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Article
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Endocytic 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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| Open Access
Phosphoglycerate kinase 1 acts as a cargo adaptor to promote EGFR transport to the lysosome
The epidermal growth factor receptor (EGFR) plays important roles in cell growth and motility. Here, authors reveal an unexpected function for a metabolic enzyme PGK1 and advance the mechanistic understanding of lysosomal transport of EGFR.
- Shao-Ling Chu
- , Jia-Rong Huang
- & Jia-Wei Hsu
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Endosomal Arl4A attenuates EGFR degradation by binding to the ESCRT-II component VPS36
Endosomal EGFR signaling and lysosomal degradation play important roles in controlling numerous biological processes. Here, the authors show that Arl4A negatively regulates EGFR degradation by binding to VPS36 and attenuating ESCRT-mediated late endosomal EGFR sorting.
- Shin-Jin Lin
- , Ming-Chieh Lin
- & Fang-Jen S. Lee
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| Open Access
Cyclic fasting bolsters cholesterol biosynthesis inhibitors’ anticancer activity
Nutritional stress induced by short-term dietary restriction has been shown to alter the activity of some anti-tumour drugs. Here, the authors demonstrate that periodic fasting enhances the anti-tumour effect of cholesterol biosynthesis inhibitors via decreased AKT-STAT3 signaling and oxidative phosphorylation.
- Amr Khalifa
- , Ana Guijarro
- & Alessio Nencioni
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The Lin28b/Wnt5a axis drives pancreas cancer through crosstalk between cancer associated fibroblasts and tumor epithelium
Crosstalk between tumor cells and the microenvironment is essential for tumor progression. Here, the authors show Pancreatic ductal adenocarcinoma (PDAC) epithelial cells with high level of Lin28b secrete Wnt5a to upregulate Lin28b expression in cancer-associated fibroblasts, which in turn promote growth of PDAC cells via production of PCSK9.
- Zhaoqi Shu
- , Minghe Fan
- & Ying Zhao
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Article
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The USP46 complex deubiquitylates LRP6 to promote Wnt/β-catenin signaling
Wnt receptors are controlled by their ubiquitin-mediated proteolysis. The authors show that the USP46 deubiquitylase complex potentiates Wnt signaling in human cells, Xenopus, and zebrafish by inhibiting cell surface LRP6 degradation.
- Victoria H. Ng
- , Zachary Spencer
- & Ethan Lee
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The TNFR Wengen regulates the FGF pathway by an unconventional mechanism
Mechanistic studies of receptor action have aided our understanding of developmental processes and facilitated drug development. Here they show that the TNFR-Wengen acts by forming a complex with the FGFR-Breathless, regulating its activity during cell differentiation in the developing respiratory system of Drosophila.
- Annalisa Letizia
- , Maria Lluisa Espinàs
- & Marta Llimargas
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Fgf signalling triggers an intrinsic mesodermal timer that determines the duration of limb patterning
The limb bud is patterned by crosstalk between the mesoderm and the overlying apical ectodermal ridge, but it has been difficult to determine the requirement for different ligands in this process. Here the authors use a chick wing explant system to show that fibroblast growth factors trigger a mesodermal programme that is key for timing limb bud patterning.
- Sofia Sedas Perez
- , Caitlin McQueen
- & Matthew Towers
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Spinal cord repair is modulated by the neurogenic factor Hb-egf under direction of a regeneration-associated enhancer
Zebrafish can regenerate after paralyzing spine injuries and regain locomotor ability, unlike mammals. Here authors show that the neurogenic factor Hb-egf promotes spinal cord regeneration in zebrafish and is regulated by an enhancer that can similarly direct expression in the pro-regenerative setting of neonatal mice.
- Valentina Cigliola
- , Adam Shoffner
- & Kenneth D. Poss
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Circular RNA encoded MET variant promotes glioblastoma tumorigenesis
MET signalling is required for glioblastoma (GBM) stem cell maintenance. Here the authors identify a circular RNA from the MET gene (circMET) that encodes a MET variant protein (MET404) and show that it can promote GBM tumorigenesis by directly activating the MET receptor independent of HGF stimulation.
- Jian Zhong
- , Xujia Wu
- & Nu Zhang
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| Open Access
Structural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3
PEAK pseudokinases are emerging disease targets, which regulate cell migration and proliferation through protein scaffolding. Here, the authors present the cryo-EM structure of the PEAK3/14-3-3 complex and reveal how 14-3-3 modulates PEAK3 localization and protein-protein interactions.
- Hayarpi Torosyan
- , Michael D. Paul
- & Kliment A. Verba
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| Open Access
Antibody blockade of Jagged1 attenuates choroidal neovascularization
Current treatment for neovascular age-related macular degeneration (nAMD) does not help all patients. Here, the authors show that using antibodies to block Jagged1 reduces disease burden in a model of nAMD, which could enable new treatment options.
- Torleif Tollefsrud Gjølberg
- , Jonas Aakre Wik
- & Eirik Sundlisæter
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| Open Access
A blocking monoclonal antibody reveals dimerization of intracellular domains of ALK2 associated with genetic disorders
Mutant forms of the transmembrane receptor activin receptor-like kinase 2 are associated with different genetic diseases. Here, the authors report that disease-associated forms of this receptor cause intracellular domains to dimerize in response to ligand binding of extracellular domains.
- Takenobu Katagiri
- , Sho Tsukamoto
- & Kiyosumi Takaishi
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Endothelial cell-derived stem cell factor promotes lipid accumulation through c-Kit-mediated increase of lipogenic enzymes in brown adipocytes
Although it is known that cellular crosstalk between endothelial cells and brown adipocytes is essential, it remains poorly understood. Here the authors show that SCF derived from the surrounding endothelial cells promotes lipid accumulation in BAT by enhancing lipogenic enzymes in through c-Kit activation.
- Hyuek Jong Lee
- , Jueun Lee
- & Gou Young Koh
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Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling
EGFR is a receptor that is upregulated in many cancers, but the mechanisms that control EGFR function are incompletely understood. Here the authors used single particle tracking to identify a role for tetraspanin CD81 in EGFR ligand binding, mobility, and signaling.
- Michael G. Sugiyama
- , Aidan I. Brown
- & Costin N. Antonescu
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AGGF1 therapy inhibits thoracic aortic aneurysms by enhancing integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signaling
Thoracic aortic aneurysm (TAA) causes many sudden deaths each year, however, no effective drug treatment is available. Here, the authors show that AGGF1 protein therapy attenuates TAA in three different mouse models through integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signalling.
- Xingwen Da
- , Ziyan Li
- & Qing K. Wang
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Domain-specific p53 mutants activate EGFR by distinct mechanisms exposing tissue-independent therapeutic vulnerabilities
Here the authors identify distinct mechanisms by which domain-specific p53 mutations activate cancer cell growth via the epidermal growth factor receptor (EGFR). These mechanisms affect sensitivity to EGFR inhibitors, opening avenues for targeted therapy.
- Teresa Lai Fong Ho
- , May Yin Lee
- & Ashok R. Venkitaraman
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The Wnt/TCF7L1 transcriptional repressor axis drives primitive endoderm formation by antagonizing naive and formative pluripotency
Signal transduction and gene expression regulation via downstream transcription factors shape the early mammalian embryo. Here the authors show that Wnt/TCF7L1 transcriptional repressive activity is required for primitive endoderm lineage formation.
- Paraskevi Athanasouli
- , Martina Balli
- & Frederic Lluis
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Sensory nerve niche regulates mesenchymal stem cell homeostasis via FGF/mTOR/autophagy axis
Sensory nerves are important for tissue homeostasis. Here the authors show that sensory nerves contribute to Mesenchymal stem cell maintenance via FGF1, mTOR signaling and autophagy.
- Fei Pei
- , Li Ma
- & Yang Chai
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| Open Access
An extracellular receptor tyrosine kinase motif orchestrating intracellular STAT activation
Specificity in signaling activated by receptor tyrosine kinases is typically attributed to characteristics of their intracellular domains. Here, the authors demonstrate that an extracellular receptor sequence motif controls intracellular signaling as a result of extracellular glycan interactions.
- Katri Vaparanta
- , Anne Jokilammi
- & Klaus Elenius
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Interaction of a viral insulin-like peptide with the IGF-1 receptor produces a natural antagonist
The authors previously identified a family of viral insulin-like peptides (VILPs) with high homology to human insulin/IGF−1. Here, they report that one of these VILPs exhibits antagonist properties associated with a unique conformation of the IGF1R.
- Francois Moreau
- , Nicholas S. Kirk
- & C. Ronald Kahn
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WASH activation controls endosomal recycling and EGFR and Hippo signaling during tumor-suppressive cell competition
Polarity-deficient epithelial cells are eliminated through Sas-Ptp10D-mediated suppression of EGFR signalling during cell competition. Here the authors show the constitutively active, phosphomimetic WASH can activate both EGFR and Hippo signalling and thereby, induces the overgrowth of these polarity-deficient cells in Drosophila and in proliferating epithelial cells, WASH activation differentially affects the separate recycling routes of EGFR and its inhibitor Ptp10D.
- Dan Liu
- , Vasilios Tsarouhas
- & Christos Samakovlis
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The Hippo pathway links adipocyte plasticity to adipose tissue fibrosis
Adipose tissue fibrosis is connected to obesity-related metabolic dysfunction. Qiu and colleagues discover that the Hippo pathway acts as a molecular switch in the initiation and development of adipose tissue fibrosis upon TGFβ stimulation.
- Hongyu Shen
- , Xun Huang
- & Yifu Qiu
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Specificity of TGF-β1 signal designated by LRRC33 and integrin αVβ8
Microenvironment localization and activation of L-TGF-β1 determine its specific function. Here, the authors elucidated the underlying mechanisms of specific presentation of L-TGF-β1 on the surface of myeloid lineage cells designated by LRRC33, and its activation by integrin αVβ8.
- Zelin Duan
- , Xuezhen Lin
- & Zhe Zhang
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| Open Access
Structural basis for assembly and disassembly of the IGF/IGFBP/ALS ternary complex
Insulin-like growth factor 1 (IGF1) regulates growth and differentiation. Here, authors report the atomic structure of the ternary complex (IGF1/IGF-binding protein3/acid labile subunit) and its assembly/disassembly mechanism for IGF bioavailability.
- Hyojin Kim
- , Yaoyao Fu
- & Ho Min Kim
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A Nodal enhanced micropeptide NEMEP regulates glucose uptake during mesendoderm differentiation of embryonic stem cells
Fu et al. identify the highly conserved, transmembrane micropeptide, NEMEP, as a direct target of Nodal signaling, essential for mesendoderm differentiation. NEMEP interacts with the glucose transporters GLUT1/GLUT3 and promotes glucose uptake.
- Haipeng Fu
- , Tingyu Wang
- & Qiaoran Xi
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Mast4 determines the cell fate of MSCs for bone and cartilage development
Controlling fate decision of mesenchymal stromal cells (MSC) is important for their clinical application. Here the authors demonstrate that TGF-β-induced Mast4 suppression and Wnt-mediated Mast4 stabilization regulate MSC differentiation into cartilage and bone, respectively.
- Pyunggang Kim
- , Jinah Park
- & Seong-Jin Kim
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Ligand-induced transmembrane conformational coupling in monomeric EGFR
EGFR regulates cellular processes across the animal kingdom. Here, the authors show that transmembrane conformational coupling is the first step in EGFR signaling, providing evidence for the existence of transmembrane intramolecular conformational changes in a single pass membrane protein.
- Shwetha Srinivasan
- , Raju Regmi
- & Gabriela S. Schlau-Cohen
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Inactivation of the Hippo tumor suppressor pathway promotes melanoma
Activating mutations of BRAF alone are inadequate to drive melanoma formation. Here the authors show that activation of Hippo signalling by oncogenic BRAF represents an additional safeguard to limit BRAF-dependent human melanocyte growth and melanoma formation.
- Marc A. Vittoria
- , Nathan Kingston
- & Neil J. Ganem
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A scalable, open-source implementation of a large-scale mechanistic model for single cell proliferation and death signaling
Mechanistic models of how single cells respond to different perturbations can help integrate disparate big data sets or predict response to varied drug combinations. Here the authors develop a scalable, open-source pipeline for constructing and simulating large-scale, single-cell mechanistic models, an important building block for clinically-predictive mechanistic models and interpretable big data integration.
- Cemal Erdem
- , Arnab Mutsuddy
- & Marc R. Birtwistle
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GPI-anchored FGF directs cytoneme-mediated bidirectional contacts to regulate its tissue-specific dispersion
Cytonemes are signaling filopodia that mediate target-specific long-distance communications of signals like FGFs. Du et al. show that a Drosophila FGF is anchored to the FGF-producing cell surface, inhibiting free FGF secretion and activating contact-dependent bidirectional FGF-FGFR interactions, controlling target-specific cytoneme contacts and contact-dependent FGF release.
- Lijuan Du
- , Alex Sohr
- & Sougata Roy
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Article
| Open Access
EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation
Breast cancer cells are known to metastasize to the bone but why the cells should migrate and metastasize to this particular organ is not clearly understood. Here, the authors show that EZH2 activates an integrin B1 and FAK signaling pathway in breast cancer cells, which activates TGFB signaling to drive metastasis in the bone.
- Lin Zhang
- , Jingkun Qu
- & Dihua Yu
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| Open Access
Distinctive molecular features of regenerative stem cells in the damaged male germline
Male germline regeneration after damage is dependent on spermatogonial stem cells (SSCs) but pathways mediating the regenerative response are unclear. Here the authors define roles for growth factor signalling and mTORC1 in SSC-driven regeneration.
- Hue M. La
- , Jinyue Liao
- & Robin M. Hobbs
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Crystal structures of BMPRII extracellular domain in binary and ternary receptor complexes with BMP10
Mutations in BMPR2 is the major genetic cause for pulmonary arterial hypertension (PAH). Here by solving crystal structures of BMPRII in binary and ternary receptor complexes with BMP10, the authors report the molecular recognition between BMPRII and BMP10, and its implication in PAH.
- Jingxu Guo
- , Bin Liu
- & Wei Li
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| Open Access
S6K1-mediated phosphorylation of PDK1 impairs AKT kinase activity and oncogenic functions
The direct upstream regulation of PDK1 is not fully understood. Here the authors demonstrate that S6K1 directly phosphorylates PDK1 to inhibit AKT kinase activity and its ability to drive tumourigenesis.
- Qiwei Jiang
- , Xiaomei Zhang
- & Jianping Guo
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| Open Access
Menin directs regionalized decidual transformation through epigenetically setting PTX3 to balance FGF and BMP signaling
The decidualization of endometrial stroma is critical for pregnancy maintenance. Here the authors reveal that Menin ensures the expression of PTX3 through H3K4me3 modification, to balance the BMP and FGF signal in the decidua for normal pregnancy.
- Mengying Liu
- , Wenbo Deng
- & Shuangbo Kong
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Dual clathrin and integrin signaling systems regulate growth factor receptor activation
The integration and organization of growth factor signaling, adhesion, and endocytosis is poorly understood. Here the authors use light and electron microscopy to shed light on the role of flat clathrin lattices and cell adhesion in growth factor signaling.
- Marco A. Alfonzo-Méndez
- , Kem A. Sochacki
- & Justin W. Taraska
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| Open Access
Mesenchymal-epithelial crosstalk shapes intestinal regionalisation via Wnt and Shh signalling
The small intestine forms via crosstalk between epithelial and mesenchymal cell compartments. Here, the authors show that a gradient of Wnt signalling along the anterior-posterior axis regulates Sonic Hedgehog which is required for correct formation and regionalization of the small intestine.
- Martti Maimets
- , Marianne Terndrup Pedersen
- & Kim B. Jensen
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Article
| Open Access
Endothelial cell-specific expression of serine/threonine kinase 11 modulates dendritic cell differentiation
In the bone marrow, dendritic cell development is governed by supporting cells, such as endothelial cells. Here authors show that expression of serine/threonine kinase 11 in endothelial cells regulates differentiation of dendritic cell precursors via modulating secretion of stem cell factor.
- Qiang Zhao
- , Young-Min Han
- & Ming-Hui Zou
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Article
| Open Access
Electron transfer-triggered imaging of EGFR signaling activity
Here, the authors design a nanoprobe for in vivo imaging of electronic transfer, consisting of a ferrocene-DNA polymer to transfer electrons to luminescent nanoparticles, changing their optical signal. Using this probe, they map activation of EGFR signalling during tumour treatment.
- Jie Tan
- , Hao Li
- & Quan Yuan
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Article
| Open Access
Endosomal trafficking defects alter neural progenitor proliferation and cause microcephaly
Mutations in the human WDR81 gene result in severe microcephaly. Carpentieri et al. show that mutation of WDR81, a gene coding for an endosomal regulator, alters intracellular processing of the EGF receptor, leading to reduced proliferation rates of neuronal progenitors and to microcephaly.
- Jacopo A. Carpentieri
- , Amandine Di Cicco
- & Alexandre D. Baffet
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Article
| Open Access
Spatial-proteomics reveals phospho-signaling dynamics at subcellular resolution
Protein activity regulated by phosphorylation can result in subcellular relocation. Here, the authors present a high throughput spatial phosphoproteomics approach to profile six subcellular compartments, providing insights into EGFR and stress signalling dynamics.
- Ana Martinez-Val
- , Dorte B. Bekker-Jensen
- & Jesper V. Olsen
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Article
| Open Access
Comprehensive targeting of resistance to inhibition of RTK signaling pathways by using glucocorticoids
TNF signalling was reported to mediate resistance to EGFR inhibition in non-small cell lung cancer (NSCLC). Here, the authors examine the efficacy of a broad versus focused targeting of this resistance, and they show that a broad inhibitor of inflammation, prednisone is the most effective.
- Ke Gong
- , Gao Guo
- & Amyn A. Habib
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Article
| Open Access
ATR inhibition enables complete tumour regression in ALK-driven NB mouse models
Effective therapeutic options are still needed in neuroblastoma treatment. Here, the authors, through a comprehensive proteomics analysis, identify ATR as a potential therapeutic target of neuroblastoma and demonstrate the efficacy of the ATR inhibitor BAY1895344 in combination with the ALK tyrosine kinase inhibitor lorlatinib.
- Joanna Szydzik
- , Dan E. Lind
- & Ruth H. Palmer
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| Open Access
Nuclear-capture of endosomes depletes nuclear G-actin to promote SRF/MRTF activation and cancer cell invasion
Effective delivery of signals from the cell surface to the nucleus is a key to activate gene transcription. Here, the authors show how endosomes containing EphA2 are transported and captured at the nuclear surface, triggering depletion of G-actin from the nucleus and activating MRTF signalling.
- Sergi Marco
- , Matthew Neilson
- & Jim C. Norman
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Article
| Open Access
HER2 + breast cancers evade anti-HER2 therapy via a switch in driver pathway
Resistance to HER2 inhibition in HER2- amplified breast cancer is common in the metastatic setting and the underlying molecular mechanisms remain unknown. Here, the authors, perform genomic profiling of 733 HER2-amplified breast cancers and propose genetic activation of MAPK as a resistance mechanism.
- Alison E. Smith
- , Emanuela Ferraro
- & Sarat Chandarlapaty
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| Open Access
Smad4 controls signaling robustness and morphogenesis by differentially contributing to the Nodal and BMP pathways
The role of the transcriptional effector SMAD4 in vertebrate embryo development remains unresolved. Here the authors show that in the absence of Smad4, dorsal/ventral embryo patterning is disrupted due to the loss of BMP signaling, while Nodal signaling is maintained, but insufficient for optimal endoderm specification.
- Luca Guglielmi
- , Claire Heliot
- & Caroline S. Hill
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| Open Access
Endothelial deletion of SHP2 suppresses tumor angiogenesis and promotes vascular normalization
SHP2 regulates pro-angiogenic VEGF-VEGFR signalling, but its role in tumour angiogenesis is unclear. Here the authors show that endothelial cell-specific deletion of SHP2 impairs tumour growth and angiogenesis in syngeneic mouse models through ASK1-c-JunSOX7 signalling axis.
- Zhiyong Xu
- , Chunyi Guo
- & Hongqiang Cheng
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Article
| Open Access
FBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth
Aberrant EGFR activation is commonly found in non-small cell lung cancer (NSCLC). Here the authors show that E3 ubiquitin ligase FBXL2 targets EGFR and EGFR tyrosine kinase inhibitor (TKI)-resistant mutants for proteasome-mediated degradation to inhibit EGFR-driven NSCLC growth and TKI resistance.
- Mengmeng Niu
- , Jing Xu
- & Zhi-Xiong Jim Xiao
Nerve growth factor receptor limits inflammation to promote remodeling and repair of osteoarthritic joints