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Structure of the nutrient-sensing hub GATOR2
The 3D structure of the human nutrient-sensing complex GATOR2 is resolved using cryo-electron microscopy.
- Max L. Valenstein
- , Kacper B. Rogala
- & David M. Sabatini
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Article
| Open AccessPeptidoglycan maturation controls outer membrane protein assembly
Peptidoglycan stem peptides in the Gram-negative bacterial cell wall regulate the insertion of essential outer membrane proteins, thus representing a potential target for antibiotic design.
- Gideon Mamou
- , Federico Corona
- & Waldemar Vollmer
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Article
| Open AccessGenetic instability from a single S phase after whole-genome duplication
Extensive DNA damage occurs during the first interphase following induction of tetraploidy in human cells, largely as a result of the lower amount of protein relative to DNA.
- Simon Gemble
- , René Wardenaar
- & Renata Basto
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Article |
A non-canonical tricarboxylic acid cycle underlies cellular identity
A non-canonical tricarboxylic acid cycle is required for changes in cell state.
- Paige K. Arnold
- , Benjamin T. Jackson
- & Lydia W. S. Finley
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Article
| Open AccessTMK-based cell-surface auxin signalling activates cell-wall acidification
Auxin induces transmembrane-kinase-dependent activation of H+-ATPase in the plasma membrane through phosphorylation of its penultimate threonine residue, promoting apoplastic acidification and hypocotyl cell elongation in Arabidopsis.
- Wenwei Lin
- , Xiang Zhou
- & Zhenbiao Yang
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Matters Arising |
Hippo signalling maintains ER expression and ER+ breast cancer growth
- Shenghong Ma
- , Zhengming Wu
- & Kun-Liang Guan
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Article |
Control of osteoblast regeneration by a train of Erk activity waves
The rate of scale regeneration in zebrafish is controlled by the frequency of rhythmic travelling waves of Erk activity, which are broadcast from a central source to induce ring-like patterns of osteoblast tissue growth.
- Alessandro De Simone
- , Maya N. Evanitsky
- & Stefano Di Talia
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Article |
Serine restriction alters sphingolipid diversity to constrain tumour growth
In xenograft tumour models in mice, modulation of dietary serine, serine palmitoyltransferase or phosphoglycerate dehydrogenase activity enables control of the endogenous synthesis of deoxysphingolipids, sensitizing the tumours to metabolic stress and slowing their progression.
- Thangaselvam Muthusamy
- , Thekla Cordes
- & Christian M. Metallo
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Article |
Distinct modes of cell competition shape mammalian tissue morphogenesis
Cell competition in the developing mouse epithelium involves apoptosis and engulfment when the epithelium has only one layer, but switches to involve asymmetric cell division and differentiation of ‘loser’ cells as the epithelium becomes stratified.
- Stephanie J. Ellis
- , Nicholas C. Gomez
- & Elaine Fuchs
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Article |
Excised linear introns regulate growth in yeast
A set of 34 excised introns in Saccharomyces cerevisiae, characterized by having a short distance between the lariat branch point and the 3′ splice site, have a biological function within the TOR growth-signalling network.
- Jeffrey T. Morgan
- , Gerald R. Fink
- & David P. Bartel
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Letter |
Subcellular transcriptomes and proteomes of developing axon projections in the cerebral cortex
A subcellular sorting approach enables quantitative analysis of subtypes of growth cones in the brain, and reveals subcellular relationships between local mRNA and local proteomes in developing projection neurons.
- Alexandros Poulopoulos
- , Alexander J. Murphy
- & Jeffrey D. Macklis
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Letter |
RAP2 mediates mechanoresponses of the Hippo pathway
The Ras-related GTPase RAP2 is a key intracellular signal transducer by which extracellular matrix rigidity controls mechanosensitive cellular activities through YAP and TAZ.
- Zhipeng Meng
- , Yunjiang Qiu
- & Kun-Liang Guan
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Letter |
KLHL22 activates amino-acid-dependent mTORC1 signalling to promote tumorigenesis and ageing
In response to amino acid stimulation, the ubiquitin E3 ligase CUL3–KLHL22 promotes the activation of mTORC1, which may drive tumour growth in breast cancer.
- Jie Chen
- , Yuhui Ou
- & Ying Liu
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Letter |
An evolutionarily conserved ribosome-rescue pathway maintains epidermal homeostasis
Loss of the ribosome-rescue factor Pelo in a subset of mouse epidermal stem cells results in hyperproliferation and altered differentiation of these cells.
- Kifayathullah Liakath-Ali
- , Eric W. Mills
- & Fiona M. Watt
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Letter |
Structure of the insulin receptor–insulin complex by single-particle cryo-EM analysis
Cryo-electron microscopy structures of insulin in a complex with the insulin receptor define the S2 binding site on the receptor and suggest a mechanism for downstream propagation of insulin signalling.
- Giovanna Scapin
- , Venkata P. Dandey
- & Bridget Carragher
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Article |
Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40
The cryo-electron microscopy and crystal structures of several mTORC1 complexes, and accompanying biochemical analyses, shed light on how mTORC1 is regulated and how cancer mutations lead to its hyperactivation.
- Haijuan Yang
- , Xiaolu Jiang
- & Nikola P. Pavletich
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Review Article |
Nutrient acquisition strategies of mammalian cells
A review of cellular strategies for nutrient sensing and acquisition, including how these strategies can be exploited by cancer cells.
- Wilhelm Palm
- & Craig B. Thompson
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Letter |
Dystrophin–glycoprotein complex sequesters Yap to inhibit cardiomyocyte proliferation
After injury in the heart, postnatal mouse hearts deficient in the Hippo pathway show efficient repair, and in the hearts of Mdx mice (a model of Duchenne muscular dystrophy) Hippo deficiency protects against overload-induced heart failure.
- Yuka Morikawa
- , Todd Heallen
- & James F. Martin
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Letter |
TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling
Ubiquitination of the GβL subunit, a component of both mTORC1 and mTORC2, acts as a regulatory switching mechanism to balance levels of mTORC1 and mTORC2; the failure of this mechanism in some cancers leads to elevated mTORC2 formation and tumorigenesis.
- Bin Wang
- , Zuliang Jie
- & Wenyi Wei
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Letter |
KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1
A protein complex composed of KPTN, ITFG2, C12orf66 and SZT2, named KICSTOR, is necessary for lysosomal localization of GATOR1, interaction of GATOR1 with the Rag GTPases and GATOR2, and nutrient-dependent mTORC1 modulation.
- Rachel L. Wolfson
- , Lynne Chantranupong
- & David M. Sabatini
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Letter |
The ligand Sas and its receptor PTP10D drive tumour-suppressive cell competition
Wild-type Drosophila epithelial cells outcompete proto-oncogenic cells through translocation of the ligand Sas to the wild-type–tumour cell interface, where it binds the PTP10D receptor of the tumour cell, initiating pro-apoptotic signalling.
- Masatoshi Yamamoto
- , Shizue Ohsawa
- & Tatsushi Igaki
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Letter |
Microenvironmental autophagy promotes tumour growth
During early-stage tumour growth in Drosphila, tumour cells acquire necessary nutrients by triggering autophagy in surrounding cells in the tumour microenvironment.
- Nadja S. Katheder
- , Rojyar Khezri
- & Tor Erik Rusten
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Letter |
mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide
The polypeptide SPAR is encoded by a long non-coding RNA, localizes to the late endosome and lysosome, and regulates muscle regeneration by inhibiting mTORC1.
- Akinobu Matsumoto
- , Alessandra Pasut
- & Pier Paolo Pandolfi
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Letter |
Control of mitochondrial function and cell growth by the atypical cadherin Fat1
Fragments of the atypical cadherin Fat1 accumulate in the mitochondria of vascular smooth muscle cells where they reduce respiration, leading to a regulated proliferative response to arterial injury.
- Longyue L. Cao
- , Dario F. Riascos-Bernal
- & Nicholas E. S. Sibinga
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Letter |
Mechanism of arginine sensing by CASTOR1 upstream of mTORC1
Structural data on the protein CASTOR1 reveal how the mTORC1 pathway senses intracellular arginine, suggesting a repurposing of an evolutionarily pre-metazoan mechanism.
- Robert A. Saxton
- , Lynne Chantranupong
- & David M. Sabatini
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Letter |
Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury
The transcription factor Pitx2 is upregulated in injured neonatal and Hippo-deficient mouse hearts, where it interacts with the Hippo effector protein Yap to activate reactive oxygen species scavengers, thus preventing the heart from oxidative damage.
- Ge Tao
- , Peter C. Kahr
- & James F. Martin
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Letter |
Hedgehog actively maintains adult lung quiescence and regulates repair and regeneration
It is generally thought that the quiescence of tissue is not actively maintained, but rather a state reflecting the absence of proliferative signal; here the authors find that quiescence is actively maintained by paracrine hedgehog signalling provided by the epithelium in the mouse adult lung, and that hedgehog is dynamically regulated during injury repair and resolution for proper restoration of tissue homeostasis after injury.
- Tien Peng
- , David B. Frank
- & Edward E. Morrisey
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Letter |
In situ structural analysis of the human nuclear pore complex
The most comprehensive architectural model to date of the nuclear pore complex reveals previously unknown local interactions, and a role for nucleoporin 358 in Y-complex oligomerization.
- Alexander von Appen
- , Jan Kosinski
- & Martin Beck
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Letter |
eIF3 targets cell-proliferation messenger RNAs for translational activation or repression
Eukaryotic initiation factor 3 (eIF3)—the deregulation of which has been linked with diverse cancers—is shown to bind to and direct the specialized translation of a subset of messenger RNAs, primarily involved in cell proliferation, differentiation and apoptosis, and can exert either translational activation or repression.
- Amy S. Y. Lee
- , Philip J. Kranzusch
- & Jamie H. D. Cate
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Letter |
SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1
The mTORC1 protein kinase complex integrates nutrient and growth stimuli to modulate signalling pathways that regulate cellular metabolism and physiology, but the molecular nature of the amino acid sensing mechanism at the lysosome is unknown; here, an orphan member of the human solute carrier group of proteins, SLC38A9, is shown to be an integral component of the lysosomal machinery that can directly sense amino acids and activate mTORC1.
- Manuele Rebsamen
- , Lorena Pochini
- & Giulio Superti-Furga
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Letter |
Inhibition of cell expansion by rapid ABP1-mediated auxin effect on microtubules
In roots and dark-grown hypocotyls of Arabidopsis thaliana, ABP1-mediated auxin signalling induces swift re-orientation of the microtubule cytoskeleton from transverse to longitudinal, thus inhibiting cell expansion.
- Xu Chen
- , Laurie Grandont
- & Jiří Friml
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Letter |
Rb suppresses human cone-precursor-derived retinoblastoma tumours
The nature of the retinal cell-type-specific circuitry that predisposes to retinoblastoma is demonstrated, in which a program that is unique to post-mitotic human cone precursors sensitizes to the oncogenic effects of retinoblastoma (Rb) protein depletion; hence, the loss of Rb collaborates with the molecular framework of cone precursors to initiate tumorigenesis.
- Xiaoliang L. Xu
- , Hardeep P. Singh
- & David Cobrinik
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Article |
RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer
The translation of many messenger RNAs that encode important oncogenes and transcription factors depends on the eIF4A RNA helicase to resolve G-quadruplex structures, implying eIF4A inhibition as an effective cancer therapy.
- Andrew L. Wolfe
- , Kamini Singh
- & Hans-Guido Wendel
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Letter |
Structural basis for molecular recognition of folic acid by folate receptors
Folate receptor-α (FRα) is overexpressed in many cancer cells and is therefore an important therapeutic target: here the X-ray crystal structure of folate-bound FRα is presented, revealing details of the ligand-binding pocket that may be useful in the development of small-molecule inhibitors for anticancer therapy.
- Chen Chen
- , Jiyuan Ke
- & Karsten Melcher
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Article |
mTOR kinase structure, mechanism and regulation
Co-crystal structures of a number of complexes involving truncated mammalian target of rapamycin, a phosphoinositide 3-kinase-related protein kinase, reveal an intrinsically active kinase conformation and show how rapamycin–FKBP12 directly blocks substrate recruitment to the kinase domain.
- Haijuan Yang
- , Derek G. Rudge
- & Nikola P. Pavletich
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Letter |
Mitochondrial defect drives non-autonomous tumour progression through Hippo signalling in Drosophila
In a Drosophila imaginal epithelial disc system, mutations that lead to mitochondrial dysfunction can also promote tumorigenic growth of neighbouring cells expressing an activated Ras oncogene.
- Shizue Ohsawa
- , Yoshitaka Sato
- & Tatsushi Igaki
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News & Views |
A healthy diet for stem cells
Understanding how a low calorie intake slows ageing could revolutionize the way that we treat age-related diseases. One potential key to such treatments could be to enhance the local environment of stem cells. See Article p.490
- Fresnida J. Ramos
- & Matt Kaeberlein
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Article |
mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake
In the mouse intestine, calorie restriction enhances the regenerative capacity of intestinal stem cells by reducing mTORC1 signalling in their Paneth cell niche.
- Ömer H. Yilmaz
- , Pekka Katajisto
- & David M. Sabatini
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News & Views |
The director's cut
A genome-wide characterization of active translation of messenger RNA following inhibition of mTOR will transform our view of this signalling protein's regulatory role in cancer. See Article p.55 & Letter p.109
- Antonio Gentilella
- & George Thomas
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Letter |
Live-cell delamination counterbalances epithelial growth to limit tissue overcrowding
To maintain homeostasis in epithelial cell layers in Drosophila, cell overcrowding causes a proportion of cells to undergo a loss of cell adhesive junctions and be squeezed out by neighbouring cells.
- Eliana Marinari
- , Aida Mehonic
- & Buzz Baum
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News & Views |
Sacrifice for survival
Cancer cells ignore oxygen availability, opting for less efficient, anaerobic ways of generating energy. The wisdom behind this choice seems to be in preventing the accumulation of reactive oxygen species, and so oxidative damage.
- Nana-Maria Grüning
- & Markus Ralser
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Letter |
Control of Drosophila endocycles by E2F and CRL4CDT2
- Norman Zielke
- , Kerry J. Kim
- & Bruce A. Edgar
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Research Highlights |
'Braille code' for cell growth
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Research Highlights |
Sugar sweetens cell cooperation
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Letter |
mTORC1 controls fasting-induced ketogenesis and its modulation by ageing
During periods of fasting the liver produces ketone bodies, which the peripheral tissues can use as a source of energy. Here it is shown that fasting inhibits multi-component mTOR complex 1 (mTORC1) in the liver. Inhibition of mTORC1 is required for activation of PPARα, a master regulator that switches on genes involved in ketogenesis. Livers from aged mice have increased mTORC1 signalling, reduced PPARα activity, and reduced ketone production. The observation that mTORC1 promotes an ageing phenotype in the liver fits well with the observation that inhibition of this pathway increases lifespan in several organisms.
- Shomit Sengupta
- , Timothy R. Peterson
- & David M. Sabatini
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News & Views |
When abnormality is beneficial
One might think that aneuploidy — having an abnormal number of chromosomes — would be harmful, and would reduce an organism's fitness. Not necessarily: it all depends on the type of aneuploidy and the associated conditions. See Letter p.321
- Judith Berman
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Research Highlights |
Neuroscience: Quick mood lift
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Letter |
Termination of autophagy and reformation of lysosomes regulated by mTOR
When cells are starved, the enzyme TOR is inhibited, inducing autophagy. In this process, autophagosomes sequester intracellular components and then fuse with lysosomes, producing autolysosomes in which cargo is degraded to regenerate nutrients. Now, a mechanism is revealed by which lysosomes are re-formed. When starvation conditions are prolonged, mTOR is re-activated; this attenuates autophagy and results in tubules and vesicles extruding from the autolysosome and maturing into functional lysosomes.
- Li Yu
- , Christina K. McPhee
- & Michael J. Lenardo