Featured
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Article |
Architecture of the human GATOR1 and GATOR1–Rag GTPases complexes
Cryo-electron microscopy and biochemical analyses of the GATOR1 protein complex reveal that two binding modes underpin its ability to regulate Rag GTPases as a GTPase-activating protein for RAGA.
- Kuang Shen
- , Rick K. Huang
- & David M. Sabatini
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Letter |
Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance
Hepatocytes secrete DPP4, which promotes adipose tissue inflammation and insulin resistance in obese mice, suggesting a new specific target for treatment of metabolic disorders.
- Devram S. Ghorpade
- , Lale Ozcan
- & Ira Tabas
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Letter |
The SMAD2/3 interactome reveals that TGFβ controls m6A mRNA methylation in pluripotency
The SMAD2 and SMAD3 protein interactome links TGFβ signalling to diverse effectors including m6A methyltransferase, which has a role in regulating differentiation of human pluripotent stem cells.
- Alessandro Bertero
- , Stephanie Brown
- & Ludovic Vallier
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Letter |
MEK drives BRAF activation through allosteric control of KSR proteins
KSR–MEK complexes allosterically activate BRAF through the action of N-terminal regulatory region and kinase domain contacts, thus challenging the accepted role of KSR as a scaffold for MEK recruitment to RAF.
- Hugo Lavoie
- , Malha Sahmi
- & Marc Therrien
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Letter |
Structure of the glucagon receptor in complex with a glucagon analogue
The crystal structure of the full-length glucagon receptor in complex with a glucagon analogue NNC1702 reveals how the peptide ligand interacts with its target and shows the conformational changes required for receptor activation.
- Haonan Zhang
- , Anna Qiao
- & Beili Wu
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Letter |
IL-11 is a crucial determinant of cardiovascular fibrosis
Fibroblast-specific Il-11 expression causes heart and kidney fibrosis and organ failure, whereas IL-11 inhibition prevents fibroblast activation and organ fibrosis, indicating that IL-11 inhibition is a potential therapeutic strategy to treat fibrotic diseases.
- Sebastian Schafer
- , Sivakumar Viswanathan
- & Stuart A. Cook
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Letter |
Single-molecule imaging reveals receptor–G protein interactions at cell surface hot spots
G-protein-coupled receptors and their G protein partners are studied by single-molecule imaging in living cells, which reveals hot spots on the cell membrane where receptors and G proteins interact and signal.
- Titiwat Sungkaworn
- , Marie-Lise Jobin
- & Davide Calebiro
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Letter |
PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas
BRAF-inhibition resistance in metastatic melanoma occurs through p21-activated kinase-mediated reactivation of ERK, whereas resistance to combined BRAF and MEK inhibition occurs through p21-activated kinase-mediated regulation of JNK and β-catenin phosphorylation, mTOR pathway activation and apoptosis inhibition in many patients.
- Hezhe Lu
- , Shujing Liu
- & Wei Guo
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Letter |
Competing memories of mitogen and p53 signalling control cell-cycle entry
Mother cells transmit mitogen-induced CCND1 mRNA and DNA damage-induced p53 protein to newly born daughter cells, where synthesized cyclin D1 and the p53-regulated CDK inhibitor p21 directly compete to decide between proliferation and quiescence.
- Hee Won Yang
- , Mingyu Chung
- & Tobias Meyer
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Letter |
Structural insights into ligand recognition by the lysophosphatidic acid receptor LPA6
Determination of the crystal structure of the zebrafish LPA6 receptor shows that the lipid ligand binds to an unusual ligand-binding pocket in the receptor that is laterally accessible through the membrane.
- Reiya Taniguchi
- , Asuka Inoue
- & Osamu Nureki
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Letter |
Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK
Glucose starvation activates AMPK via an AMP/ADP-independent mechanism that involves fructose-1,6-bisphosphate and aldolase.
- Chen-Song Zhang
- , Simon A. Hawley
- & Sheng-Cai Lin
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Letter |
Crystal structures of agonist-bound human cannabinoid receptor CB1
Crystal structures of the human cannabinoid receptor 1 (CB1) bound to the agonists AM11542 and AM841 reveal notable structural rearrangements upon receptor activation, and this flexibility may be a common feature among other G-protein-coupled receptors.
- Tian Hua
- , Kiran Vemuri
- & Zhi-Jie Liu
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Letter |
mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer
mTOR complex 1 signalling regulates polyamine metabolism and thereby promotes tumorigenesis, through regulation of the stability of a key enzyme, AMD1.
- Amaia Zabala-Letona
- , Amaia Arruabarrena-Aristorena
- & Arkaitz Carracedo
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Letter |
BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation
BRCA1-associated protein 1 (BAP1) regulates calcium flux in the endoplasmic reticulum to facilitate the execution of apoptosis, unveiling a new facet of the role of BAP1 as an environmental tumour suppressor.
- Angela Bononi
- , Carlotta Giorgi
- & Michele Carbone
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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 |
Genetic wiring maps of single-cell protein states reveal an off-switch for GPCR signalling
Random mutagenesis in haploid human cells coupled to quantitative protein measurements with different antibodies is used as a readout for individual cellular phenotypes.
- Markus Brockmann
- , Vincent A. Blomen
- & Thijn R. Brummelkamp
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Letter |
CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells
In human cell lines with mutant KRAS and loss of LKB1, CPS1 expression correlates inversely with LKB1 expression; silencing CPS1 in these cells induces DNA damage and cell death as a result of pyrimidine depletion rather than ammonia toxicity.
- Jiyeon Kim
- , Zeping Hu
- & Ralph J. DeBerardinis
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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 |
Surrogate Wnt agonists that phenocopy canonical Wnt and β-catenin signalling
The authors describe water-soluble surrogate Wnt agonists, with specificity towards some frizzled (FZD) receptors, which can maintain human intestinal organoid cultures and have effects on the mouse liver in vivo.
- Claudia Y. Janda
- , Luke T. Dang
- & K. Christopher Garcia
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Letter |
FGF-dependent metabolic control of vascular development
Fibroblast growth factor receptor (FGFR) signalling is a crucial regulator of endothelial metabolism and vascular development.
- Pengchun Yu
- , Kerstin Wilhelm
- & Michael Simons
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Letter |
The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability
Conditional deletion of the mitochondrial Na+/Ca2+ exchanger NCLX in adult mouse hearts causes sudden death due to mitochondrial calcium overload, whereas its overexpression limits cell death elicited by ischaemia reperfusion injury and heart failure.
- Timothy S. Luongo
- , Jonathan P. Lambert
- & John W. Elrod
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Article |
Structural basis for selectivity and diversity in angiotensin II receptors
Crystal structures of two complexes of the angiotensin II receptor AT2R with distinct tightly bound ligands reveal an active-like state of the receptor, in which helix VIII adopts a non-canonical position that blocks binding of G proteins and β-arrestins.
- Haitao Zhang
- , Gye Won Han
- & Vadim Cherezov
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Article |
Postsynaptic synaptotagmins mediate AMPA receptor exocytosis during LTP
Postsynaptic synaptotagmin-1 and synaptotagmin-7 mediate calcium-dependent exocytosis of AMPA receptors during long-term potentiation.
- Dick Wu
- , Taulant Bacaj
- & Thomas C. Südhof
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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 |
SZT2 dictates GATOR control of mTORC1 signalling
SZT2 recruits GATOR1 and GATOR2 to form a SZT2-orchestrated GATOR (SOG) complex at the lysosome that is essential for GATOR- and SESN-dependent nutrient sensing and mTORC1 regulation.
- Min Peng
- , Na Yin
- & Ming O. Li
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Article |
Force interacts with macromolecular structure in activation of TGF-β
Integrin αVβ6 binds the transforming growth factor-β1 precursor (pro-TGF-β1) in an orientation that is biologically relevant for force-dependent release of TGF-β from its latent form.
- Xianchi Dong
- , Bo Zhao
- & Timothy A. Springer
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Article |
IL-17 is a neuromodulator of Caenorhabditis elegans sensory responses
Interleukin-17 functions as a neuromodulator in the roundworm Caenorhabditis elegans, acting directly on RMG hub interneurons to alter their response properties and contribution to behaviour.
- Changchun Chen
- , Eisuke Itakura
- & Mario de Bono
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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 |
Inhibition of mTOR induces a paused pluripotent state
Inhibition of mechanistic target of rapamycin (mTOR) suspends mouse blastocyst development and the cells remain ‘paused’ in a reversible pluripotent state, allowing prolonged culture.
- Aydan Bulut-Karslioglu
- , Steffen Biechele
- & Miguel Ramalho-Santos
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Article |
Frizzled proteins are colonic epithelial receptors for C. difficile toxin B
Here, a genome-wide CRISPR–Cas9 screen is used to identify the Wnt receptors frizzled as physiologically relevant Clostridium difficile toxin B receptors, providing new therapeutic targets for treating C. difficile infections.
- Liang Tao
- , Jie Zhang
- & Min Dong
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Letter |
Rho GTPase complementation underlies BDNF-dependent homo- and heterosynaptic plasticity
The three small GTPases Rac1, RhoA and Cdc42 are differentially involved in structural long-term potentiation of rodent dendritic spines, simultaneously ensuring signal specificity and also priming the system for plasticity.
- Nathan G. Hedrick
- , Stephen C. Harward
- & Ryohei Yasuda
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Letter |
A blue-light photoreceptor mediates the feedback regulation of photosynthesis
Algae rely on blue-light-sensitive phototropin to trigger induction of LHCRS3, allowing it to dissipate energy from excess light that would otherwise compromise the fitness of the organism.
- Dimitris Petroutsos
- , Ryutaro Tokutsu
- & Jun Minagawa
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Letter |
Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling
A class of small molecules that stabilize a previously unrecognized inactive state of KSR is reported; the agonists synergize with MEK inhibitors to prevent growth of Ras mutant cell lines.
- Neil S. Dhawan
- , Alex P. Scopton
- & Arvin C. Dar
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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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Article |
An evolutionarily conserved pathway controls proteasome homeostasis
Proteasome abundance is crucial for cell survival, but how cells maintain adequate amounts of proteasome is unclear; an analysis in yeast identifies TORC1 and Mpk1 as central components of a pathway regulating proteasome homeostasis through the coordinated regulation of regulatory particle assembly chaperones and proteasome subunits—this pathway is evolutionarily conserved with mTOR and ERK5 regulating proteasome abundance in mammals.
- Adrien Rousseau
- & Anne Bertolotti
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Letter |
Coordinating cardiomyocyte interactions to direct ventricular chamber morphogenesis
A complex interplay involving Notch- and Erbb2-mediated signalling between cardiomyocytes guides the morphogenesis of the ventricular wall.
- Peidong Han
- , Joshua Bloomekatz
- & Neil C. Chi
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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 |
Maintenance and propagation of a deleterious mitochondrial genome by the mitochondrial unfolded protein response
In the context of mitochondrial genome heteroplasmy that causes defective oxidative phosphorylation in C. elegans, the ATFS-1-mediated mitochondrial unfolded protein response maintains the deleterious mitochondrial DNA in an attempt to recover oxidative phosphorylation activity and avoid cellular dysfunction.
- Yi-Fan Lin
- , Anna M. Schulz
- & Cole M. Haynes
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Letter |
The conformational signature of β-arrestin2 predicts its trafficking and signalling functions
A series of intramolecular fluorescent FlAsH BRET reporters is used to monitor conformational changes in β-arrestin2 following activation of seven G-protein-coupled receptors (GPCRs), showing that different GPCRs produce distinct β-arrestin2 conformational signatures that correlate with the stability of the receptor–arrestin complex and the role of β-arrestin2 in activating or dampening downstream signalling events, which explains how different GPCRs can use a common effector for different purposes.
- Mi-Hye Lee
- , Kathryn M. Appleton
- & Louis M. Luttrell
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Letter |
Primary cilia are not calcium-responsive mechanosensors
Mechanosensation, if it originates in primary cilia, is not via calcium signalling.
- M. Delling
- , A. A. Indzhykulian
- & D. E. Clapham
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Letter |
β-Arrestin biosensors reveal a rapid, receptor-dependent activation/deactivation cycle
A series of FRET-based β-arrestin2 biosensors are used to study the dynamics and conformational changes that occur when β-arrestin2 binds to and dissociates from the β2-adrenergic receptor in living cells; results show that after β-arrestin2 dissociates from the β2-adrenergic receptor, it stays at the cell membrane in an active conformation for a while, indicating that β-arrestin is able to signal in a G-protein-coupled receptor (GPCR)-free state.
- Susanne Nuber
- , Ulrike Zabel
- & Carsten Hoffmann
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Letter |
Visualization of a short-range Wnt gradient in the intestinal stem-cell niche
Generation of an epitope-tagged, functional Wnt3 knock-in allele, the signal produced by Paneth cells to regulate intestinal stem cells.
- Henner F. Farin
- , Ingrid Jordens
- & Hans Clevers
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Letter |
Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites
Epithelial tuft cells secretion of IL-25 is shown to regulate type 2 epithelial responses to helminth parasite infection via an IL-13/IL-4Rα-dependent feedback loop.
- François Gerbe
- , Emmanuelle Sidot
- & Philippe Jay
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Letter |
Germline variant FGFR4 p.G388R exposes a membrane-proximal STAT3 binding site
A gain-of-function effect of the cancer-associated rs351855 single-nucleotide polymorphism encoding the FGFR4 Arg388 allele in humans.
- Vijay K. Ulaganathan
- , Bianca Sperl
- & Axel Ullrich
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Article |
Signal integration by Ca2+ regulates intestinal stem-cell activity
Drosophila intestinal stem cells (ISCs) respond to changes in diet, particularly L-glutamate levels, by modulating Ca2+ signalling to adapt their proliferation rate; furthermore, Ca2+ is shown to be central to the response of ISCs to a wide range of dietary and stress stimuli.
- Hansong Deng
- , Akos A. Gerencser
- & Heinrich Jasper
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Letter |
Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung
Inhibitory antibodies to two specific human and mouse Notch ligands, Jagged1 and Jagged2, are generated and shown to have beneficial effects in a goblet cell metaplasia asthma model; systemic Jagged1 inhibition transdifferentiates secretory cells into ciliated cells in the mouse, demonstrating that Jagged1 from ciliated cells normally holds back secretory cells to adopt the ciliated fate.
- Daniel Lafkas
- , Amy Shelton
- & Christian W. Siebel
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Article |
Dpp spreading is required for medial but not for lateral wing disc growth
The morphogen Decapentaplegic (Dpp) has been implicated in both wing patterning and growth in fruitflies; here, a nanobody-based morphotrap approach has been developed that rules out a role for the Dpp gradient in regulating lateral wing growth.
- Stefan Harmansa
- , Fisun Hamaratoglu
- & Emmanuel Caussinus
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Article |
Combinatorial gene regulation by modulation of relative pulse timing
Many gene-regulatory proteins have been shown to activate in pulses, but whether cells exploit the dynamic interaction between pulses of different regulatory proteins has remained unexplored; here single-cell videos show that yeast cells modulate the relative timing between the pulsatile transcription factors Msn2 and Mig1—a gene activator and a repressor, respectively—to control the expression of target genes in response to diverse environmental conditions.
- Yihan Lin
- , Chang Ho Sohn
- & Michael B. Elowitz
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Letter |
RAF inhibitors that evade paradoxical MAPK pathway activation
Next-generation RAF inhibitors that inhibit oncogenic BRAF without inducing paradoxical pathway activation in cells with mutant RAS might yield improved safety and more durable efficacy.
- Chao Zhang
- , Wayne Spevak
- & Gideon Bollag