Cell signalling

  • Article
    | Open Access

    The authors show that post-transcriptional regulation of the cilia-driven leftward flow target dand5 is central to symmetry breakage in frog, fish and mouse and is mediated by a 139 nt Bicc1 responsive element in the dand5 3′UTR, and they present evidence that Pkd2 regulates this Bicc1/dand5 module.

    • Markus Maerker
    • , Maike Getwan
    •  & Axel Schweickert
  • Article
    | Open Access

    The mechanisms underlying the activity of non-receptor tyrosine kinase, TNK1, in cancers are unclear. Here the authors show that MARK mediates 14-3-3 and TNK1 interaction which restrains TNK1 activity, while the release of TNK1 from 14-3-3 leads to TNK1 activation through its interaction with ubiquitin and thus results in TNK1-mediated tumor growth in vivo

    • Tsz-Yin Chan
    • , Christina M. Egbert
    •  & Joshua L. Andersen
  • Article
    | Open Access

    PAK4 is a kinase involved in cell-cell junctions, though the identify of the  local protein network involving PAK4 is unclear. Here, the authors performed proximity proteomic analysis on mammalian PAK4 and find  that PAK4 is associated with Afadin-dependent junctions, and report putative PAK4 phosphorylation substrates at this site.

    • Yohendran Baskaran
    • , Felicia Pei-Ling Tay
    •  & Edward Manser
  • Article
    | Open Access

    Cells in the developing embryo interpret WNT signalling with context-dependence, but the mechanism decoding these cues is unclear. Here, the authors show that combinatorial TALE/HOX activity destabilizes nucleosomes at WNT-responsive regions to activate paraxial mesodermal genes.

    • Luca Mariani
    • , Xiaogang Guo
    •  & Elisabetta Ferretti
  • Article
    | Open Access

    Osteoporosis and bone fractures affect millions of patients worldwide and are often due to increased bone resorption. Here the authors identify the cytoplasmic protein ELMO1 as an important ‘signaling node’ promoting the bone resorption function of osteoclasts.

    • Sanja Arandjelovic
    • , Justin S. A. Perry
    •  & Kodi S. Ravichandran
  • Article
    | Open Access

    RAS-induced senescence is a safeguarding process against tumour development. Here, the authors show that RAS activation destabilises the transcription factor ZNF768, which blocks ZNF768- dependent repression of p53 activity and thus induces senescence.

    • Romain Villot
    • , Audrey Poirier
    •  & Mathieu Laplante
  • Article
    | Open Access

    Soft tissue trauma can result in aberrant osteochondral differentiation of local mesenchymal progenitor cells. Here the authors show that, in mice, soft tissue trauma results in NGF expression by perivascular cells, which leads to axonal invasion and drives abnormal osteochondral differentiation, and show that this process can be prevented by inhibition of NGF signaling.

    • Seungyong Lee
    • , Charles Hwang
    •  & Benjamin Levi
  • Article
    | Open Access

    Bone morphogenetic protein (BMP) receptors are single pass transmembrane serine/threonine kinases that form tetrameric complexes comprised of two type I and two type II BMP receptors. Here the authors characterize a structure of an active type I/type II kinase tetramer providing insight into molecular mechanism driving ligand-induced signaling.

    • Christopher Agnew
    • , Pelin Ayaz
    •  & Natalia Jura
  • Article
    | Open Access

    Cellular cholesterol levels are tightly regulated. Here, the authors show that the hedgehog signalling receptor PTCH is a cholesterol transporter. Reduction in PTCH activity leads to cellular cholesterol accumulation, changes in nuclear hormone receptor activity and fatty acid metabolism.

    • Carla E. Cadena del Castillo
    • , J. Thomas Hannich
    •  & Anne Spang
  • Article
    | Open Access

    While Ras is a promising target for cancer therapy, development of inhibitors targeting Ras signaling has proven challenging. Here, the authors report the discovery of Rasarfin, a small molecule from a phenotypic screen on G protein-coupled receptor (GPCR) endocytosis that acts as a dual Ras and ARF6 inhibitor.

    • Jenna Giubilaro
    • , Doris A. Schuetz
    •  & Stéphane A. Laporte
  • Article
    | Open Access

    Glucocorticoids are associated with stress. Here, the authors show that high levels of glucocorticoid stress promote secretory autophagy of matrix metalloproteinase 9 via a stress responsive chaperone, increasing brain-derived neurotrophic factor processing and potentially altering adult synaptic plasticity.

    • Silvia Martinelli
    • , Elmira A. Anderzhanova
    •  & Nils C. Gassen
  • Article
    | Open Access

    Here, the authors show that microglia depletion results in unstable wakefulness and altered levels of ceramide, influencing microglia in the mouse thalamic reticular nucleus (TRN). Stable wakefulness can be restored by activation of the TRN or inhibition of ceramide production in the mouse brain.

    • Hanxiao Liu
    • , Xinxing Wang
    •  & Qiaojie Xiong
  • Article
    | Open Access

    Hedgehog signaling is essential for bone formation. Here, the authors show that the transmembrane protein SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts, suggesting it may be a potential therapeutic target to enhance bone formation.

    • Jun Sun
    • , Dong Yeon Shin
    •  & Matthew B. Greenblatt
  • Article
    | Open Access

    S-acylation is the post-translational covalent attachment of fatty acids (FA) onto cysteines. Nuskova et al. find that exposure of cells to different FAs affects which FA is used to S-acylate GNAI proteins, thereby altering GNAI function and EGFR pathway activation, linking metabolism to signaling.

    • Hana Nůsková
    • , Marina V. Serebryakova
    •  & Aurelio A. Teleman
  • Article
    | Open Access

    Environmental and genetic risk factors affect the distal airway epithelium in idiopatic pulmonary fibrosis (IPF) but the role of the epithelium in IPF remains unclear. Here the authors show that pathologic activation of the ERBB-YAP axis induces dynamic and structural dysfunction in the distal airway epithelium eliciting a pro-fibrotic phenotype in mesenchymal cells.

    • Ian T. Stancil
    • , Jacob E. Michalski
    •  & David A. Schwartz
  • Article
    | Open Access

    Nutrient status in the cell regulates autophagy via mTORC1 activity. Here, the authors show that the ubiquitous G protein subunit Gαq contributes to nutrient sensing by promoting formation of an mTOR-p62-Raptor complex in replete conditions, modulating autophagy.

    • Sofía Cabezudo
    • , Maria Sanz-Flores
    •  & Catalina Ribas
  • Article
    | Open Access

    The transmembrane protein Wntless (WLS) is essential for the secretion of Wnt proteins, which are signaling molecules of the Wnt signaling pathways. Here, the authors present the 2.2 Å cryo-EM structure of human WLS in complex with Wnt3a and discuss mechanistic implications for the palmitoleoylation of Wnt3a that is required for WLS mediated Wnt secretion.

    • Qing Zhong
    • , Yanyu Zhao
    •  & Dan Ma
  • Article
    | Open Access

    Calcium signals initiated by IP3 receptors in ER membranes regulate most cellular activities. Here, the authors show that KRas-induced actininteracting protein (KRAP) tethers a small subset of IP3 receptors to actin and licenses them to evoke cytosolic calcium signals.

    • Nagendra Babu Thillaiappan
    • , Holly A. Smith
    •  & Colin W. Taylor
  • Article
    | Open Access

    Pannexin 1 (PANX1) is a membrane channel mediating release of signaling molecules to the extracellular space. PANX1 can be activated by GPCRs. Here, the authors elucidate a non-canonical channel activation pathway by α1-adrenergic receptor that involves HDAC6- mediated lysine deacetylation of PANX1.

    • Yu-Hsin Chiu
    • , Christopher B. Medina
    •  & Douglas A. Bayliss
  • Article
    | Open Access

    Memory T cells are particularly reliant on fatty acid oxidation as a source of energy. Here the authors show this reliance is controlled by AMPK sensing of glucose deprivation that triggers SENP1-Sirt3 signalling, driving fatty acid oxidation and memory differentiation in T cells via deacetylation of YME1L1 to induce mitochondrial fusion.

    • Jianli He
    • , Xun Shangguan
    •  & Jinke Cheng
  • Article
    | Open Access

    Rare earth elements are widely used in agriculture to promote plant growth. Here the authors show that aerial application of a rare earth element to the leaves triggers a graft-transmissible, RbohD- and jasmonic acid-dependent systemic signal that triggers endocytosis and mineral nutrient uptake in roots.

    • Mengzhu Cheng
    • , Lihong Wang
    •  & Zhenbiao Yang
  • Article
    | Open Access

    Mutations in ryanodine receptor 1 (RyR1), a Ca2+ release channel in skeletal muscle, cause malignant hyperthermia (MH) and are involved in heat stroke. Here, the authors show that an oxolinic acid-derivative RyR1 inhibitor effectively prevents and treats MH and heat stroke in various MH mouse models.

    • Toshiko Yamazawa
    • , Takuya Kobayashi
    •  & Takashi Murayama
  • Article
    | Open Access

    Extracellular matrix protein 1 (ECM1) has been associated with cancer but the underlying molecular mechanisms are not clear. Here, the authors show that while ECM1b isoform is a tumour suppressor, the secreted isoform ECM1a promotes tumourigenesis and chemoresistance through increasing stemness and alternative mRNA splicing in ovarian cancer.

    • Huijing Yin
    • , Jingshu Wang
    •  & Gong Yang
  • Article
    | Open Access

    Activation of c-MET receptor tyrosine kinase involves hepatocyte growth factor (HGF) and glycosaminoglycans, but the molecular mechanism is still under debate. Here, the authors present cryoEM structures of c-MET bound to two HGF splice variants and heparin, revealing the structural basis for c-MET activation.

    • Emiko Uchikawa
    • , Zhiming Chen
    •  & Xiao-chen Bai
  • Article
    | Open Access

    The authors show in Nematostella that the more orally expressed β-catenin targets repress the more aborally expressed β-catenin targets, thus patterning the oral-aboral axis. This likely represents the common mechanism of β-catenin-dependent axial patterning shared by Cnidaria and Bilateria.

    • Tatiana Lebedeva
    • , Andrew J. Aman
    •  & Grigory Genikhovich
  • Article
    | Open Access

    Most mutant p53 heterozygous tumours undergo loss of the remaining wildtype (WT) p53 allele which leads to stabilization of the mutant p53 protein. Here, the authors show in an autochthonous colorectal cancer model that the WT p53 allele retains partial activity and suppresses the heat shock factor 1 (HSF1)- chaperone axis to prevent mutant p53 stabilisation and mutant p53 gain-of-function activities, thereby creating selective pressure for p53 loss-of-heterozygosity.

    • Tamara Isermann
    • , Özge Çiçek Şener
    •  & Ramona Schulz-Heddergott
  • Article
    | Open Access

    Transcription factors (TFs) often form distinct networks to regulate transcriptional program during cancer progression. Here the authors show that OCT4 is a common transcriptional factor in two types of advanced PC and as such, OCT4 accelerates a TF complex formation with the FOXA1/AR in castration-resistant PC and NRF1 in neuroendocrine PC.

    • Ken-ichi Takayama
    • , Takeo Kosaka
    •  & Satoshi Inoue
  • Article
    | Open Access

    Epithelial host defense to rhinovirus infections is enhanced by targeting the mitochondrial metabolic regulator, PGC-1a. Using metabolomics and proteomics, Michi et al show that human airway epithelial cells mount a barrier-protective early glycolysis-shift in response to rhinovirus, and that by targeting PGC-1a early in infection, epithelial barrier function, viral defense and pathology are improved.

    • Aubrey N. Michi
    • , Bryan G. Yipp
    •  & David Proud
  • Article
    | Open Access

    Nonvesicular extracellular RNA (nex-RNA) that are not packed in extracellular vesicles is detected outside the cell, but it is poorly understood. Here the authors report that nex-RNA is captured by a zinc finger protein and transported to the nucleus to enhance antimetastatic characters of the cell.

    • Takeshi Tomita
    • , Masayoshi Kato
    •  & Sachie Hiratsuka
  • Article
    | Open Access

    Genetic variants in CD36 have been associated with metabolic syndrome. Here, the authors found that lymphatic vessel integrity and lipid transport are influenced by CD36 expression, and lymphatic endothelial cell CD36 deficiency causes visceral obesity and insulin resistance, which are risk factors for metabolic syndrome and diabetes.

    • Vincenza Cifarelli
    • , Sila Appak-Baskoy
    •  & Nada A. Abumrad
  • Article
    | Open Access

    Clinical CDK4/6 inhibitors are used and tested to treat a variety of cancer types. Here, the authors identify that these drugs work in two ways, a known catalytic role to inhibit kinase activity and a newly discovered noncatalytic role to displace CDK inhibitor p21 from CDK4 but not CDK6 complexes.

    • Lindsey R. Pack
    • , Leighton H. Daigh
    •  & Tobias Meyer
  • Article
    | Open Access

    Hepatic gluconeogenesis is important for glucose homeostasis and a therapeutic target for type 2 diabetes. Here, the authors show that the RNA-binding adaptor protein Sam68 promotes the expression level of gluconeogenic genes and increases blood glucose levels by stabilizing the transcriptional coactivator CRTC2, while hepatic Sam68 deletion alleviates hyperglycemia in mice.

    • Aijun Qiao
    • , Junlan Zhou
    •  & Gangjian Qin
  • Article
    | Open Access

    P53 is a well-known tumour suppressor, however its role in intestinal type 2 immunity is currently unclear. Here authors report that during parasitic infections, p53 triggers tuft cell Ca2+ influx and IL-25 release, and shows a regulatory role for p53 in intestinal type 2 immunity via transcriptional regulation of the Lrmp gene.

    • Chun-Yuan Chang
    • , Jianming Wang
    •  & Wenwei Hu
  • Article
    | Open Access

    Perilipin 5 is a lipid droplet protein that interacts with PGC1α in the nucleus to regulate mitochondrial metabolism. Here the authors use genetically engineered mouse models to determine the physiologic role of Perilipin 5, and show that it regulates mitochondrial adaptations to cold, as well as systemic energy metabolism.

    • Violeta I. Gallardo-Montejano
    • , Chaofeng Yang
    •  & Perry E. Bickel
  • Article
    | Open Access

    Natural selection may favor traits underlying aging-related diseases if they benefit the young. Wang et al. find that oxidative activation of CaMKII provides physiological benefits critical to the initial and continued success of vertebrates but at the cost of disease, frailty, and shortened lifespan.

    • Qinchuan Wang
    • , Erick O. Hernández-Ochoa
    •  & Mark E. Anderson
  • Article
    | Open Access

    How dynamic transcription factors temporally interact to regulate stress survival in yeast is currently unclear. Here the authors integrate single-cell imaging, RNA-seq, and modeling to identify a new cell fate control mechanism mediated by temporal redundancy modulation during yeast stress response.

    • Yan Wu
    • , Jiaqi Wu
    •  & Yihan Lin
  • Article
    | Open Access

    The PI(3,4)P2 4-phosphatase, INPP4B, functions as a tumour suppressor in triple negative breast cancer. Here, the authors show that INPP4B enhances proliferation and growth of PIK3CA-mutant ER+ breast cancers by promoting PI3Kα-dependent late endosome formation and trafficking that leads to the activation of Wnt/β-catenin signalling.

    • Samuel J. Rodgers
    • , Lisa M. Ooms
    •  & Christina A. Mitchell
  • Article
    | Open Access

    Supplementation of magnesium (Mg2+) or its inclusion in biomaterials has beneficial effects for bone formation, but it has also been reported that it can have detrimental effects. Here, the authors analyse dose- and time-dependent effects of Mg2+ on bone regeneration and show that it can stimulate monocyte-macrophage lineage cells to support bone formation in the early phases of repair, but inhibit bone repair and mineralization in later stages by promoting a pro-inflammatory environment.

    • Wei Qiao
    • , Karen H. M. Wong
    •  & Kelvin W. K. Yeung
  • Article
    | Open Access

    Resistance to Trastuzumab in HER2 gastric cancer patients remains a clinical challenge. In this study, the authors demonstrate that HER2 promotes tumorigenesis in gastric cancer by regulating mitotic progression through a Shc1-SHCBP1-PLK1-MISP axis and they identify a compound, TFBG, able to disrupt SHCBP1/PLK1 interaction and to synergize with trastuzumab.

    • Wengui Shi
    • , Gengyuan Zhang
    •  & Zuoyi Jiao
  • Article
    | Open Access

    Alteration of circadian rhythms is often observed in patients with chronic kidney disease (CKD). Here, the authors show that CKD-induced dysfunction of the circadian clock increases the expression of G protein-coupled receptor 68 in circulating monocytes and that their cardiac infiltration exacerbates inflammation and fibrosis of heart.

    • Yuya Yoshida
    • , Naoya Matsunaga
    •  & Shigehiro Ohdo