Kim, Hyo-Jung Lee, Sung-Hoon Kim
Though lambertianic acid (LA) is reported to have hypolipidemic activity in liver, its underlying anticancer mechanism is poorly understood so far. Thus, in the present study, apoptotic mechanism of LA was elucidated in HepG2 and SK-Hep1 hepatocellular carcinoma (HCC) cells. Here LA increased cytotoxicity, sub-G1 population and Annexin V/PI positive cells in two HCC cells. Also, LA cleaved caspase-3 and poly(ADP-ribose) polymerase (PARP), activated phosphorylation of liver kinase B1 (LKB1)/AMP activated protein kinase (AMPK)/ acetyl-CoA carboxylase (ACC) pathway and also suppressed antiapoptotic proteins such as phosphorylation of Akt/ mammalian target of rapamycin (mTOR) and the expression of B cell lymphoma-2 (Bcl-2)/ B-cell lymphoma-extra large (Bcl-xL) and cyclooxygenase-2 (COX-2) in two HCC cells...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29035613/quercetin-induced-amp-activated-protein-kinase-activation-attenuates-vasoconstriction-through-lkb1-ampk-signaling-pathway
#9
Seul Gi Kim, Jae-Ryong Kim, Hyoung Chul Choi
The vascular tone plays an important role in blood pressure and flow. It is influenced by the contraction of vascular smooth muscle cells (VSMCs), which in turn is regulated by the balance between the myosin light chain kinase (MLCK) and the phosphorylated myosin light chain (p-MLC). Quercetin is a common flavonoid which is found in many fruits and red wine. Although quercetin has been widely reported to be involved in cell proliferation, migration, and apoptosis in VSMCs, it has not yet been demonstrated whether quercetin is related to vasocontraction, a function regulated by the AMP-activated protein kinase (AMPK) signaling pathway...
October 16, 2017: Journal of Medicinal Food
https://www.readbyqxmd.com/read/29034085/amp-activated-protein-kinase-not-just-an-energy-sensor
#10
REVIEW
David Grahame Hardie, Sheng-Cai Lin
Orthologues of AMP-activated protein kinase (AMPK) occur in essentially all eukaryotes as heterotrimeric complexes comprising catalytic α subunits and regulatory β and γ subunits. The canonical role of AMPK is as an energy sensor, monitoring levels of the nucleotides AMP, ADP, and ATP that bind competitively to the γ subunit. Once activated, AMPK acts to restore energy homeostasis by switching on alternate ATP-generating catabolic pathways while switching off ATP-consuming anabolic pathways. However, its ancestral role in unicellular eukaryotes may have been in sensing of glucose rather than energy...
2017: F1000Research
https://www.readbyqxmd.com/read/29032027/peripheral-neuropathy-and-hindlimb-paralysis-in-a-mouse-model-of-adipocyte-specific-knockout-of-lkb1
#11
Yan Xiong, Jessica C Page, Naagarajan Narayanan, Chao Wang, Zhihao Jia, Feng Yue, Xine Shi, Wen Jin, Keping Hu, Meng Deng, Riyi Shi, Tizhong Shan, Gongshe Yang, Shihuan Kuang
Brown adipose tissues (BAT) burn lipids to generate heat through uncoupled respiration, thus representing a powerful target to counteract lipid accumulation and obesity. The tumor suppressor liver kinase b1 (Lkb1) is a key regulator of cellular energy metabolism; and adipocyte-specific knockout of Lkb1 (Ad-Lkb1 KO) leads to the expansion of BAT, improvements in systemic metabolism and resistance to obesity in young mice. Here we report the unexpected finding that the Ad-Lkb1 KO mice develop hindlimb paralysis at mid-age...
October 2017: EBioMedicine
https://www.readbyqxmd.com/read/29029395/rasal1-is-a-potent-regulator-of-hepatic-stellate-cell-activity-and-liver-fibrosis
#12
Akemi Takata, Motoyuki Otsuka, Takahiro Kishikawa, Mari Yamagami, Rei Ishibashi, Kazuma Sekiba, Tatsunori Suzuki, Motoko Ohno, Yui Yamashita, Takaya Abe, Ryota Masuzaki, Tsuneo Ikenoue, Kazuhiko Koike
Liver fibrosis, leading to cirrhosis and liver failure, can occur after chronic liver injury. The transition of hepatic stellate cells (HSCs) from quiescent cells into proliferative and fibrogenic cells is a central event in liver fibrosis. Here, we show that RAS protein activator like-1 (RASAL1), a RAS-GTPase-activating protein, which switches off RAS activity, is significantly decreased during HSC activation, and that HSC activation can be antagonized by forced expression of the RASAL1 protein. We demonstrate that RASAL1 suppresses HSC proliferation by regulating the Ras-MAPK pathway, and that RASAL1 suppresses HSC fibrogenic activity by regulating the PKA-LKB1-AMPK-SRF pathway by interacting with angiotensin II receptor, type 1...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29027899/metformin-extends-c-elegans-lifespan-through-lysosomal-pathway
#13
Jie Chen, Yuhui Ou, Yi Li, Shumei Hu, Li-Wa Shao, Ying Liu
Metformin, a widely used first-line drug for treatment of type 2 diabetes (T2D), has been shown to extend lifespan and delay the onset of age-related diseases. However, its primary locus of action remains unclear. Using a pure in vitro reconstitution system, we demonstrate that metformin acts through the v-ATPase-Ragulator lysosomal pathway to coordinate mTORC1 and AMPK, two hubs governing metabolic programs. We further show in Caenorhabditis elegans that both v-ATPase-mediated TORC1 inhibition and v-ATPase-AXIN/LKB1-mediated AMPK activation contribute to the lifespan extension effect of metformin...
October 13, 2017: ELife
https://www.readbyqxmd.com/read/29022902/differential-regulation-of-spermatogenic-process-by-lkb1-isoforms-in-mouse-testis
#14
Feifei Kong, Mei Wang, Xiaojing Huang, Qiuling Yue, Xiang Wei, Xiaowei Dou, Xiaoxu Peng, Yuanyuan Jia, Ke Zheng, Tinghe Wu, Jun Yan, Jing Li
Liver serine/threonine kinase B1 (LKB1) is a tumor suppressor associated with the pathogenesis of Peutz-Jeghers syndrome. Affected males are at increased risk of developing Sertoli cell tumors and display defective spermatogenesis. Male mice lacking the short isoform (Lkb1S) of Lkb1 were sterile and exhibited abnormal spermiogenesis. In addition to the short isoform, the long isoform of Lkb1 (Lkb1L) is also expressed in testis; however, the requirement of the long isoform for fertility and the functional difference between the isoforms remain unknown...
October 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28990606/a-combined-docosahexaenoic-acid-thyroid-hormone-protocol-upregulates-rat-liver-%C3%AE-klotho-expression-and-downstream-components-of-fgf21-signaling-as-a-potential-novel-approach-to-metabolic-stress-conditions
#15
R Vargas, B Riquelme, J Fernández, L A Videla
Liver preconditioning by a docosahexaenoic acid (DHA) and triiodothyronine (T3) combined protocol underlies peroxisome-proliferator activated receptor α (PPARα)-fibroblast growth factor 21 (FGF21) upregulation, the study of the regulatory mechanisms involved being the aim of this work. Combined DHA (daily doses of 300 mg kg(-1) for 3 days)-T3 (0.05 mg kg(-1) at the fourth day) administration elicited higher levels of liver DHA and serum T3, with enhanced hepatic nuclear/cytosolic PPARα ratios, upregulation of FGF21 and β-Klotho expression, and a small reduction in that of FGF receptor 1 (FGFR1), compared with the respective controls...
October 9, 2017: Food & Function
https://www.readbyqxmd.com/read/28988648/bat-expansion-a-panacea-against-obesity-lessons-from-lkb1
#16
Miguel López
No abstract text is available yet for this article.
October 2017: EBioMedicine
https://www.readbyqxmd.com/read/28983714/a-novel-phenylchromane-derivative-increases-the-rate-of-glucose-uptake-in-l6-myotubes-and-augments-insulin-secretion-from-pancreatic-beta-cells-by-activating-ampk
#17
Naomi Rozentul, Yosef Avrahami, Moran Shubely, Laura Levy, Anna Munder, Guy Cohen, Erol Cerasi, Shlomo Sasson, Arie Gruzman
PURPOSE: A series of novel polycyclic aromatic compounds that augment the rate of glucose uptake in L6 myotubes and increase glucose-stimulated insulin secretion from beta-cells were synthesized. Designing these molecules, we have aimed at the two main pathogenic mechanisms of T2D, deficient insulin secretion and diminished glucose clearance. The ultimate purpose of this work was to create a novel antidiabetic drug candidate with bi-functional mode of action. METHODS: All presented compounds were synthesized, and characterized in house...
October 5, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28976799/wipi-%C3%AE-propellers-function-as-scaffolds-for-stk11-lkb1-ampk-and-ampk-related-kinase-signaling-in-autophagy
#18
Daniela Bakula, Amelie J Mueller, Tassula Proikas-Cezanne
The article discusses new findings on the role of the 4 human WIPI proteins at the onset of macroautophagy/autophagy. New insights revealing a circuit scaffold function of WIPI β-propellers that interconnect autophagy signaling control with appropriate autophagosome formation are summarized.
October 4, 2017: Autophagy
https://www.readbyqxmd.com/read/28974424/lkb1-regulates-granule-cell-migration-and-cortical-folding-of-the-cerebellar-cortex
#19
Kaitlyn E Ryan, Patrick S Kim, Jonathan T Fleming, Emily Brignola, Frances Y Cheng, Ying Litingtung, Chin Chiang
Cerebellar growth and foliation require the Hedgehog-driven proliferation of granule cell precursors (GCPs) in the external granule layer (EGL). However, that increased or extended GCP proliferation generally does not elicit ectopic folds suggests that additional determinants control cortical expansion and foliation during cerebellar development. Here, we find that genetic loss of the serine-threonine kinase Liver Kinase B1 (Lkb1) in GCPs increased cerebellar cortical size and foliation independent of changes in proliferation or Hedgehog signaling...
September 30, 2017: Developmental Biology
https://www.readbyqxmd.com/read/28967900/aurora-a-mediated-phosphorylation-of-lkb1-compromises-lkb1-ampk-signaling-axis-to-facilitate-nsclc-growth-and-migration
#20
X Zheng, J Chi, J Zhi, H Zhang, D Yue, J Zhao, D Li, Y Li, M Gao, J Guo
Deletion or loss-of-function mutation of LKB1, frequently occurring in non-small cell lung cancers (NSCLCs), is a predominant caution of NSCLC initiation and progression. However, the upstream signaling pathways governing LKB1 activation are largely unknown. Here, we report that LKB1 undergoes Aurora kinase A (AURKA)-mediated phosphorylation, which largely compromises the LKB1/AMPK signaling axis, in turn leading to the elevation of NSCLC cell proliferation, invasion and migration. Mechanically, AURKA-mediated phosphorylation of LKB1 impairs LKB1 interaction with and phosphorylation of its downstream target AMPKα, which has critical roles in governing cancer cell energy metabolic homeostasis and tumorigenesis...
October 2, 2017: Oncogene
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