Erratum for the Research Article: "Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists" by A. Gillis, A. B. Gondin, A. Kliewer, J. Sanchez, H. D. Lim, C. Alamein, P. Manandhar, M. Santiago, S. Fritzw.er, F. Schmiedel, T. A. Katte, T. Reekie, N. L. Grimsey, M. Kassiou, B. Kellam, C. Krasel, M. L. Halls, M. Connor, J. R. Lane, S. Schulz, M. J. Christie, M. Canals
(Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - February 16, 2021 Category: Science Tags: STKE Errata Source Type: news

A predictive model of gene expression reveals the role of network motifs in the mating response of yeast
Cells use signaling pathways to receive and process information about their environment. These nonlinear systems rely on feedback and feedforward regulation to respond appropriately to changing environmental conditions. Mathematical models describing signaling pathways often lack predictive power because they are not trained on data that encompass the diverse time scales on which these regulatory mechanisms operate. We addressed this limitation by measuring transcriptional changes induced by the mating response in Saccharomyces cerevisiae exposed to different dynamic patterns of pheromone. We found that pheromone-induced t...
Source: Signal Transduction Knowledge Environment - February 16, 2021 Category: Science Authors: Pomeroy, A. E., Pena, M. I., Houser, J. R., Dixit, G., Dohlman, H. G., Elston, T. C., Errede, B. Tags: STKE Research Articles Source Type: news

Ligand-independent activity of the ghrelin receptor modulates AMPA receptor trafficking and supports memory formation
The biological signals of hunger, satiety, and memory are interconnected. The role of the hormone ghrelin in regulating feeding and memory makes ghrelin receptors attractive targets for associated disorders. We investigated the effects of the high ligand-independent activity of the ghrelin receptor GHS-R1a on the physiology of excitatory synapses in the hippocampus. Blocking this activity produced a decrease in the synaptic content of AMPA receptors in hippocampal neurons and a reduction in GluA1 phosphorylation at Ser845. Reducing the ligand-independent activity of GHS-R1a increased the surface diffusion of AMPA receptors...
Source: Signal Transduction Knowledge Environment - February 16, 2021 Category: Science Authors: Ribeiro, L. F., Catarino, T., Carvalho, M., Cortes, L., Santos, S. D., Opazo, P. O., Ribeiro, L. R., Oliveiros, B., Choquet, D., Esteban, J. A., Peca, J., Carvalho, A. L. Tags: STKE Research Articles Source Type: news

Drugging mutant p53
Arsenic trioxide may be effective against tumors with structural p53 mutations. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - February 16, 2021 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

ATDC KEAPs NRF2 active
ATDC promotes pancreatic cancer progression and chemoresistance by disrupting KEAP1-mediated ubiquitylation of NRF2. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - February 9, 2021 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news

The kinetoplastid-specific phosphatase KPP1 attenuates PLK activity to facilitate flagellum inheritance in Trypanosoma brucei
Trypanosoma brucei, an important human parasite, has a flagellum that controls cell motility, morphogenesis, proliferation, and cell-cell communication. Inheritance of the newly assembled flagellum during the cell cycle requires the Polo-like kinase homolog TbPLK and the kinetoplastid-specific protein phosphatase KPP1, although whether TbPLK acts on KPP1 or vice versa has been unclear. Here, we showed that dephosphorylation of TbPLK on Thr125 by KPP1 maintained low TbPLK activity in the flagellum-associated hook complex structure, thereby ensuring proper flagellum positioning and attachment. This dephosphorylation event re...
Source: Signal Transduction Knowledge Environment - February 9, 2021 Category: Science Authors: An, T., Hu, H., Li, Z. Tags: STKE Research Articles Source Type: news

Activin A promotes the development of acquired heterotopic ossification and is an effective target for disease attenuation in mice
Heterotopic ossification (HO) is a common, potentially debilitating pathology that is instigated by inflammation caused by tissue damage or other insults, which is followed by chondrogenesis, osteogenesis, and extraskeletal bone accumulation. Current remedies are not very effective and have side effects, including the risk of triggering additional HO. The TGF-β family member activin A is produced by activated macrophages and other inflammatory cells and stimulates the intracellular effectors SMAD2 and SMAD3 (SMAD2/3). Because HO starts with inflammation and because SMAD2/3 activation is chondrogenic, we tested whether...
Source: Signal Transduction Knowledge Environment - February 9, 2021 Category: Science Authors: Mundy, C., Yao, L., Sinha, S., Chung, J., Rux, D., Catheline, S. E., Koyama, E., Qin, L., Pacifici, M. Tags: STKE Research Articles Source Type: news

Activating T cells with asparagine
Extracellular asparagine stimulates Lck to promote T cell responses to cancer cells and infection. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - February 2, 2021 Category: Science Authors: Wong, W. Tags: STKE Editors ' Choice Source Type: news

Location, location, location: A compartmentalized view of TNF-induced necroptotic signaling
Necroptosis is a lytic, proinflammatory cell death pathway, which has been implicated in host defense and, when dysregulated, the pathology of many human diseases. The central mediators of this pathway are the receptor-interacting serine/threonine protein kinases RIPK1 and RIPK3 and the terminal executioner, the pseudokinase mixed lineage kinase domain–like (MLKL). Here, we review the chronology of signaling along the RIPK1-RIPK3-MLKL axis and highlight how the subcellular compartmentalization of signaling events controls the initiation and execution of necroptosis. We propose that a network of modulators surrounds t...
Source: Signal Transduction Knowledge Environment - February 2, 2021 Category: Science Authors: Samson, A. L., Garnish, S. E., Hildebrand, J. M., Murphy, J. M. Tags: STKE Reviews Source Type: news

Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimers disease
Neuronal protein synthesis is essential for long-term memory consolidation, and its dysregulation is implicated in various neurodegenerative disorders, including Alzheimer’s disease (AD). Cellular stress triggers the activation of protein kinases that converge on the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which attenuates mRNA translation. This translational inhibition is one aspect of the integrated stress response (ISR). We found that postmortem brain tissue from AD patients showed increased phosphorylation of eIF2α and reduced abundance of eIF2B, another key compo...
Source: Signal Transduction Knowledge Environment - February 2, 2021 Category: Science Authors: Oliveira, M. M., Lourenco, M. V., Longo, F., Kasica, N. P., Yang, W., Ureta, G., Ferreira, D. D. P., Mendonca, P. H. J., Bernales, S., Ma, T., De Felice, F. G., Klann, E., Ferreira, S. T. Tags: STKE Research Articles Source Type: news

A disease-associated mutation that weakens ZAP70 autoinhibition enhances responses to weak and self-ligands
The cytoplasmic kinase ZAP70 is critical for T cell antigen receptor (TCR) signaling. The R360P mutation in ZAP70 is responsible for an early-onset familial autoimmune syndrome. The structural location and biochemical signaling effects of the R360P mutation are consistent with weakening of the autoinhibitory conformation of ZAP70. Mice with a ZAP70 R360P mutation and polyclonal TCR repertoires exhibited relatively normal T cell development but showed evidence of increased signaling. In addition, the R360P mutation resulted in enhanced follicular helper T cell expansion after LCMV infection. To eliminate the possibility of ...
Source: Signal Transduction Knowledge Environment - February 2, 2021 Category: Science Authors: Shen, L., Matloubian, M., Kadlecek, T. A., Weiss, A. Tags: STKE Research Articles Source Type: news

Reprogramming CD8+ T cells
MEK1/2 inhibition enhances both the persistence and antitumor activity of CD8+ T cells in vivo. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - January 26, 2021 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

Reduced ATP-dependent proteolysis of functional proteins during nutrient limitation speeds the return of microbes to a growth state
When cells run out of nutrients, the growth rate greatly decreases. Here, we report that microorganisms, such as the bacterium Salmonella enterica serovar Typhimurium, speed up the return to a rapid growth state by preventing the proteolysis of functional proteins by ATP-dependent proteases while in the slow-growth state or stationary phase. This reduction in functional protein degradation resulted from a decrease in the intracellular concentration of ATP that was nonetheless sufficient to allow the continued degradation of nonfunctional proteins by the same proteases. Protein preservation occurred under limiting magnesium...
Source: Signal Transduction Knowledge Environment - January 26, 2021 Category: Science Authors: Yeom, J., Groisman, E. A. Tags: STKE Research Articles Source Type: news

PERK inhibition attenuates vascular remodeling in pulmonary arterial hypertension caused by BMPR2 mutation
Pulmonary arterial hypertension (PAH) is a fatal disease characterized by excessive pulmonary vascular remodeling. However, despite advances in therapeutic strategies, patients with PAH bearing mutations in the bone morphogenetic protein receptor type 2 (BMPR2)–encoding gene present severe phenotypes and outcomes. We sought to investigate the effect of PER-like kinase (PERK), which participates in one of three major pathways associated with the unfolded protein response (UPR), on PAH pathophysiology in BMPR2 heterozygous mice. BMPR2 heterozygosity in pulmonary artery smooth muscle cells (PASMCs) decreased the abundan...
Source: Signal Transduction Knowledge Environment - January 26, 2021 Category: Science Authors: Shimizu, T., Higashijima, Y., Kanki, Y., Nakaki, R., Kawamura, T., Urade, Y., Wada, Y. Tags: STKE Research Articles Source Type: news

Augmented BMP signaling commits cranial neural crest cells to a chondrogenic fate by suppressing autophagic {beta}-catenin degradation
Cranial neural crest cells (CNCCs) are a population of multipotent stem cells that give rise to craniofacial bone and cartilage during development. Bone morphogenetic protein (BMP) signaling and autophagy have been individually implicated in stem cell homeostasis. Mutations that cause constitutive activation of the BMP type I receptor ACVR1 cause the congenital disorder fibrodysplasia ossificans progressiva (FOP), which is characterized by ectopic cartilage and bone in connective tissues in the trunk and sometimes includes ectopic craniofacial bones. Here, we showed that enhanced BMP signaling through the constitutively ac...
Source: Signal Transduction Knowledge Environment - January 12, 2021 Category: Science Authors: Yang, J., Kitami, M., Pan, H., Nakamura, M. T., Zhang, H., Liu, F., Zhu, L., Komatsu, Y., Mishina, Y. Tags: STKE Research Articles Source Type: news

Respiring with H2O2
Intestinal microbes exploit host-derived H2O2 for respiration under both normal and inflammatory conditions. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - January 12, 2021 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news

Cytoplasmic short linear motifs in ACE2 and integrin {beta}3 link SARS-CoV-2 host cell receptors to mediators of endocytosis and autophagy
The spike protein of SARS-CoV-2 binds the angiotensin-converting enzyme 2 (ACE2) on the host cell surface and subsequently enters host cells through receptor-mediated endocytosis. Additional cell receptors may be directly or indirectly involved, including integrins. The cytoplasmic tails of ACE2 and integrins contain several predicted short linear motifs (SLiMs) that may facilitate internalization of the virus as well as its subsequent propagation through processes such as autophagy. Here, we measured the binding affinity of predicted interactions between SLiMs in the cytoplasmic tails of ACE2 and integrin β3 with pro...
Source: Signal Transduction Knowledge Environment - January 12, 2021 Category: Science Authors: Kliche, J., Kuss, H., Ali, M., Ivarsson, Y. Tags: STKE Research Articles Source Type: news

Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications
We examined the sequences of ACE2 and integrins with the Eukaryotic Linear Motif (ELM) resource and identified candidate short linear motifs (SLiMs) in their short, unstructured, cytosolic tails with potential roles in endocytosis, membrane dynamics, autophagy, cytoskeleton, and cell signaling. These SLiM candidates are highly conserved in vertebrates and may interact with the μ2 subunit of the endocytosis-associated AP2 adaptor complex, as well as with various protein domains (namely, I-BAR, LC3, PDZ, PTB, and SH2) found in human signaling and regulatory proteins. Several motifs overlap in the tail sequences, suggestin...
Source: Signal Transduction Knowledge Environment - January 12, 2021 Category: Science Authors: Meszaros, B., Samano-Sanchez, H., Alvarado-Valverde, J., Calyseva, J., Martinez-Perez, E., Alves, R., Shields, D. C., Kumar, M., Rippmann, F., Chemes, L. B., Gibson, T. J. Tags: STKE Research Resources Source Type: news

The Campylobacter jejuni chemoreceptor Tlp10 has a bimodal ligand-binding domain and specificity for multiple classes of chemoeffectors
Campylobacter jejuni is a bacterial pathogen that is a common cause of enteritis in humans. We identified a previously uncharacterized type of sensory domain in the periplasmic region of the C. jejuni chemoreceptor Tlp10, termed the DAHL domain, that is predicted to have a bimodular helical architecture. Through two independent ligand-binding sites in this domain, Tlp10 responded to molecular aspartate, isoleucine, fumarate, malate, fucose, and mannose as attractants and to arginine, galactose, and thiamine as repellents. Tlp10 also recognized glycan ligands when present as terminal and intermediate residues of complex str...
Source: Signal Transduction Knowledge Environment - January 5, 2021 Category: Science Authors: Elgamoudi, B. A., Andrianova, E. P., Shewell, L. K., Day, C. J., King, R. M., Taha, , Rahman, H., Hartley-Tassell, L. E., Zhulin, I. B., Korolik, V. Tags: STKE Research Articles Source Type: news

Mitochondrial DNA alterations underlie an irreversible shift to aerobic glycolysis in fumarate hydratase-deficient renal cancer
Understanding the mechanisms of the Warburg shift to aerobic glycolysis is critical to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by biallelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed impairment of the mitochondrial respiratory chain in tumors from patients with HLRCC. Biochemical and transcriptomic analyses revealed that respiratory chain dysfunction in the tumors was due to loss of expression of mitochondrial DNA (mtDNA)&n...
Source: Signal Transduction Knowledge Environment - January 5, 2021 Category: Science Authors: Crooks, D. R., Maio, N., Lang, M., Ricketts, C. J., Vocke, C. D., Gurram, S., Turan, S., Kim, Y.-Y., Cawthon, G. M., Sohelian, F., De Val, N., Pfeiffer, R. M., Jailwala, P., Tandon, M., Tran, B., Fan, T. W.- M., Lane, A. N., Ried, T., Wangsa, D., Malayeri Tags: STKE Research Articles Source Type: news

Structural basis for transcriptional coactivator recognition by SMAD2 in TGF-{beta} signaling
Transforming growth factor–β (TGF-β) proteins regulate multiple cellular functions, including cell proliferation, apoptosis, and extracellular matrix formation. The dysregulation of TGF-β signaling causes diseases such as cancer and fibrosis, and therefore, understanding the biochemical basis of TGF-β signal transduction is important for elucidating pathogenic mechanisms in these diseases. SMAD proteins are transcription factors that mediate TGF-β signaling–dependent gene expression. The transcriptional coactivator CBP directly interacts with the MH2 domains of SMAD2 to activate SMAD co...
Source: Signal Transduction Knowledge Environment - December 15, 2020 Category: Science Authors: Miyazono, K.-i., Ito, T., Fukatsu, Y., Wada, H., Kurisaki, A., Tanokura, M. Tags: STKE Research Articles Source Type: news

A{beta} oligomers induce pathophysiological mGluR5 signaling in Alzheimers disease model mice in a sex-selective manner
The prevalence, presentation, and progression of Alzheimer’s disease (AD) differ between men and women, although β-amyloid (Aβ) deposition is a pathological hallmark of AD in both sexes. Aβ-induced activation of the neuronal glutamate receptor mGluR5 is linked to AD progression. However, we found that mGluR5 exhibits distinct sex-dependent profiles. Specifically, mGluR5 isolated from male mouse cortical and hippocampal tissues bound with high affinity to Aβ oligomers, whereas mGluR5 from female mice exhibited no such affinity. This sex-selective Aβ-mGluR5 interaction did not appear to depend ...
Source: Signal Transduction Knowledge Environment - December 15, 2020 Category: Science Authors: Abd-Elrahman, K. S., Albaker, A., de Souza, J. M., Ribeiro, F. M., Schlossmacher, M. G., Tiberi, M., Hamilton, A., Ferguson, S. S. G. Tags: STKE Research Articles Source Type: news

Establishing patterns of signaling
The phosphorylation pattern of a GPCR C-terminal tail determines the effect on arrestin recruitment and conformation. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - December 15, 2020 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

New connections: Restoring immune balance
New targets to expand regulatory T cell populations may be therapeutic for autoimmune and inflammatory diseases. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - December 8, 2020 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

A novel TNFR2 agonist antibody expands highly potent regulatory T cells
Regulatory T cells (Treg cells) restrict immune system activity, such as in response to self-antigens, and are switched on by tumor necrosis factor receptor 2 (TNFR2). Therapeutic activation of TNFR2, thereby expanding Treg cells and suppressing immune activity, may be beneficial to patients with various inflammatory diseases. Here, we characterized a new human TNFR2-directed antibody agonist isolated from mice. We found that the antibody agonist expanded the number of Treg cells within cultures of primary human CD4+ T cells from healthy donors and patients with type 1 diabetes or Sézary syndrome. These Treg cells h...
Source: Signal Transduction Knowledge Environment - December 8, 2020 Category: Science Authors: Torrey, H., Kühtreiber, W. M., Okubo, Y., Tran, L., Case, K., Zheng, H., Vanamee, E., Faustman, D. L. Tags: STKE Research Resources Source Type: news

A small sustained increase in NOD1 abundance promotes ligand-independent inflammatory and oncogene transcriptional responses
Small, genetically determined differences in transcription [expression quantitative trait loci (eQTLs)] are implicated in complex diseases through unknown molecular mechanisms. Here, we showed that a small, persistent increase in the abundance of the innate pathogen sensor NOD1 precipitated large changes in the transcriptional state of monocytes. A ~1.2- to 1.3-fold increase in NOD1 protein abundance resulting from loss of regulation by the microRNA cluster miR-15b/16 lowered the threshold for ligand-induced activation of the transcription factor NF-B and the MAPK p38. An additional sustained increase in NOD1 abundance to ...
Source: Signal Transduction Knowledge Environment - December 8, 2020 Category: Science Authors: Rommereim, L. M., Akhade, A. S., Dutta, B., Hutcheon, C., Lounsbury, N. W., Rostomily, C. C., Savan, R., Fraser, I. D. C., Germain, R. N., Subramanian, N. Tags: STKE Research Articles Source Type: news

Targeting the ion channel TRPM7 promotes the thymic development of regulatory T cells by promoting IL-2 signaling
The thymic development of regulatory T (Treg) cells, crucial suppressors of the responses of effector T (Teff) cells, is governed by the transcription factor FOXP3. Despite the clinical importance of Treg cells, there is a dearth of druggable molecular targets capable of increasing their numbers in vivo. We found that inhibiting the function of the TRPM7 chanzyme (ion channel and enzyme) potentiated the thymic development of Treg cells in mice and led to a substantially higher frequency of functional Treg cells in the periphery. In addition, TRPM7-deficient mice were resistant to T cell–driven hepatitis. Deletion of ...
Source: Signal Transduction Knowledge Environment - December 8, 2020 Category: Science Authors: Mendu, S. K., Stremska, M. E., Schappe, M. S., Moser, E. K., Krupa, J. K., Rogers, J. S., Stipes, E. J., Parker, C. A., Braciale, T. J., Perry, J. S. A., Desai, B. N. Tags: STKE Research Articles Source Type: news

Acid-addicted cells
PRL3 enables cells to tolerate acidic pH and promotes metastasis by stimulating TRPML-dependent lysosome exocytosis. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - December 1, 2020 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news

2'3'-cGAMP triggers a STING- and NF-{kappa}B-dependent broad antiviral response in Drosophila
We previously reported that an ortholog of STING regulates infection by picorna-like viruses in Drosophila. In mammals, STING is activated by the cyclic dinucleotide 2'3'-cGAMP produced by cGAS, which acts as a receptor for cytosolic DNA. Here, we showed that injection of flies with 2'3'-cGAMP induced the expression of dSTING-regulated genes. Coinjection of 2'3'-cGAMP with a panel of RNA or DNA viruses resulted in substantially reduced viral replication. This 2'3'-cGAMP–mediated protection was still observed in flies with mutations in Atg7 and AGO2, genes that encode key components of the autophagy and small interfer...
Source: Signal Transduction Knowledge Environment - December 1, 2020 Category: Science Authors: Cai, H., Holleufer, A., Simonsen, B., Schneider, J., Lemoine, A., Gad, H. H., Huang, J., Huang, J., Chen, D., Peng, T., Marques, J. T., Hartmann, R., Martins, N. E., Imler, J.-L. Tags: STKE Research Articles Source Type: news

Unlike LGR4, LGR5 potentiates Wnt-{beta}-catenin signaling without sequestering E3 ligases
LGR4 and LGR5 encode two homologous receptors with critical, yet distinct, roles in organ development and adult stem cell survival. Both receptors are coexpressed in intestinal crypt stem cells, bind to R-spondins (RSPOs) with high affinity, and potentiate Wnt–β-catenin signaling, presumably by the same mechanism: forming RSPO-bridged complexes with the E3 ligases RNF43 and ZNRF3 to inhibit ubiquitylation of Wnt receptors. However, direct evidence for RSPO-bound, full-length LGR5 interacting with these E3 ligases in whole cells has not been reported, and only LGR4 is essential for the self-renewal of intestinal ...
Source: Signal Transduction Knowledge Environment - December 1, 2020 Category: Science Authors: Park, S., Wu, L., Tu, J., Yu, W., Toh, Y., Carmon, K. S., Liu, Q. J. Tags: STKE Research Articles Source Type: news

Transomics analysis reveals allosteric and gene regulation axes for altered hepatic glucose-responsive metabolism in obesity
Impaired glucose tolerance associated with obesity causes postprandial hyperglycemia and can lead to type 2 diabetes. To study the differences in liver metabolism in healthy and obese states, we constructed and analyzed transomics glucose-responsive metabolic networks with layers for metabolites, expression data for metabolic enzyme genes, transcription factors, and insulin signaling proteins from the livers of healthy and obese mice. We integrated multiomics time course data from wild-type and leptin-deficient obese (ob/ob) mice after orally administered glucose. In wild-type mice, metabolic reactions were rapidly regulat...
Source: Signal Transduction Knowledge Environment - December 1, 2020 Category: Science Authors: Kokaji, T., Hatano, A., Ito, Y., Yugi, K., Eto, M., Morita, K., Ohno, S., Fujii, M., Hironaka, K.-i., Egami, R., Terakawa, A., Tsuchiya, T., Ozaki, H., Inoue, H., Uda, S., Kubota, H., Suzuki, Y., Ikeda, K., Arita, M., Matsumoto, M., Nakayama, K. I., Hiray Tags: STKE Research Resources Source Type: news

Kallikrein 13 serves as a priming protease during infection by the human coronavirus HKU1
Human coronavirus HKU1 (HCoV-HKU1) is associated with respiratory disease and is prevalent worldwide, but an in vitro model for viral replication is lacking. An interaction between the coronaviral spike (S) protein and its receptor is the primary determinant of tissue and host specificity; however, viral entry is a complex process requiring the concerted action of multiple cellular elements. Here, we found that the protease kallikrein 13 (KLK13) was required for the infection of human respiratory epithelial cells and was sufficient to mediate the entry of HCoV-HKU1 into nonpermissive RD cells. We also demonstrated the clea...
Source: Signal Transduction Knowledge Environment - November 24, 2020 Category: Science Authors: Milewska, A., Falkowski, K., Kulczycka, M., Bielecka, E., Naskalska, A., Mak, P., Lesner, A., Ochman, M., Urlik, M., Diamandis, E., Prassas, I., Potempa, J., Kantyka, T., Pyrc, K. Tags: STKE Research Articles Source Type: news

A more rhythmic heartbeat with calcitonin
Cardiomyocyte-released calcitonin acts on fibroblasts to limit atrial fibrosis and arrhythmia. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - November 24, 2020 Category: Science Authors: Wong, W. Tags: STKE Editors ' Choice Source Type: news

Airway relaxation mechanisms and structural basis of osthole for improving lung function in asthma
Overuse of β2-adrenoceptor agonist bronchodilators evokes receptor desensitization, decreased efficacy, and an increased risk of death in asthma patients. Bronchodilators that do not target β2-adrenoceptors represent a critical unmet need for asthma management. Here, we characterize the utility of osthole, a coumarin derived from a traditional Chinese medicine, in preclinical models of asthma. In mouse precision-cut lung slices, osthole relaxed preconstricted airways, irrespective of β2-adrenoceptor desensitization. Osthole administered in murine asthma models attenuated airway hyperresponsiveness, a hallmar...
Source: Signal Transduction Knowledge Environment - November 24, 2020 Category: Science Authors: Wang, S., Xie, Y., Huo, Y.-W., Li, Y., Abel, P. W., Jiang, H., Zou, X., Jiao, H.-Z., Kuang, X., Wolff, D. W., Huang, Y.-G., Casale, T. B., Panettieri, R. A., Wei, T., Cao, Z., Tu, Y. Tags: STKE Research Articles Source Type: news

ELP-dependent expression of MCL1 promotes resistance to EGFR inhibition in triple-negative breast cancer cells
Targeted therapeutics for cancer generally exploit "oncogene addiction," a phenomenon in which the growth and survival of tumor cells depend on the activity of a particular protein. However, the efficacy of oncogene-targeted therapies varies substantially. For instance, targeting epidermal growth factor receptor (EGFR) signaling is effective in some non–small cell lung cancer (NSCLC) but not in triple-negative breast cancer (TNBC), although these cancers show a similar degree of increase in EGFR activity. Using a genome-wide CRISPR-Cas9 genetic knockout screen, we found that the Elongator (ELP) complex medi...
Source: Signal Transduction Knowledge Environment - November 17, 2020 Category: Science Authors: Cruz-Gordillo, P., Honeywell, M. E., Harper, N. W., Leete, T., Lee, M. J. Tags: STKE Research Articles Source Type: news

NF-{kappa}B activation persists into the remodeling phase of tendon healing and promotes myofibroblast survival
Although inflammation is necessary during the early phases of tissue repair, persistent inflammation contributes to fibrosis. Acute tendon injuries often heal through a fibrotic mechanism, which impedes regeneration and functional recovery. Because inflammation mediated by nuclear factor B (NF-B) signaling is implicated in this process, we examined the spatial, temporal, and cell type–specific activation profile of canonical NF-B signaling during tendon healing. NF-B signaling was maintained through all phases of tendon healing in mice, including the remodeling phase, and tenocytes and myofibroblasts from the Sclerax...
Source: Signal Transduction Knowledge Environment - November 17, 2020 Category: Science Authors: Best, K. T., Nichols, A. E. C., Knapp, E., Hammert, W. C., Ketonis, C., Jonason, J. H., Awad, H. A., Loiselle, A. E. Tags: STKE Research Articles Source Type: news

MAPping PI3K signaling to endosomes
The microtubule-associated protein MAP4 recruits PI3Kα from the plasma membrane to endosomes to activate Akt signaling. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - November 17, 2020 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

EGF promotes DKK1 transcription in hepatocellular carcinoma by enhancing the phosphorylation and acetylation of histone H3
The protein Dickkopf-1 (DKK1) is frequently overexpressed at the transcript level in hepatocellular carcinoma (HCC) and promotes metastatic progression through the induction of β-catenin, a Wnt signaling effector. We investigated how DKK1 expression is induced in HCC and found that activation of the epidermal growth factor receptor (EGFR) promoted parallel MEK-ERK and PI3K-Akt pathway signaling that converged to epigenetically stimulate DKK1 transcription. In HCC cell lines stimulated with EGF, EGFR-activated ERK phosphorylated the kinase PKM2 at Ser37, which promoted its nuclear translocation. Also in these cells, EG...
Source: Signal Transduction Knowledge Environment - November 10, 2020 Category: Science Authors: Niu, J., Li, W., Liang, C., Wang, X., Yao, X., Yang, R.-H., Zhang, Z.-S., Liu, H.-F., Liu, F.-Y., Pei, S.-H., Li, W.-Q., Sun, H., Fang, D., Xie, S.-Q. Tags: STKE Research Articles Source Type: news

In PDAC, "bad" cholesterol is good
LDL-lowering statins can promote the development of an aggressive subtype of pancreatic cancer. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - November 10, 2020 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

Engineered chemotaxis core signaling units indicate a constrained kinase-off state
Bacterial chemoreceptors, the histidine kinase CheA, and the coupling protein CheW form transmembrane molecular arrays with remarkable sensing properties. The receptors inhibit or stimulate CheA kinase activity depending on the presence of attractants or repellants, respectively. We engineered chemoreceptor cytoplasmic regions to assume a trimer of receptor dimers configuration that formed well-defined complexes with CheA and CheW and promoted a CheA kinase-off state. These mimics of core signaling units were assembled to homogeneity and investigated by site-directed spin-labeling with pulse-dipolar electron-spin resonance...
Source: Signal Transduction Knowledge Environment - November 10, 2020 Category: Science Authors: Muok, A. R., Chua, T. K., Srivastava, M., Yang, W., Maschmann, Z., Borbat, P. P., Chong, J., Zhang, S., Freed, J. H., Briegel, A., Crane, B. R. Tags: STKE Research Articles Source Type: news

MTORC1-dependent reprogramming
DDIT4 and IFRD1 trigger the inhibition and reactivation of MTORC1 during regenerative repair. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - November 3, 2020 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news

G{beta}{gamma} is a direct regulator of endogenous p101/p110{gamma} and p84/p110{gamma} PI3K{gamma} complexes in mouse neutrophils
The PI3K isoform is activated by Gi-coupled GPCRs in myeloid cells, but the extent to which the two endogenous complexes of PI3K, p101/p110 and p84/p110, receive direct regulation through Gβ or indirect regulation through RAS and the sufficiency of those inputs is controversial or unclear. We generated mice with point mutations that prevent Gβ binding to p110 (RK552DD) or to p101 (VVKR777AAAA) and investigated the effects of these mutations in primary neutrophils and in mouse models of neutrophilic inflammation. Loss of Gβ binding to p110 substantially reduced the activation of both p101/p110 and p84/p110 in...
Source: Signal Transduction Knowledge Environment - November 3, 2020 Category: Science Authors: Rynkiewicz, N. K., Anderson, K. E., Suire, S., Collins, D. M., Karanasios, E., Vadas, O., Williams, R., Oxley, D., Clark, J., Stephens, L. R., Hawkins, P. T. Tags: STKE Research Articles Source Type: news

Mutation-induced remodeling of the BfmRS two-component system in Pseudomonas aeruginosa clinical isolates
This study highlights the plasticity of TCSs mediated by spontaneous mutations and suggests that mutation-induced activation of BfmRS may contribute to host adaptation by P. aeruginosa during chronic infections. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - November 3, 2020 Category: Science Authors: Cao, Q., Yang, N., Wang, Y., Xu, C., Zhang, X., Fan, K., Chen, F., Liang, H., Zhang, Y., Deng, X., Feng, Y., Yang, C.-G., Wu, M., Bae, T., Lan, L. Tags: STKE Research Articles Source Type: news

Modulation of PKM activity affects the differentiation of TH17 cells
Small molecules that promote the metabolic activity of the pyruvate kinase isoform PKM2, such as TEPP-46 and DASA-58, limit tumorigenesis and inflammation. To understand how these compounds alter T cell function, we assessed their therapeutic activity in a mouse model of T cell–mediated autoimmunity that mimics multiple sclerosis (MS). TH17 cells are believed to orchestrate MS pathology, in part, through the production of two proinflammatory cytokines: interleukin-17 (IL-17) and GM-CSF. We found that both TEPP-46 and DASA-58 suppressed the development of IL-17–producing TH17 cells but increased the generation o...
Source: Signal Transduction Knowledge Environment - October 27, 2020 Category: Science Authors: Seki, S. M., Posyniak, K., McCloud, R., Rosen, D. A., Fernandez-Castaneda, A., Beiter, R. M., Serbulea, V., Nanziri, S. C., Hayes, N., Spivey, C., Gemta, L., Bullock, T. N. J., Hsu, K.-L., Gaultier, A. Tags: STKE Research Articles Source Type: news

A checkpoint for pyroptosis
The nuclear pool of an immune checkpoint protein promotes pyroptosis and tumor necrosis downstream of TNFα. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - October 27, 2020 Category: Science Authors: Wong, W. Tags: STKE Editors ' Choice Source Type: news

Spatial heterogeneities shape the collective behavior of signaling amoeboid cells
We present experimental data and numerical simulations on the pattern formation of signaling Dictyostelium cells in the presence of periodic arrays of millimeter-sized pillars. We observed concentric cAMP waves that initiated almost synchronously at the pillars and propagated outward. In response to these circular waves, the Dictyostelium cells streamed toward the pillars, forming aggregates arranged in patterns that reflected the periodicity of the lattice of pillars. Our results suggest that, in nature, the excitability threshold and synchronization level of the cells are two key parameters that control the nature of the...
Source: Signal Transduction Knowledge Environment - October 27, 2020 Category: Science Authors: Eckstein, T. F., Vidal-Henriquez, E., Bae, A. J., Gholami, A. Tags: STKE Research Articles Source Type: news

Emerging roles for angiomotin in the nervous system
Angiomotins are a family of molecular scaffolding proteins that function to organize contact points (called tight junctions in vertebrates) between adjacent cells. Some angiomotin isoforms bind to the actin cytoskeleton and are part of signaling pathways that influence cell morphology and migration. Others cooperate with components of the Hippo signaling pathway and the associated networks to control organ growth. The 130-kDa isoform, AMOT-p130, has critical roles in neural stem cell differentiation, dendritic patterning, and synaptic maturation—attributes that are essential for normal brain development and are consi...
Source: Signal Transduction Knowledge Environment - October 27, 2020 Category: Science Authors: Wigerius, M., Quinn, D., Fawcett, J. P. Tags: STKE Reviews Source Type: news

Hug and hold tight: Dimerization controls the turnover of the ubiquitin-conjugating enzyme UBE2S
Precise control of the activity and abundance of ubiquitin-conjugating enzymes (E2s) ensures fidelity in ubiquitin chain synthesis. In this issue of Science Signaling, Liess et al. demonstrate that the human anaphase-promoting complex (APC/C)–associated E2 UBE2S adopts an autoinhibited dimeric state that increases the half-life of UBE2S by preventing its autoubiquitination-driven turnover. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - October 20, 2020 Category: Science Authors: Bremm, A. Tags: STKE Focus Source Type: news

Dimerization regulates the human APC/C-associated ubiquitin-conjugating enzyme UBE2S
At the heart of protein ubiquitination cascades, ubiquitin-conjugating enzymes (E2s) form reactive ubiquitin-thioester intermediates to enable efficient transfer of ubiquitin to cellular substrates. The precise regulation of E2s is thus crucial for cellular homeostasis, and their deregulation is frequently associated with tumorigenesis. In addition to driving substrate ubiquitination together with ubiquitin ligases (E3s), many E2s can also autoubiquitinate, thereby promoting their own proteasomal turnover. To investigate the mechanisms that balance these disparate activities, we dissected the regulatory dynamics of UBE2S, ...
Source: Signal Transduction Knowledge Environment - October 20, 2020 Category: Science Authors: Liess, A. K. L., Kucerova, A., Schweimer, K., Schlesinger, D., Dybkov, O., Urlaub, H., Mansfeld, J., Lorenz, S. Tags: STKE Research Articles Source Type: news

SMAR1 repression by pluripotency factors and consequent chemoresistance in breast cancer stem-like cells is reversed by aspirin
The high abundance of drug efflux pumps in cancer stem cells (CSCs) contributes to chemotherapy resistance. The transcriptional regulator SMAR1 suppresses CSC expansion in colorectal cancer, and increased abundance of SMAR1 is associated with better prognosis. Here, we found in breast tumors that the expression of SMAR1 was decreased in CSCs through the cooperative interaction of the pluripotency factors Oct4 and Sox2 with the histone deacetylase HDAC1. Overexpressing SMAR1 sensitized CSCs to chemotherapy through SMAR1-dependent recruitment of HDAC2 to the promoter of the gene encoding the drug efflux pump ABCG2. Treating ...
Source: Signal Transduction Knowledge Environment - October 20, 2020 Category: Science Authors: Bhattacharya, A., Mukherjee, S., Khan, P., Banerjee, S., Dutta, A., Banerjee, N., Sengupta, D., Basak, U., Chakraborty, S., Dutta, A., Chattopadhyay, S., Jana, K., Sarkar, D. K., Chatterjee, S., Das, T. Tags: STKE Research Articles Source Type: news