Featured
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Article |
A MYC–GCN2–eIF2α negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer
Schmidt et al. show that the translation initiation factor eIF2B5 regulates stress responses and MYC translation to prevent apoptosis, thereby presenting a targetable vulnerability in colorectal cancer.
- Stefanie Schmidt
- , David Gay
- & Armin Wiegering
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Article |
Phagolysosome resolution requires contacts with the endoplasmic reticulum and phosphatidylinositol-4-phosphate signalling
Levin-Konigsberg et al. show that resorption of the phagolysosome after degradation of its contents requires transfer of PI4P and tethering to the ER, both mediated by oxysterol-binding protein-related protein 1L (ORP1L).
- Roni Levin-Konigsberg
- , Fernando Montaño-Rendón
- & Sergio Grinstein
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Letter |
Protein kinase N controls a lysosomal lipid switch to facilitate nutrient signalling via mTORC1
Wallroth et al. uncover a mechanism by which protein kinase N activates mTORC1 nutrient signalling at the lysosome by inhibiting PI3KC2-β-mediated PtdIns(3,4)P2 synthesis downstream of mTORC2.
- Alexander Wallroth
- , Philipp A. Koch
- & Volker Haucke
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News & Views |
HER2 joins AKT to inhibit STING immunity
Activation of the receptor EGFR (ERBB1) occurs in response to viral infections and regulates antiviral immunity. A new study now shows that the receptor HER2 (ERBB2) negatively regulates STING signaling in response to DNA viruses and expands the model and mechanisms by which surface-receptor tyrosine kinases perform important intracellular regulatory functions.
- Ian D. Odell
- & Richard A. Flavell
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Article |
HER2 recruits AKT1 to disrupt STING signalling and suppress antiviral defence and antitumour immunity
Wu et al. demonstrate that HER2 recruits AKT1 to disrupt the STING signalosome, thereby suppressing damage-induced cellular senescence and STING-mediated antiviral and antitumour responses in vivo.
- Shiying Wu
- , Qian Zhang
- & Pinglong Xu
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Article |
ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression
Activating transcription factor 4 (ATF4) promotes MYC-driven tumour progression. Tameire et al. identify ATF4 and its target eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) as regulators of MYC-mediated amino acid biosynthesis and protein synthesis, thereby modulating tumour progression and survival in mice.
- Feven Tameire
- , Ioannis I. Verginadis
- & Constantinos Koumenis
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News & Views |
IRE1α modulates ER and mitochondria crosstalk
IRE1α is an endoplasmic reticulum (ER) transmembrane protein known for a crucial role in regulating the unfolding protein response. A study now shows that IRE1α interacts with the main ER Ca2+ channel InsP3Rs and facilitates the transfer of Ca2+ from the ER into mitochondria, thus driving cellular metabolism.
- Roland Malli
- & Wolfgang F. Graier
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Article |
EGFR is required for Wnt9a–Fzd9b signalling specificity in haematopoietic stem cells
Grainger et al. demonstrate that, in zebrafish and human cells, EGFR-mediated phosphorylation of Fzd9b promotes internalization of the Wnt9a–Fzd9b–LRP signalosome and subsequent signal transduction.
- Stephanie Grainger
- , Nicole Nguyen
- & David Traver
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Article |
Non-canonical function of IRE1α determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics
Carreras-Sureda et al. uncover a non-canonical role for IRE1α as a scaffold that stabilizes InsP3Rs at MAMs to control calcium uptake, fine-tunes ER–mitochondrial communication and regulates energy metabolism via AMPK.
- Amado Carreras-Sureda
- , Fabián Jaña
- & Claudio Hetz
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Article |
Extracellular vesicle-packaged HIF-1α-stabilizing lncRNA from tumour-associated macrophages regulates aerobic glycolysis of breast cancer cells
Chen et al. show that tumour-associated macrophages transmit HIF-1α-stabilizing long noncoding RNA through extracellular vesicles to breast cancer cells, thereby enhancing tumour glycolysis and chemoresistance.
- Fei Chen
- , Jianing Chen
- & Erwei Song
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Article |
A nuclear phosphoinositide kinase complex regulates p53
Choi et al. show that the stability of nuclear stress-activated wild-type and mutant p53 is regulated by the type I phosphatidylinositol phosphate kinase PIPK1-α and the lipid messenger PtdIns(4,5)P2.
- Suyong Choi
- , Mo Chen
- & Richard A. Anderson
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Article |
AMPK-mediated activation of MCU stimulates mitochondrial Ca2+ entry to promote mitotic progression
Zhao et al. find that AMPK phosphorylates and activates the mitochondrial Ca2+ uniporter in response to low energy status in mitosis, allowing Ca2+ entry into mitochondria to boost mitochondrial respiration.
- Haixin Zhao
- , Teng Li
- & Xin Pan
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News & Views |
IRE1α maintains HSC stemness under ER-stress
Healthy and malignant haematopoietic stem cells (HSCs) must overcome a variety of cell intrinsic and extrinsic stresses to maintain their functionality. Now, IRE1α –XBP1 signalling is shown to protect HSCs and to promote survival of, and confer competitive advantages to, NRAS-mutated pre-leukaemic cells.
- Marina Scheller-Wendorff
- & Carsten Müller-Tidow
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Article |
Adaptive endoplasmic reticulum stress signalling via IRE1α–XBP1 preserves self-renewal of haematopoietic and pre-leukaemic stem cells
Liu et al. show that the adaptive branch of unfolded protein response signalling, IRE1α–XBP1, protects haematopoietic stem cells and N-Ras pre-leukaemic stem cells from endoplasmic reticulum stress-induced apoptosis and supports their self-renewal.
- Lu Liu
- , Meiling Zhao
- & Qing Li
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News & Views |
Oncogenic AKTivation by methylation
AKT, also known as protein kinase B, is one of the most frequently dysregulated serine/threonine kinases in cancer, and its hyperactivity drives tumorigenesis and chemotherapy resistance. Two studies now find that AKT methylation by the methyltransferase SETDB1 is an early step in its oncogenic activation.
- Amelia K. Luciano
- & David A. Guertin
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Article |
AKT methylation by SETDB1 promotes AKT kinase activity and oncogenic functions
Guo et al. identify SETDB1 and KDM4B as the methyltransferase and demethylase, respectively, for AKT. AKT methylation promotes its kinase activity and the subsequent tumorigenesis.
- Jianping Guo
- , Xiangpeng Dai
- & Wenyi Wei
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Article |
SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis
Wang et al. show that Akt methylation by SETDB1 is recognized by demethylase JMJD2A, which then recruits E3 ligases to induce K63-linked Akt ubiquitination, leading to Akt activation and tumorigenesis.
- Guihua Wang
- , Jie Long
- & Hui-Kuan Lin
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Article |
ALK phosphorylates SMAD4 on tyrosine to disable TGF-β tumour suppressor functions
Zhang et al. show that ALK phosphorylates SMAD4 at Tyr 95 to block its binding to DNA, representing a mutation-independent mechanism for blocking the tumour suppressor function of TGF-β in ALK-positive cancers.
- Qianting Zhang
- , Mu Xiao
- & Xin-Hua Feng
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Article |
An IRAK1–PIN1 signalling axis drives intrinsic tumour resistance to radiation therapy
Performing a small-molecule screen, Liu et al. identify IRAK as a regulator of PIDDosome activity and tumour radioresistance, and demonstrate a synergistic effect of targeting IRAK1 and PIN1 in response to ionizing radiation.
- Peter H. Liu
- , Richa B. Shah
- & Samuel Sidi
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Perspective |
Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication
In this Perspective, Théry and co-authors discuss our current understanding of the biogenesis, secretion and uptake of exosomes and extracellular vesicles.
- Mathilde Mathieu
- , Lorena Martin-Jaular
- & Clotilde Théry
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Review Article |
The lysosome as a cellular centre for signalling, metabolism and quality control
In this Review, Lawrence and Zoncu discuss the central role of the lysosome in cellular metabolism, including in macromolecular catabolism and nutrient recycling, and organelle crosstalk. They highlight the emerging function of the lysosome as a centre for nutrient sensing and metabolic signal transduction.
- Rosalie E. Lawrence
- & Roberto Zoncu
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News & Views |
Memory of ancestral mitochondrial stress
Ancestral experience of mitochondrial stress is now found to render progeny of the roundworm Caenorhabditis elegans more resistant to the same insult for up to four generations. A DNA modification, N6-methyldeoxyadenine, is implicated in the inheritance of this stress adaptation.
- Sarah-Lena Offenburger
- , Marcos Francisco Perez
- & Ben Lehner
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Letter |
N6-methyldeoxyadenine is a transgenerational epigenetic signal for mitochondrial stress adaptation
Ma et al. show that exposure of Caenorhabditis elegans to mitochondrial stress triggers stress adaptation in offspring, which is mediated by 6mA DNA modification at mitochondrial unfolded-protein-response genes.
- Chengchuan Ma
- , Rong Niu
- & Ying Liu
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Article |
Pancreatic islet-autonomous insulin and smoothened-mediated signalling modulate identity changes of glucagon+ α-cells
Cigliola et al. show that β-cell loss activates insulin production in a small number of α-cells and that insulin and Hedgehog signalling actively maintain and enforce the α-cell fate.
- Valentina Cigliola
- , Luiza Ghila
- & Pedro L. Herrera
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Turning Points |
Confidence to go the way science takes you
Anne Simonsen is a Professor at the Department of Molecular Medicine at the Institute of Basic Medical Sciences of the University of Oslo, Norway. Her work focuses on lipid-binding proteins in membrane trafficking and autophagy, and their links to disease.
- Anne Simonsen
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News & Views |
Mechanical signals regulate TORC2 activity
Maintaining plasma membrane tension is important for eukaryotic cells. How altered membrane tension is sensed and relayed to downstream factors, such as the target of rapamyin complex 2 (TORC2), is poorly understood. Reorganization of a signalling lipid into discrete membrane domains is now shown to inactivate TORC2 in yeast.
- Michael Ebner
- & Volker Haucke
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News & Views |
Lysosomal catch-and-release controls mTORC1
Rag GTPases facilitate mTORC1 activation by recruiting it to Rheb at the lysosome when amino acids are abundant. A study now shows that the amino acid-induced change in the GTP/GDP-binding state of the Rag heterodimer paradoxically increases its dynamic release from the Ragulator at the lysosome and may limit mTORC1 activation.
- Aaron M. Hosios
- & Brendan D. Manning
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Article |
Decrease in plasma membrane tension triggers PtdIns(4,5)P2 phase separation to inactivate TORC2
Using a small-molecule modulator of TORC2 signalling and a mechanosensitive probe, Riggi et al. reveal that decreased plasma membrane tension induces distinct PIP2-enriched domains that sequester and inactivate TORC2.
- Margot Riggi
- , Karolina Niewola-Staszkowska
- & Robbie Loewith
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Article |
RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers
Nichols et al. identify an SHP2 inhibitor that disrupts SOS1-mediated RAS–GTP loading with demonstrated efficacy in various types of tumour driven by mutant BRAF, NF1 or RAS.
- Robert J. Nichols
- , Franziska Haderk
- & Trever G. Bivona
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News & Views |
Shaping up with morphogen gradients
During embryo development, concentration gradients of signalling molecules instruct formation of different cell types. How these gradients adapt to variable embryo sizes to form a properly scaled individual remains elusive. A simple system of an activator and an inhibitor, with different diffusion properties, may give an answer.
- Laurence Garric
- & Jeroen Bakkers
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Letter |
FBP17 and CIP4 recruit SHIP2 and lamellipodin to prime the plasma membrane for fast endophilin-mediated endocytosis
Chan Wah Hak et al. show how plasma membrane patches are primed for fast endophilin-mediated endocytosis and disassembly, in the absence of receptor stimulation, through FBP17 and CIP4 binding to SHIP2 and lamellipodin.
- Laura Chan Wah Hak
- , Shaheen Khan
- & Emmanuel Boucrot
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Article |
A nutrient-induced affinity switch controls mTORC1 activation by its Rag GTPase–Ragulator lysosomal scaffold
Lawrence et al. show that mTORC1 capture and activation at the lysosome are regulated by nutrients that destabilize Rag GTPase–Ragulator binding, and delineate how cancer-specific Rag mutants increase mTORC1 signalling.
- Rosalie E. Lawrence
- , Kelvin F. Cho
- & Roberto Zoncu
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Article |
Scale-invariant patterning by size-dependent inhibition of Nodal signalling
Almuedo-Castillo et al. show that extirpated embryos are reduced in size but exhibit normal proportions. Following a computational screen, the authors identify an increased concentration of the Nodal inhibitor Lefty to be responsible for the size scaling.
- María Almuedo-Castillo
- , Alexander Bläßle
- & Patrick Müller
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News & Views |
FAPs are sensors for skeletal myofibre atrophy
Skeletal muscle denervation leads to myofibre atrophy with fibrosis and fatty infiltration of muscle-resident fibroadipogenic progenitors (FAPs). A study shows that on denervation, FAPs activate pathogenic STAT3–IL-6 signalling. Inhibition of this pathway prevents atrophy and points to potential therapeutic targets.
- Giovanna Marazzi
- & David Sassoon
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Article |
Denervation-activated STAT3–IL-6 signalling in fibro-adipogenic progenitors promotes myofibres atrophy and fibrosis
Madaro et al. show that denervation induces accumulation of IL-6–STAT3-activated fibro-adipogenic progenitors without inflammation or muscle regeneration, leading to muscle atrophy and fibrosis.
- Luca Madaro
- , Magda Passafaro
- & Pier Lorenzo Puri
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News & Views |
Limited gut cell repertoire for multiple hormones
Enteroendocrine (EE) cells secrete diverse peptide hormones, regulating food intake, digestion and metabolism. A study now challenges the traditional view that each hormone is the dominant product of a distinct EE cell type, showing that in response to local cues the same cell produces different hormones in different tissue compartments.
- Ramesh A. Shivdasani
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Letter |
Enteroendocrine cells switch hormone expression along the crypt-to-villus BMP signalling gradient
Beumer et al. show that intestinal enteroendocrine cells adjust their hormonal profile during migration from the crypt to the villus, depending on region-specific BMP signalling.
- Joep Beumer
- , Benedetta Artegiani
- & Hans Clevers
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Article |
Pericyte-like spreading by disseminated cancer cells activates YAP and MRTF for metastatic colonization
Massagué and colleagues show that disseminated cancer cells use L1CAM to spread on capillaries and to achieve their outgrowth through activating YAP signalling.
- Ekrem Emrah Er
- , Manuel Valiente
- & Joan Massagué
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Review Article |
Mitochondrial dynamics in adaptive and maladaptive cellular stress responses
Mitochondria sense and respond to many stressors and can support cell survival or death through energy production and signalling pathways. Mitochondrial responses depend on fusion–fission dynamics that dilute and segregate damaged mitochondria. Mitochondrial motility and inter-organellar interactions, such as with the endoplasmic reticulum, also function in cellular adaptation to stress. In this Review, we discuss how stressors influence these components, and how they contribute to the complex adaptive and pathological responses that lead to disease.
- Verónica Eisner
- , Martin Picard
- & György Hajnóczky
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News & Views |
GNAS shifts metabolism in pancreatic cancer
Specific combinations of mutations cause unique signalling and metabolic requirements. Concurrent G-protein αs (GNAS) and KRAS mutations in a subset of pancreatic tumours are now shown to inhibit SIK kinases through aberrant cAMP–PKA activation, triggering a metabolic program defined by lipid metabolism and fatty acid oxidation.
- Pablo E. Hollstein
- & Reuben J. Shaw
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Article |
Mutant GNAS drives pancreatic tumourigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism
Bardeesy and colleagues show that mutant GNAS suppresses salt-inducible kinases by activating PKA, leading to lipid remodelling and pancreatic tumourigenesis
- Krushna C. Patra
- , Yasutaka Kato
- & Nabeel Bardeesy
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News & Views |
Pro-tumorigenic AMPK in glioblastoma
AMPK is a key metabolic sensor promoting cellular energy homeostasis under low-nutrient conditions and other stresses. However, its role in cancer is context-dependent and not fully understood. A study now shows that glioma stem cells co-opt an AMPK-dependent pathway to rewire metabolism, promoting tumour growth.
- Nektaria Maria Leli
- & Constantinos Koumenis
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Article |
AMP kinase promotes glioblastoma bioenergetics and tumour growth
Signalling by the energy sensor kinase AMPK is generally tumour suppressive, but Chhipa et al. show that AMPK is upregulated in glioblastoma, where it phosphorylates CREB1 to enhance HIF1α and GABPA transcription and to support tumour bioenergetics.
- Rishi Raj Chhipa
- , Qiang Fan
- & Biplab Dasgupta
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News & Views |
Paraspeckle factor turns TGF-β1 pro-metastatic
The roles of transforming growth factor β (TGF-β) depend on the cellular context. Paraspeckle component 1 now arises as a driver of epithelial-to-mesenchymal transition and stemness transcription factors to redirect effectors from tumour suppressive to pro-metastatic gene promoters, emerging as a contextual determinant of TGF-β function.
- Fernando Salvador
- & Roger R. Gomis
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News & Views |
CK1α promotes tumour suppressive autophagy
The phosphatase PTEN is thought to govern tumour suppression predominantly through PI-3 kinase pathway regulation. A study now shows that a non-catalytic function of CK1α outcompetes the E3 ligase NEDD4-1 to stabilize PTEN, which activates FOXO3A-dependent ATG7 expression and stimulates tumour suppressive autophagy.
- Ivana Hermanova
- & Arkaitz Carracedo
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Article |
PSPC1 mediates TGF-β1 autocrine signalling and Smad2/3 target switching to promote EMT, stemness and metastasis
Yeh et al. find that PSPC1 is upregulated in cancer and interacts with Smad2/3 to induce TGF-β1. This leads to increased autocrine TGF-β1 signalling and a switch to pro-metastatic TGF-β1-dependent gene expression.
- Hsi-Wen Yeh
- , En-Chi Hsu
- & Yuh-Shan Jou
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Article |
CK1α suppresses lung tumour growth by stabilizing PTEN and inducing autophagy
Cai et al. show that CK1α suppresses lung cancer growth by inducing autophagy through a PTEN–AKT–FOXO3a pathway that ultimately leads to ATG7 expression.
- Junchao Cai
- , Rong Li
- & Mengfeng Li
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Article |
TP53INP2 regulates adiposity by activating β-catenin through autophagy-dependent sequestration of GSK3β
Romero et al. show that the autophagy regulator TP53INP2 represses adipogenesis by promoting GSK3β sequestration and activation of β-catenin through an autophagy-dependent and ESCRT-dependent mechanism.
- Montserrat Romero
- , Alba Sabaté-Pérez
- & Antonio Zorzano
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