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| Open AccessTRIM25 predominately associates with anti-viral stress granules
Different environmental stressors induce different subtypes of stress granules (SGs), and each of them presumably have distinct functions. Here the authors provide a framework for understanding the compositional and functional heterogeneity of SGs, and see that TRIM25 mainly associates with anti-viral SGs.
- Zehua Shang
- , Sitao Zhang
- & Da Jia
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Article
| Open AccessmTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism
How cells adapt to glucose starvation is still elusive. Here, Levy et al. show that the mTOR substrate 4EBP1 protects human, mouse, and yeast cells from glucose starvation and is exploited by cancer cells to promote tumorigenesis.
- Tal Levy
- , Kai Voeltzke
- & Gabriel Leprivier
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Article
| Open AccessA genetically encoded biosensor to monitor dynamic changes of c-di-GMP with high temporal resolution
The ubiquitous second messenger c-di-GMP regulates many biological processes in bacteria, including cell cycle, motility, virulence and biofilm formation. Here, Kaczmarczyk et al. develop a c-di-GMP biosensor that enables dynamic real-time tracking of c-di-GMP levels in individual living cells.
- Andreas Kaczmarczyk
- , Simon van Vliet
- & Urs Jenal
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Article
| Open AccessCadmium binding by the F-box domain induces p97-mediated SCF complex disassembly to activate stress response programs
The F-box domain is a conserved structural motif in ubiquitin ligases known only to bind Skp1. Here, the authors show the F-box domain is also an environmental cadmium sensor that changes conformation upon binding to disassemble the active ligase, protecting the cell from cadmium stress.
- Linda Lauinger
- , Anna Andronicos
- & Peter Kaiser
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Article
| Open AccessPrecise immunofluorescence canceling for highly multiplexed imaging to capture specific cell states
Multiplexed imaging to study cellular pathways can be hampered by lack of antibody specificity, especially when assessing signal activation. Here, the authors present Precise Emission Canceling Antibodies (PECAbs), which enable high-specificity sequential imaging and the study of signaling pathways.
- Kosuke Tomimatsu
- , Takeru Fujii
- & Yasuyuki Ohkawa
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Article
| Open AccessAn interphase actin wave promotes mitochondrial content mixing and organelle homeostasis
A mitochondrial actin wave fragments mitochondria. Here, the authors find that the wave produces force that is resisted by mitochondrial tethering, inducing fission, with subsequent fusion promoting mitochondrial content mixing and mitochondrial homeostasis.
- Stephen M. Coscia
- , Andrew S. Moore
- & Erika L. F. Holzbaur
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Article
| Open AccessAllosteric regulation by c-di-AMP modulates a complete N-acetylglucosamine signaling cascade in Saccharopolyspora erythraea
c-di-AMP is essential for bacterial signaling. Here, the authors identify the GlcNAc-sensing regulator DasR as a c-di-AMP receptor and provide molecular insight into their signaling effect on the developmental and antibiotic biosynthesis control across Actinobacteria.
- Di You
- , Liu-Chang Zhao
- & Bang-Ce Ye
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Article
| Open AccessHPK1 citron homology domain regulates phosphorylation of SLP76 and modulates kinase domain interaction dynamics
In this work, the authors unveil a mechanism where the Citron homology domain regulates HPK1’s kinase domain, shedding light on the relationship between HPK1’s structure and function. This enhances our understanding of HPK1, an intracellular target for cancer immunotherapy and provides a direction for immuno-oncology drug discovery.
- Avantika S. Chitre
- , Ping Wu
- & Weiru Wang
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Article
| Open AccessRinRK1 enhances NF receptors accumulation in nanodomain-like structures at root-hair tip
RinRK1 interacts with NFR1 and NFR5 through their extracellular domains, facilitating a complex with Flot1. This interaction promotes their localization at root hair tip nanodomains, crucial for mediating the rhizobial infection.
- Ning Zhou
- , Xiaolin Li
- & Fang Xie
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Article
| Open AccessDietary L-Glu sensing by enteroendocrine cells adjusts food intake via modulating gut PYY/NPF secretion
Enteroendocrine cells in the gut sense food to regulate feeding behavior. Here, the authors show in Drosophila L-glutamate reduces the frequency of calcium oscillations in enteroendocrine cells and decreases the release of NPF, thereby reducing the activation of a pair of anorexic enteric neurons.
- Junjun Gao
- , Song Zhang
- & Zheng Guo
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Article
| Open AccessNumb positively regulates Hedgehog signaling at the ciliary pocket
The precise regulatory mechanisms controlling ciliary Hedgehog signaling remain incomplete. Here, the authors use ciliary proteomics to reveal that Numb facilitates the endocytosis of the receptor Ptch1 from the ciliary pocket, thereby enabling activation of Hedgehog signaling.
- Xiaoliang Liu
- , Patricia T. Yam
- & Xuecai Ge
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Article
| Open AccessTemporal coordination of the transcription factor response to H2O2 stress
H2O2 stress is known to activate a slew of transcription factors that restore redox balance. Here, the authors use live-cell imaging and single-cell analysis to reveal that the transcription factors that are activated and their timing of activation is dose dependent.
- Elizabeth Jose
- , Woody March-Steinman
- & Andrew L. Paek
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Article
| Open AccessHost response during unresolved urinary tract infection alters female mammary tissue homeostasis through collagen deposition and TIMP1
Urinary tract infections (UTIs) can elicit systemic host-responses. Here the authors report that, in a mouse model, unresolved UTI is associated with alterations of the mammary tissue, including collagen deposition and hyperplasia.
- Samantha Henry
- , Steven Macauley Lewis
- & Camila Oresco dos Santos
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Article
| Open AccessNerve growth factor receptor limits inflammation to promote remodeling and repair of osteoarthritic joints
Osteoarthritis is a painful and debilitating condition. Here, the authors show that NGFR, a receptor for NGF, restricts NF-κB activation and its deficiency in skeletal cells impairs the remodeling and repair of osteoarthritic joints.
- Lan Zhao
- , Yumei Lai
- & Jian Huang
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Article
| Open AccessLipopolysaccharide binding protein resists hepatic oxidative stress by regulating lipid droplet homeostasis
Oxidative stress triggers lipid accumulation in cells by sequestering triglycerides in lipid droplets. Here, the authors show that lipopolysaccharide-binding protein interacts with redox sensor PRDX4 to control lipid-redox balance and promotes triglyceride accumulation in droplets by capturing unsaturated lipids.
- Qilun Zhang
- , Xuting Shen
- & Haoshu Fang
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Article
| Open AccessNardilysin-regulated scission mechanism activates polo-like kinase 3 to suppress the development of pancreatic cancer
Polo-like kinase 3 (Plk3) has a tumor suppressive role through the induction of apoptosis, however, the mechanism underlying its activation is unclear. Here, in pancreatic cancer, the authors show that activation of Plk3 is dependent on its cleavage into p41Plk3, by the metalloendopeptidase nardilysin.
- Jie Fu
- , Jianhua Ling
- & Paul J. Chiao
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Article
| Open AccessLDL receptor-related protein 5 selectively transports unesterified polyunsaturated fatty acids to intracellular compartments
The mechanisms transporting fatty acids into the cell are not completely understood. Here, the authors discover a selective transporter for a specific class of lipids, and show its role in regulating neutrophil function during myocardial ischemia-reperfusion injury.
- Wenwen Tang
- , Yi Luan
- & Dianqing Wu
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Article
| Open AccessGadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms
Different gene mutations have been reported as drivers for myeloproliferative neoplasms (MPN). Here, the authors show that Gadd45g insufficiency induces MPN in mouse models and associates with MPN in patients.
- Peiwen Zhang
- , Na You
- & Xiaotong Ma
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Article
| Open AccessDifferentiation granules, a dynamic regulator of T. brucei development
The African trypanosome Trypanosoma brucei has been shown to form stress granules in vitro that might be repurposed to enable differentiation and facilitate parasite transmission. Here, Cayla et al. show that differentiation between slender and stumpy forms does involve membrane-less granules that are different from nutritional stress granules.
- Mathieu Cayla
- , Christos Spanos
- & Keith R. Matthews
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Article
| Open AccessCompensatory growth and recovery of cartilage cytoarchitecture after transient cell death in fetal mouse limbs
How growing organs recover from transient injuries is unclear. Here, authors used mouse models of transient cell death in the limb cartilage to identify cellular and molecular mechanisms (e.g. mTORC1) involved in cartilage repair and catch-up growth.
- Chee Ho H’ng
- , Shanika L. Amarasinghe
- & Alberto Rosello-Diez
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Article
| Open AccessEph-ephrin signaling couples endothelial cell sorting and arterial specification
Arteries are vital blood vessels for our body and their growth and patterning are critical for proper blood flow. Here they use a retina model to show that a balance of EphB4 receptor and ephrin-B2 ligand integrate a well-wired molecular network to control arteriovenous patterning and vascular growth.
- Jonas Stewen
- , Kai Kruse
- & Mara E. Pitulescu
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Article
| Open AccessCold-induced FOXO1 nuclear transport aids cold survival and tissue storage
How tissues adapt to extreme cold is not well understood. Here, the authors discover a mechanism that promotes FOXO1-mediated cold survival gene transcription at low temperatures, with potential implications for long-term tissue storage for transplantation.
- Xiaomei Zhang
- , Lihao Ge
- & Jingxing Ou
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Article
| Open AccessEndocytic vesicles act as vehicles for glucose uptake in response to growth factor stimulation
Growth factors rapidly raise cellular glycolysis. Here, authors unveil a mechanism where RTK/GLUT1-containing endocytic vesicles deliver glucose to glycolytic enzymes near mitochondria without upregulating cell surface glucose transporters.
- Ryouhei Tsutsumi
- , Beatrix Ueberheide
- & Yoshiro Saito
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Article
| Open AccessPCSK9 stimulates Syk, PKCδ, and NF-κB, leading to atherosclerosis progression independently of LDL receptor
Proprotein convertase subtilisin/kexin type-9 (PCSK9) binds to and degrades low-density lipoprotein (LDL) receptor, leading to an increase of LDL cholesterol in blood. Here the authors show that PCSK9 itself directly induces inflammation and aggravates atherosclerosis independently of the LDL receptor.
- Dasom Shin
- , Soungchan Kim
- & Hyo-Soo Kim
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Article
| Open AccessMitochondrial H2O2 release does not directly cause damage to chromosomal DNA
Nuclear DNA damage downstream of mitochondrial ROS is often cited to contribute to cancer initiation and aging. However, here the authors show that although H2O2 induces DNA mutations when produced near DNA, it does not when released by mitochondria.
- Daan M. K. van Soest
- , Paulien E. Polderman
- & Tobias B. Dansen
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Article
| Open AccessActivation of the insulin receptor by insulin-like growth factor 2
IGF2 has a distinct binding affinity for two insulin receptor (IR) isoforms and mimics insulin’s function. Here, the authors present the activation mechanism of IR by IGF2 and reveal the molecular basis for IGF2’s different affinity for two IR isoforms.
- Weidong An
- , Catherine Hall
- & Eunhee Choi
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Article
| Open AccessNon-catalytic role of phosphoinositide 3-kinase in mesenchymal cell migration through non-canonical induction of p85β/AP2-mediated endocytosis
PI3 kinase is known to promote cell migration through its catalytic activity. Here, the authors show that the kinase also induces endocytosis through a non-catalytic pathway that actually decreases migratory speed and persistence, revealing a more subtle regulation of motility.
- Hideaki T. Matsubayashi
- , Jack Mountain
- & Takanari Inoue
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Article
| Open AccessThe EIF3H-HAX1 axis increases RAF-MEK-ERK signaling activity to promote colorectal cancer progression
Eukaryotic initiation translation factor 3 subunit h (EIF3H) possesses an alternative “moonlighting” function of deubiquitinase, while its role in colorectal carcinogenesis remains to be explored. Here the authors show that EIF3H deubiquitinates and stabilizes HAX1, which enhances RAF-MEK-ERK signaling to promote colorectal tumor growth and metastasis.
- Huilin Jin
- , Xiaoling Huang
- & Mong-Hong Lee
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Article
| Open AccessAn evolutionary mechanism to assimilate new nutrient sensors into the mTORC1 pathway
Unmet expectations, a previously uncharacterized fly protein, is a SAM sensor for the mTORC1 pathway. Tracing the evolution of Unmet reveals that the pathway uses the GATOR2 complex to capture and repurpose ancestral enzymes as nutrient sensors.
- Grace Y. Liu
- , Patrick Jouandin
- & David M. Sabatini
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Article
| Open AccessAberrant non-canonical NF-κB signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma
The downstream molecular mechanisms following the activation of the NF-κB pathway in multiple myeloma (MM) remain to be characterised. Here, it is shown that aberrant non-canonical NF-κB signalling causes epigenomic reprogramming leading to transcriptional changes that favour MM progression.
- Daniel A. Ang
- , Jean-Michel Carter
- & Yinghui Li
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Article
| Open AccessEpigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner
Efforts to treat heart failure with antioxidants have failed. Here, authors reveal a robust sex-dependent endogenous defense against oxidative damage and demonstrate antioxidative treatment’s efficacy solely in subjects with inadequate redox capacity.
- Zaher ElBeck
- , Mohammad Bakhtiar Hossain
- & Christer Betsholtz
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Article
| Open AccessA fast-acting lipid checkpoint in G1 prevents mitotic defects
Lipid synthesis increases during the cell cycle to ensure sufficient membrane mass. Here, authors identify a lipid checkpoint in G1 phase that prevents cells from starting the cell cycle if lipid synthesis is low, thereby preventing mitotic defects.
- Marielle S. Köberlin
- , Yilin Fan
- & Tobias Meyer
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Article
| Open AccessHepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver
The liver is segregated into spatially organized areas that serve distinct functions, though how these zones are patterned remains unclear. Here they show that mTORC1 controls spatial segregation of liver metabolic functions via modulation of Wnt signaling, and find that impaired zonation is also observed in pigs given total parenteral nutrition.
- Ana Belén Plata-Gómez
- , Lucía de Prado-Rivas
- & Alejo Efeyan
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Article
| Open AccessStem Leydig cells support macrophage immunological homeostasis through mitochondrial transfer in mice
The role of stem Leydig cells in restoration of male fertility after acute injury is not clear. In an acute injury mouse model of testicular torsion, the authors show that Stem Leydig cells can restore testicular immunological homeostasis by mitochondria transfer to macrophages in a TRPM7-mediated manner.
- Ani Chi
- , Bicheng Yang
- & Min Zhang
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Article
| Open AccessInhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing
The role of folate metabolism in leukemic stem cells remains understudied. Here, the authors show that inhibition of mitochondrial folate metabolism leads to differentiation of leukemic cells through depletion of purines and suppression of mTORC1.
- Martha M. Zarou
- , Kevin M. Rattigan
- & G. Vignir Helgason
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Article
| Open AccessA GREB1-steroid receptor feedforward mechanism governs differential GREB1 action in endometrial function and endometriosis
The endometrium is activated by the pregnancy hormones estrogen and progesterone to facilitate embryo implantation, and errors in endometrial responsiveness can lead to reduced fertility or endometriosis. Here they show that GREB1 interacts with hormone receptors in the endometrium, leading to normal or pathological consequences depending on the hormones involved.
- Sangappa B. Chadchan
- , Pooja Popli
- & Ramakrishna Kommagani
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Article
| Open AccessA spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling
Kang et al. reveal structural and functional differences in mitochondria across the hepatic lobule. Mitochondrial distinct phosphoproteome influences their functions highlighting how nutrient availability helps to shape mitochondria zonation.
- Sun Woo Sophie Kang
- , Rory P. Cunningham
- & Natalie Porat-Shliom
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Article
| Open AccessTBC1D23 mediates Golgi-specific LKB1 signaling
The LKB1 signaling is differentially regulated and has distinct functions at different subcellular compartments. Tu et al reports that TBC1D23 specifically regulates Golgi-LKB1 signaling and link this pathway to neurodevelopment disorders.
- Yingfeng Tu
- , Qin Yang
- & Da Jia
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Article
| Open AccessBicarbonate signalling via G protein-coupled receptor regulates ischaemia-reperfusion injury
The acid–base balance regulates cellular responses, but little has been known about its molecular mechanism. Here, the authors unveil a bicarbonate-sensing GPCR, GPR30, that underlies cerebral ischemia–reperfusion injury by regulating blood flow recovery.
- Airi Jo-Watanabe
- , Toshiki Inaba
- & Takehiko Yokomizo
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Article
| Open AccessNoncanonical function of folate through folate receptor 1 during neural tube formation
Neural tube defects are common birth defects that have been shown to be reduced through periconceptional folate supplementation, though the mechanism for this effect is unclear. Here they show that FOLR1 is necessary for neural tube formation in human neural organoids and Xenopus laevis embryos, and that this role is independent of its folate transport function.
- Olga A. Balashova
- , Alexios A. Panoutsopoulos
- & Laura N. Borodinsky
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Article
| Open AccessCis inhibition of NOTCH1 through JAGGED1 sustains embryonic hematopoietic stem cell fate
Notch signaling is critical for HSC emergence. Here, the authors identify a sub-set of hemogenic endothelial cells with high Notch activity that it is gradually shut down through cis inhibition of NOTCH1 by JAG1, and report that this process sustains HSC.
- Roshana Thambyrajah
- , Maria Maqueda
- & Anna Bigas
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Article
| Open AccessPhosphorylation of plasma membrane H+-ATPase Thr881 participates in light-induced stomatal opening
Comprehensive phosphoproteomic analysis using guard cell protoplasts revealed that Thr881 phosphorylation in addition of a penultimate residue, Thr948 of plasma membrane H+-ATPase are important for its function and light-induced stomatal opening.
- Yuki Hayashi
- , Kohei Fukatsu
- & Toshinori Kinoshita
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Article
| Open AccessLight-induced stomatal opening requires phosphorylation of the C-terminal autoinhibitory domain of plasma membrane H+-ATPase
Light-induced stomatal opening is crucial for photosynthesis. Here the authors show that blue light triggers phosphorylation of two Thr residues in the C-terminal autoinhibitory domain of plasma membrane H+-ATPase, thereby promoting stomatal opening.
- Saashia Fuji
- , Shota Yamauchi
- & Atsushi Takemiya
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Article
| Open AccessPIBF1 regulates trophoblast syncytialization and promotes cardiovascular development
The genetic link between placenta function and congenital heart defects has been established, though the cellular mechanisms underlying this connection is less clear. Here they show that PIBF1 regulates syncytiotrophoblast fusion and that loss of PIBF1 also negatively impacts heart development, providing a potential link between the development of these two organs.
- Jong Geol Lee
- , Jung-Min Yon
- & In-Jeoung Baek
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| Open AccessDIAPH1-MFN2 interaction decreases the endoplasmic reticulum-mitochondrial distance and promotes cardiac injury following myocardial ischemia
Contact between organelles such as the mitochondria (Mito) and endoplasmic reticulum (ER) is crucial to coordinate vital cellular homeostatic processes. Here we discuss recent work showing that Mito-ER proximity is regulated by heterotypic complexes between the F-actin polymerizing protein Diaphanous-1) and the mitochondrial dynamics protein Mitofusin 2, which confers increased susceptibility to ischemia/reperfusion injury.
- Lorrie A. Kirshenbaum
- , Rimpy Dhingra
- & Sergio Lavandero
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Article
| Open AccessRegulation of long-range BMP gradients and embryonic polarity by propagation of local calcium-firing activity
Identical twins from a single embryo are formed in multiple species, albeit rarely. It is not clear how such twinning is suppressed during early development. Here they show that calcium signalling activity is propagated through the extraembryonic tissue to prevent ectopic primitive streak formation during gastrulation.
- Hyung Chul Lee
- , Nidia M. M. Oliveira
- & Claudio D. Stern
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Article
| Open AccessDistinct functional constraints driving conservation of the cofilin N-terminal regulatory tail
Here the authors screen a saturation mutagenesis library of the disordered N-terminal tail of the actin severing protein cofilin. Their results reveal how a key phosphorylation site can balance competing sequence constraints on function and regulation.
- Joel A. Sexton
- , Tony Potchernikov
- & Benjamin E. Turk
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Article
| Open AccessMolecular basis of VEGFR1 autoinhibition at the plasma membrane
Spontaneous activation of VEGFRs is a hallmark of diabetes and several cancers. Here, the authors show how in VEGFR1 a juxtamembrane segment connecting the catalytic and ligand-binding domains of the receptor can prevent its spontaneous activation.
- Manas Pratim Chakraborty
- , Diptatanu Das
- & Rahul Das
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Article
| Open AccessAggresome formation promotes ASK1/JNK signaling activation and stemness maintenance in ovarian cancer
The role of aggresomes in tumorigenesis and cancer progression remains to be explored. Here, the authors perform multi-omics and reveal that aggresome formation supports ovarian cancer stem cell properties via OTUD1 and ASK1/JNK signalling activation.
- Yurou Chen
- , Yulong Qiang
- & Feng Li