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| Open AccessG9a regulates breast cancer growth by modulating iron homeostasis through the repression of ferroxidase hephaestin
G9a is a histone methyltransferase highly expressed in several cancers including breast cancer. Here the authors propose a mechanism through which G9a promotes breast cancer by regulating iron metabolism through the repression of ferroxidase hephaestin.
- Ya-fang Wang
- , Jie Zhang
- & Yi Chen
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Article
| Open AccessChronic activation of JNK JAK/STAT and oxidative stress signalling causes the loser cell status
Cell competition causes the removal of less fit cells (‘losers’) but why some gene mutations turn cells into losers is unclear. Here, the authors show that Drosophila wing disc cells carrying some loser mutations activate Nrf2 and JNK signalling, which contribute to the loser status.
- Iwo Kucinski
- , Michael Dinan
- & Eugenia Piddini
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Article
| Open AccessMembrane-binding and activation of LKB1 by phosphatidic acid is essential for development and tumour suppression
LKB1 regulates various cellular processes such as cell proliferation, energy homeostasis and cell polarity and is frequently downregulated in various tumours. Here the authors show that LKB1 activation requires direct binding to phospholipids and show this has an implication for carcinogenesis.
- Giada Dogliotti
- , Lars Kullmann
- & Michael P. Krahn
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Article
| Open AccessContrasting mechanisms of growth in two model rod-shaped bacteria
Protein MreB participates in elongation of sidewalls during growth of most rod-shaped bacteria. Here, the authors use fluorescence microscopy and single-particle tracking to visualize MreB, showing thatBacillus subtilis and Escherichia coliappear to use different strategies to adapt to growth rate variations.
- Cyrille Billaudeau
- , Arnaud Chastanet
- & Rut Carballido-López
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Article
| Open AccessEGFR-dependent TOR-independent endocycles support Drosophila gut epithelial regeneration
In response to gut epithelial damage,Drosophilastem cells proliferate to produce large polyploid enterocytes (EC), which comprise the bulk of the epithelium. Here, the authors show that stress-dependent EGFR/MAP kinase signalling drives both endoreplication and cell growth in newborn ECs.
- Jinyi Xiang
- , Jennifer Bandura
- & Bruce A. Edgar
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Article
| Open AccessCell-size dependent progression of the cell cycle creates homeostasis and flexibility of plant cell size
The mechanistic coupling of cell growth and cell cycle control with cell size regulation in tissues is not well understood. Here, the authors show that within the shoot apical meristem of Arabidopsis cell size depends on developmental stage, genotype and environmental signals; however cell growth and cell division are cell-autonomously coordinated.
- Angharad R. Jones
- , Manuel Forero-Vargas
- & James A. H. Murray
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Article
| Open AccessA genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells
Individual human epidermal cells differ in their self-renewal ability. Here the authors perform genome-wide pooled RNAi screens to uncover the molecular basis for this heterogeneity, and identify genes conferring a clonal growth advantage on normal and neoplastic human epidermal cells.
- Gernot Walko
- , Samuel Woodhouse
- & Fiona M. Watt
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Article
| Open AccessThe pro-inflammatory signalling regulator Stat4 promotes vasculogenesis of great vessels derived from endothelial precursors
Stat4 is a transcription factor known to regulate pro-inflammatory signalling. Here, Menget al. show that Stat4 is not only regulating inflammation but it is also crucial for great vessels development and endothelial precursor proliferation in zebrafish, by inhibiting the expression of hdac3and counteracting the effect of Stat1a.
- Zhao-Zheng Meng
- , Wei Liu
- & Yong Zhou
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Article
| Open AccessmTORC2 signalling regulates M2 macrophage differentiation in response to helminth infection and adaptive thermogenesis
mTORC1 and mTORC2 are alternatively required for differentiation of T cells into Th1/Th17 or Th2 cells. Here the authors show mTORC2 signalling is also needed for IL-4-induced M2 activation with functional evidence provided by aN. brasiliensisinfection model and cold challenge to model adaptive thermogenesis.
- R. W. Hallowell
- , S. L. Collins
- & M. R. Horton
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Article
| Open AccessmTORC1 inhibition in cancer cells protects from glutaminolysis-mediated apoptosis during nutrient limitation
Inhibitors of the mTORC1 pathway are considered anti-cancer drugs. Here, the authors show that on nutrient restriction, glutaminolysis-induced activation of mTORC1 induces apoptosis via inhibiting autophagy, highlighting that under such conditions inhibition of mTORC1 results in survival of cancer cells.
- Victor H. Villar
- , Tra Ly Nguyen
- & Raúl V. Durán
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Article
| Open AccessOptimality and sub-optimality in a bacterial growth law
Organisms improve their fitness by adjusting their gene expression to the environment, for example bacteria scale the expression of metabolic enzymes near linearly to their growth rate. Here, the authors show that such linear scaling often maximizes growth rate, but that linear scaling is suboptimal under some conditions.
- Benjamin D. Towbin
- , Yael Korem
- & Uri Alon
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Article
| Open Accessα3 Chains of type V collagen regulate breast tumour growth via glypican-1
Collagen has a role in cancer and is particularly important for breast cancer. Here the authors show that the expression of α3 type V collagen and one of its receptors- glipican-1- in the same cell, contributes to a deregulated growth of breast cancer cells.
- Guorui Huang
- , Gaoxiang Ge
- & Daniel S. Greenspan
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Article
| Open AccessStarved epithelial cells uptake extracellular matrix for survival
Inhibition of PI3K/mTOR, which mimics nutrient starvation, causes death of detached but not matrix-attached cancer cells. Here the authors show that nutrient restriction of epithelial cells causes uptake of the matrix protein laminin, which results in increased intracellular amino acids and enhanced mTORC1 signalling.
- Taru Muranen
- , Marcin P. Iwanicki
- & Nada Y. Kalaany
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Article
| Open AccessThe Hippo signalling pathway coordinates organ growth and limits developmental variability by controlling dilp8 expression
The hormone Dipl8 regulates organ growth inDrosophila whereas the Hippo pathway controls organ size. Here, the authors show that the expression of Dipl8 is regulated by the Hippo pathway, thus linking organ growth or organ size in Drosophila.
- Emilie Boone
- , Julien Colombani
- & Pierre Léopold
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Article
| Open AccessThe oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway
Oncogenic mutations of isocitrate dehydrogenases 1 and 2 result in the production of the oncometabolite R-2-hydroxyglutarate. Here the authors show that the oncometabolite promotes mTOR activation in a PTEN/PI3K-independent manner by regulating DEPTOR stability via inhibition of KDM4A activity.
- Mélissa Carbonneau
- , Laurence M. Gagné
- & Frédérick A. Mallette
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Article
| Open AccessProteome-wide association studies identify biochemical modules associated with a wing-size phenotype in Drosophila melanogaster
How genetic diversity generates complex phenotypes along a continuum remains a fundamental question of biology. Here—applying the emerging SWATH proteomics technology—the authors describe a proteome wide association study (PWAS) of Drosophila wing size and identify functional protein clusters associated with this trait.
- Hirokazu Okada
- , H. Alexander Ebhardt
- & Ernst Hafen
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Article
| Open AccessMRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity
Mrf4 is a transcription factor important for muscle development, but despite high expression its function in adults is unknown. Here the authors show that interfering with Mrf4 in adult mice leads to muscle hypertrophy by activating MEF2-dependent transcription and promoting protein synthesis.
- Irene Moretti
- , Stefano Ciciliot
- & Stefano Schiaffino
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Article
| Open AccessA critical role for NF2 and the Hippo pathway in branching morphogenesis
Branching morphogenesis is essential for the formation of most epithelial organs. Here, the authors show that Neurofibromatosis 2 (NF2), the Hippo pathway kinases LATS1 and LATS2, and the transcriptional co-activators YAP and TAZ control tip identity, RET signalling and branching morphogenesis in the mouse kidney.
- Antoine Reginensi
- , Leonie Enderle
- & Helen McNeill
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| Open AccessOptimal myelin elongation relies on YAP activation by axonal growth and inhibition by Crb3/Hippo pathway
Molecular mechanisms regulating optimal myelin geometry are only partially understood. Here authors show that peripheral myelin growth is orchestrated by the Crb3/Hippo/YAP pathway, and that defects in YAP activation may underlie peripheral neuropathies caused by shorter myelin.
- Ruani N. Fernando
- , Laurent Cotter
- & Nicolas Tricaud
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Article
| Open AccessHuman NK cell development requires CD56-mediated motility and formation of the developmental synapse
CD56, a splicing variant of NCAM, marks human NK cell differentiation stages. Here the authors show that developing human NK cells form CD56-enriched synapses with stromal cells, and CD56 is critical to promote motility of NK cells that increases with their maturation.
- Emily M. Mace
- , Justin T. Gunesch
- & Jordan S. Orange
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Article
| Open AccessRegulation of PERK–eIF2α signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes
The molecular mechanisms regulating myelination are only partially understood. Here authors show that Tsc1ablation in oligodendrocyte lineage activates ER stress and apoptotic programs in mice, and that enhancing PERK-eIF2α signalling partially rescues the myelination defects in Tsc1 mutants.
- Minqing Jiang
- , Lei Liu
- & Q. Richard Lu
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Article
| Open AccessRETRACTED ARTICLE: SARI inhibits angiogenesis and tumour growth of human colon cancer through directly targeting ceruloplasmin
Ceruloplasmin has an important role in the stabilization and nuclear transport of HIF-1α, thus regulating VEGF expression. Here the authors show that the transcription factor SARI reduces colorectal cancer growth and angiogenesis in vivoby inducing the degradation of ceruloplasmin, thereby inhibiting the HIFα/VEGF axis.
- Lei Dai
- , Xueliang Cui
- & Hongxin Deng
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Article
| Open AccessA splicing isoform of TEAD4 attenuates the Hippo–YAP signalling to inhibit tumour proliferation
The Hippo/Yap signalling pathway is found deregulated in several cancers. Here, the authors uncover an additional mechanism of YAP regulation that occurs via alternately spliced isoform of TEAD4, which acts as a dominant negative regulator of YAP-TEAD signalling.
- Yangfan Qi
- , Jing Yu
- & Zefeng Wang
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Article
| Open Access14-3-3 proteins regulate Tctp–Rheb interaction for organ growth in Drosophila
14-3-3 proteins regulate several signalling pathways but often act redundantly; however, the molecular mechanisms behind such redundancy are unclear. Here, the authors show that 14-3-3 proteins regulate two interacting components of Tor signalling in Drosophila, Tctp and Rheb, disrupting organ development.
- Thao Phuong Le
- , Linh Thuong Vuong
- & Kwang-Wook Choi
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Article
| Open AccessCircular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs
Circular RNAs are formed from exon back-splicing, the significance of these endogenous RNAs is beginning to be unraveled. Here, the authors identify thousands of circular RNAs differentially expressed between normal and cancer tissues and show that an abundant circular RNA generated from HIPK3regulates cell growth.
- Qiupeng Zheng
- , Chunyang Bao
- & Shenglin Huang
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Article
| Open AccessmTORC1 regulates PTHrP to coordinate chondrocyte growth, proliferation and differentiation
mTORC1 is crucial for chondrocyte proliferation and bone growth, but the downstream signalling is not clear. Here, the authors use rapamycin and chondrocyte-specific Tsc1 knockout mice to show that S6K1 can cause nuclear accumulation of Gli2, thus driving PTHrP expression and preventing terminal differentiation of prehypertrophic chondrocytes.
- Bo Yan
- , Zhongmin Zhang
- & Xiaochun Bai
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Article
| Open AccessmTORC1 and CK2 coordinate ternary and eIF4F complex assembly
Ternary complex (TC) and eIF4F complex assembly are rate-limiting steps in translation initiation that are regulated by eIF2α phosphorylation and the mTOR/4E-BP pathway. Here the authors show that the protein kinases mTORC1 and CK2 coordinate TC and eIF4F complex assembly through eIF2β to stimulate cell proliferation.
- Valentina Gandin
- , Laia Masvidal
- & Ivan Topisirovic
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Article
| Open AccessMondo complexes regulate TFEB via TOR inhibition to promote longevity in response to gonadal signals
Removal of the C. elegans germline substantially increases organismal lifespan. Here, Nakamura et al. show that the transcription factors MML-1 and MXL-2 coordinate this process in that they reduce TOR signalling and increase autophagy by regulating activity of HLH-30.
- Shuhei Nakamura
- , Özlem Karalay
- & Adam Antebi
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Article
| Open AccessThe Hippo signalling pathway maintains quiescence in Drosophila neural stem cells
Drosophila neural stem cells (NSCs) are quiescent at early larval stages but how this is regulated is unclear. Here, Ding et al. show that quiescence of NSCs is mediated by cell-contact inhibition via the Hippo pathway transmembrane proteins Crumbs and Echinoid, which in turn are regulated by nutrient levels.
- Rouven Ding
- , Kevin Weynans
- & Christian Berger
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Article
| Open AccessSCFβ-TRCP promotes cell growth by targeting PR-Set7/Set8 for degradation
The Set8-Set7 methyltransferase plays a critical role in cell cycle progression and tumorigenesis, and is degraded through modification by the E3 ubiquitin ligase CRL4Cdt2. Here Wang et al. identify SCFβ-TRCPas an additional E3 ubiquitin ligase that marks Set8 for degradation in response to DNA damage.
- Zhiwei Wang
- , Xiangpeng Dai
- & Wenyi Wei
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Article
| Open AccessA distributed cell division counter reveals growth dynamics in the gut microbiota
Research on the gut microbiota would benefit from improved methods to study microbial population growth. Here, Myhrvold et al. present a ‘mark and recapture’ method that uses genetically encoded fluorescent particles to measure the growth rates of gut microbes in live animals.
- Cameron Myhrvold
- , Jonathan W. Kotula
- & Pamela A. Silver
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Article
| Open AccessSUMOylation of AMPKα1 by PIAS4 specifically regulates mTORC1 signalling
AMPK senses cellular energy and switches off pathways involved in protein and fatty acid synthesis, but the selectivity of AMPK for different pathways is unclear. Here, the authors show that PIAS4-dependent SUMOylation and inactivation of AMPK preferentially restores activity of the mTORC1 pathway.
- Yan Yan
- , Saara Ollila
- & Tomi P. Mäkelä
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Article
| Open AccessHistone methyltransferase SETDB1 regulates liver cancer cell growth through methylation of p53
SETDB1 is a histone methyltransferase and a role for the protein has been proposed in cancer. Here, the authors show that SETDB1 contributes to hepatocellular cancer by preferably forming a complex with mutant p53, resulting in di-methylation of a critical lysine residue and stabilization of the protein.
- Qi Fei
- , Ke Shang
- & Jianyong Shou
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Article
| Open AccessPKA antagonizes CLASP-dependent microtubule stabilization to re-localize Pom1 and buffer cell size upon glucose limitation
In fission yeast, cell growth is co-ordinated with division by the cell tip-localized DYRK kinase Pom1, which inhibits the medially placed mitotic activator Cdr2. Here, Kelkar and Martin show that, upon glucose starvation, microtubules are destabilized in a PKA-dependent manner, leading to the deposition of Pom1 at cell sides where it delays mitosis.
- Manasi Kelkar
- & Sophie G. Martin
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Article
| Open AccessMAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway
A variety of signals have been reported to either activate or inhibit the Hippo kinase cascade. Here, Meng et al. show that mitogen activated protein kinase kinase kinase kinase (MAP4K) family members function in parallel to and are partially redundant with MST1/2 in regulating LATS in response to upstream signals.
- Zhipeng Meng
- , Toshiro Moroishi
- & Kun-Liang Guan
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Article
| Open AccessLocalization of Hippo signalling complexes and Warts activation in vivo
Components of the Hippo signalling pathway localize to apical junctions in epithelial cells, where they regulate growth in response to mechanical and biochemical cues. Sun et al. show that these proteins are organized into distinct junctional complexes, which reorganize up on Hippo pathway activation.
- Shuguo Sun
- , B. V. V. G. Reddy
- & Kenneth D. Irvine
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Article
| Open AccessRhomboid domain containing 1 promotes colorectal cancer growth through activation of the EGFR signalling pathway
Rhomboid proteins are involved in human cancer progression. Here, the authors show that RHBDD1, a rhomboid intramembrane serine protease, promotes tumor growth in colorectal cancer via cleavage and secretion of TGFα, and activation of the EGFR/Raf/MEK/ERK signalling pathway.
- Wei Song
- , Wenjie Liu
- & Linfang Wang
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Article
| Open AccessSlow-growing cells within isogenic populations have increased RNA polymerase error rates and DNA damage
Isogenic cells growing in the same environment show a large degree of variability. Here, by sorting yeast cells based on growth rate, the authors show that the slow-growing subpopulation exhibits stress responses, a high level of transcriptional diversity, and decreased RNA polymerase fidelity.
- David van Dijk
- , Riddhiman Dhar
- & Lucas B. Carey
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Article
| Open AccessSnf1/AMP-activated protein kinase activates Arf3p to promote invasive yeast growth via a non-canonical GEF domain
Snf1p is the yeast homologue of AMP-activated protein kinase, a key regulator of cellular energy homeostasis. Here, Hsu et al.identify Snf1p as a non-canonical guanine nucleotide-exchange factor for the Arf3p GTPase, regulating the yeast invasive response to glucose depletion.
- Jia-Wei Hsu
- , Kuan-Jung Chen
- & Fang-Jen S. Lee
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Article
| Open AccessLAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation
Essential amino acids such as leucine activate mTORC1 signalling after entering the lysosome, but the molecular basis for lysosomal amino-acid uptake is unclear. Here Milkereit et al. show that LAPTM4b, a lysosomal membrane protein, recruits a leucine transporter to the lysosome and promotes amino-acid influx and mTORC1 signalling.
- Ruth Milkereit
- , Avinash Persaud
- & Daniela Rotin
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Article |
Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2
Angiogenesis is regulated by dynamic changes in endothelial cell contact. Here, the authors show that signals from endothelial cell junctions affect the subcellular localization and function of Yes-associated protein, ultimately modifying angiopoietin-2 expression and angiogenic activity of endothelial cells.
- Hyun-Jung Choi
- , Haiying Zhang
- & Young-Guen Kwon
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Article |
Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells
Transcriptional regulators Sox2 and YAP maintain expression of stemness genes in normal and cancerous cells. Here the authors show that, in osteosarcomas, Sox2 activates YAP by directly repressing transcription of its upstream negative regulators Nf2 and WWC1, promoting cancer cell stemness.
- Upal Basu-Roy
- , N. Sumru Bayin
- & Claudio Basilico
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Article
| Open AccessCyclic stretching of soft substrates induces spreading and growth
Cells grown on a stiff substrate are stimulated through physical cues to spread, create actin stress fibres and proliferate. Here Cui et al. show that cyclic stretching cells on a soft pillar substrate has the same effect as growth on a stiff substrate, and results in nuclear translocation of YAP and MRTF-A.
- Yidan Cui
- , Feroz M. Hameed
- & Michael Sheetz
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Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis
The Hippo pathway is a major regulator of organ size and growth control. Here Wu et al. provide evidence for a novel link between the Hippo signalling pathway and the unfolded protein response (UPR) in regulating organ growth and tumorigenesis.
- Hongtan Wu
- , Luyao Wei
- & Dawang Zhou
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Article |
NEDD4 controls intestinal stem cell homeostasis by regulating the Hippo signalling pathway
The Hippo pathway plays a role in regulating organ size and stem cell renewal but the regulatory mechanisms that fine-tune this pathway are not well understood. Here the authors report on the role of NEDD4 as a negative regulator of the Hippo signalling components, WW45 and LATS kinase, and in controlling cell proliferation and intestinal stem cell homeostasis.
- Sung Jun Bae
- , Myungjin Kim
- & Jae Hong Seol
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The Hippo pathway effector YAP is a critical regulator of skeletal muscle fibre size
The Yes-associated protein (YAP) is a core effector of the Hippo pathway, which regulates proliferation and apoptosis in organ development, but its function in adult skeletal muscle remains poorly defined. Here the authors show that YAP is an essential regulator of myofibre size in adult skeletal muscle, via interaction with TEAD transcription factors.
- K. I. Watt
- , B. J. Turner
- & P. Gregorevic
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The MST1/2-SAV1 complex of the Hippo pathway promotes ciliogenesis
Although much is known about the structural and trafficking molecules involved in generation of primary cilia, the signalling proteins that regulate ciliogenesis are poorly defined. Here, Kim et al. identify the MST1/2-SAV1 complex, a core component of the Hippo pathway, as a key regulator of ciliogenesis in cells and zebrafish.
- Miju Kim
- , Minchul Kim
- & Dae-Sik Lim
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Article
| Open AccessLAMTOR2 regulates dendritic cell homeostasis through FLT3-dependent mTOR signalling
LAMTOR2 is involved in mTOR and ERK signalling and plays a role in immunity, but its function in dendritic cells (DCs) is not clear. Here the authors show that deletion of LAMTOR2 in DCs results in increased mTOR signalling, accumulation of Flt3 on the cell surface and excessive DC proliferation in ageing mice.
- Julia M. Scheffler
- , Florian Sparber
- & Lukas A. Huber
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| Open AccessThe DUSP26 phosphatase activator adenylate kinase 2 regulates FADD phosphorylation and cell growth
Adenylate kinase 2 can bind to FADD. In this study, Kim et al.show that adenylate kinase 2 is a tumour suppressor and interacts with the phosphatase DUSP6, and this in turn regulates the phosphorylation of FADD.
- Hyunjoo Kim
- , Ho-June Lee
- & Yong-Keun Jung