Mitotic cell responses to substrate topological cues are independent of the molecular nature of adhesion
Correct selection of the cell division axis is important for cell differentiation, tissue and organ morphogenesis, and homeostasis. Both integrins, which mediate interactions with extracellular matrix (ECM) components such as fibronectin, and cadherins, which mediate interactions between cells, are implicated in the determination of spindle orientation. We found that both cadherin- and integrin-based adhesion resulted in cell divisions parallel to the attachment plane and elicited identical spindle responses to spatial adhesive cues. This suggests that adhesion topology provides purely mechanical spatial cues that are inde...
Source: Signal Transduction Knowledge Environment - February 25, 2020 Category: Science Authors: Anastasiou, O., Hadjisavva, R., Skourides, P. A. Tags: STKE Research Articles Source Type: news

Integrative analysis suggests cell type-specific decoding of NF-{kappa}B dynamics
The complex signaling dynamics of transcription factors can encode both qualitative and quantitative information about the extracellular environment, which increases the information transfer capacity and potentially supports accurate cellular decision-making. An important question is how these signaling dynamics patterns are translated into functionally appropriate gene regulation programs. To address this question for transcription factors of the nuclear factor B (NF-B) family, we profiled the single-cell dynamics of two major NF-B subunits, RelA and c-Rel, induced by a panel of pathogen-derived stimuli in immune and noni...
Source: Signal Transduction Knowledge Environment - February 25, 2020 Category: Science Authors: Martin, E. W., Pacholewska, A., Patel, H., Dashora, H., Sung, M.-H. Tags: STKE Research Articles Source Type: news

Steroids make inflamed tissues less sticky
The steroid hormone DHEA reduces inflammation by restoring production of the integrin antagonist DEL-1. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - February 25, 2020 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

SMAC mimetics and RIPK inhibitors as therapeutics for chronic inflammatory diseases
New therapeutic approaches for chronic inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, and psoriasis are needed because current treatments are often suboptimal in terms of both efficacy and the risks of serious adverse events. Inhibitor of apoptosis proteins (IAPs) are E3 ubiquitin ligases that inhibit cell death pathways and are themselves inhibited by second mitochondria-derived activator of caspases (SMAC). SMAC mimetics (SMs), small-molecule antagonists of IAPs, are being evaluated as cancer therapies in clinical trials. IAPs are also crucial regulators of inflammatory pathways because t...
Source: Signal Transduction Knowledge Environment - February 18, 2020 Category: Science Authors: Jensen, S., Seidelin, J. B., LaCasse, E. C., Nielsen, O. H. Tags: STKE Reviews Source Type: news

Functional proteomics interrogation of the kinome identifies MRCKA as a therapeutic target in high-grade serous ovarian carcinoma
High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecological cancer with few effective, targeted therapies. HGSOC tumors exhibit genomic instability with frequent alterations in the protein kinome; however, only a small fraction of the kinome has been therapeutically targeted in HGSOC. Using multiplexed inhibitor beads and mass spectrometry, we mapped the kinome landscape of HGSOC tumors from patients and patient-derived xenograft models. The data revealed a prevalent signature consisting of established HGSOC driver kinases, as well as several kinases previously unexplored in HGSOC. Loss-of-function analysi...
Source: Signal Transduction Knowledge Environment - February 18, 2020 Category: Science Authors: Kurimchak, A. M., Herrera-Montavez, C., Brown, J., Johnson, K. J., Sodi, V., Srivastava, N., Kumar, V., Deihimi, S., OBrien, S., Peri, S., Mantia-Smaldone, G. M., Jain, A., Winters, R. M., Cai, K. Q., Chernoff, J., Connolly, D. C., Duncan, J. S. Tags: STKE Research Articles Source Type: news

Mechanosensing metabolically moves cancer cells
A stiff stroma triggers metabolic changes that support invasion and metastasis in pancreatic cancer cells. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - February 18, 2020 Category: Science Authors: Wong, W. Tags: STKE Editors ' Choice Source Type: news

Fluoride exposure alters Ca2+ signaling and mitochondrial function in enamel cells
Fluoride ions are highly reactive, and their incorporation in forming dental enamel at low concentrations promotes mineralization. In contrast, excessive fluoride intake causes dental fluorosis, visually recognizable enamel defects that can increase the risk of caries. To investigate the molecular bases of dental fluorosis, we analyzed the effects of fluoride exposure in enamel cells to assess its impact on Ca2+ signaling. Primary enamel cells and an enamel cell line (LS8) exposed to fluoride showed decreased internal Ca2+ stores and store-operated Ca2+ entry (SOCE). RNA-sequencing analysis revealed changes in gene express...
Source: Signal Transduction Knowledge Environment - February 18, 2020 Category: Science Authors: Aulestia, F. J., Groeling, J., Bomfim, G. H. S., Costiniti, V., Manikandan, V., Chaloemtoem, A., Concepcion, A. R., Li, Y., Wagner, L. E., Idaghdour, Y., Yule, D. I., Lacruz, R. S. Tags: STKE Research Articles Source Type: news

Dynamic interactions of the 5-HT6 receptor with protein partners control dendritic tree morphogenesis
This study highlights the complex allosteric modulation of GPCRs by protein partners and demonstrates how dynamic interactions between GPCRs and their protein partners can control the different steps of highly coordinated cellular processes, such as dendritic tree morphogenesis. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - February 11, 2020 Category: Science Authors: Pujol, C. N., Dupuy, V., Seveno, M., Runtz, L., Bockaert, J., Marin, P., Chaumont-Dubel, S. Tags: STKE Research Articles Source Type: news

L-type Ca2+ channel-mediated Ca2+ influx adjusts neuronal mitochondrial function to physiological and pathophysiological conditions
L-type voltage-gated Ca2+ channels (LTCCs) are implicated in neurodegenerative processes and cell death. Accordingly, LTCC antagonists have been proposed to be neuroprotective, although this view is disputed, because intentional LTCC activation can also have beneficial effects. LTCC-mediated Ca2+ influx influences mitochondrial function, which plays a crucial role in the regulation of cell viability. Hence, we investigated the effect of modulating LTCC-mediated Ca2+ influx on mitochondrial function in cultured hippocampal neurons. To activate LTCCs, neuronal activity was stimulated by increasing extracellular K+ or by appl...
Source: Signal Transduction Knowledge Environment - February 11, 2020 Category: Science Authors: Hotka, M., Cagalinec, M., Hilber, K., Hool, L., Boehm, S., Kubista, H. Tags: STKE Research Articles Source Type: news

New connections: Targeted treatment options for SCLC
Various studies reveal how we might effectively treat small cell lung cancer. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - February 11, 2020 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

Reversible EMT and MET mediate amnion remodeling during pregnancy and labor
The amnion is remodeled during pregnancy to protect the growing fetus it contains, and it is particularly dynamic just before and during labor. By combining ultrastructural, immunohistochemical, and Western blotting analyses, we found that human and mouse amnion membranes during labor were subject to epithelial-to-mesenchymal transition (EMT), mediated, in part, by the p38 mitogen-activated protein kinase (MAPK) pathway responding to oxidative stress. Primary human amnion epithelial cell cultures established from amnion membranes from nonlaboring, cesarean section deliveries exhibited EMT after exposure to oxidative stress...
Source: Signal Transduction Knowledge Environment - February 11, 2020 Category: Science Authors: Richardson, L. S., Taylor, R. N., Menon, R. Tags: STKE Research Articles Source Type: news

Microbiome studies in the medical sciences and the need for closer multidisciplinary interplay
Next-generation sequencing techniques have enabled identification of the microorganisms colonizing mucosal tissues. The International Congress "MicrobiotaMi 2020" (Milan, February 2020) will focus on the mechanisms of microbiota-related functions in health and disease and their clinical application. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - February 4, 2020 Category: Science Authors: Mancini, N., Peri, F., Rescigno, M., Zanoni, I. Tags: STKE Focus Source Type: news

Probing the mutational landscape of regulators of G protein signaling proteins in cancer
The advent of deep-sequencing techniques has revealed that mutations in G protein–coupled receptor (GPCR) signaling pathways in cancer are more prominent than was previously appreciated. An emergent theme is that cancer-associated mutations tend to cause enhanced GPCR pathway activation to favor oncogenicity. Regulators of G protein signaling (RGS) proteins are critical modulators of GPCR signaling that dampen the activity of heterotrimeric G proteins through their GTPase-accelerating protein (GAP) activity, which is conferred by a conserved domain dubbed the "RGS-box." Here, we developed an experimental pi...
Source: Signal Transduction Knowledge Environment - February 4, 2020 Category: Science Authors: DiGiacomo, V., Maziarz, M., Luebbers, A., Norris, J. M., Laksono, P., Garcia-Marcos, M. Tags: STKE Research Resources Source Type: news

A structural basis for how ligand binding site changes can allosterically regulate GPCR signaling and engender functional selectivity
Signaling bias is the propensity for some agonists to preferentially stimulate G protein–coupled receptor (GPCR) signaling through one intracellular pathway versus another. We previously identified a G protein–biased agonist of the D2 dopamine receptor (D2R) that results in impaired β-arrestin recruitment. This signaling bias was predicted to arise from unique interactions of the ligand with a hydrophobic pocket at the interface of the second extracellular loop and fifth transmembrane segment of the D2R. Here, we showed that residue Phe189 within this pocket (position 5.38 using Ballesteros-Weinstein numbe...
Source: Signal Transduction Knowledge Environment - February 4, 2020 Category: Science Authors: Sanchez-Soto, M., Verma, R. K., Willette, B. K. A., Gonye, E. C., Moore, A. M., Moritz, A. E., Boateng, C. A., Yano, H., Free, R. B., Shi, L., Sibley, D. R. Tags: STKE Research Articles Source Type: news

The parkin-coregulated gene product PACRG promotes TNF signaling by stabilizing LUBAC
The Parkin-coregulated gene (PACRG), which encodes a protein of unknown function, shares a bidirectional promoter with Parkin (PRKN), which encodes an E3 ubiquitin ligase. Because PRKN is important in mitochondrial quality control and protection against stress, we tested whether PACRG also affected these pathways in various cultured human cell lines and in mouse embryonic fibroblasts. PACRG did not play a role in mitophagy but did play a role in tumor necrosis factor (TNF) signaling. Similarly to Parkin, PACRG promoted nuclear factor B (NF-B) activation in response to TNF. TNF-induced nuclear translocation of the NF-B subu...
Source: Signal Transduction Knowledge Environment - February 4, 2020 Category: Science Authors: Meschede, J., Sadic, M., Furthmann, N., Miedema, T., Sehr, D. A., Müller-Rischart, A. K., Bader, V., Berlemann, L. A., Pilsl, A., Schlierf, A., Barkovits, K., Kachholz, B., Rittinger, K., Ikeda, F., Marcus, K., Schaefer, L., Tatzelt, J., Winklhofe Tags: STKE Research Articles Source Type: news

CDK7 stabilizes Yap
CDK7 promotes cell proliferation and tissue growth by protecting the transcriptional coactivator Yap from degradation. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - February 4, 2020 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news

The Myc tag monoclonal antibody 9E10 displays highly variable epitope recognition dependent on neighboring sequence context
Epitope tags are short, linear antibody recognition sequences that enable detection of tagged fusion proteins by antibodies. Epitope tag position and neighboring sequences potentially affect its recognition by antibodies, and such context-dependent differences in tag binding may have a wide-ranging effect on data interpretation. We tested by Western blotting six antibodies that recognize the c-Myc epitope tag, including monoclonal antibodies 9E10, 4A6, 9B11, and 71D10 and polyclonal antibodies 9106 and A-14. All displayed context-dependent differences in their ability to detect N- or C-terminal Myc-tagged proteins. In part...
Source: Signal Transduction Knowledge Environment - January 28, 2020 Category: Science Authors: Schüchner, S., Behm, C., Mudrak, I., Ogris, E. Tags: STKE Research Resources Source Type: news

Fragile epitopes--Antibodys guess is as good as yours
Monoclonal antibodies recognize epitopes so specifically that altering a single residue can disrupt binding. In this issue of Science Signaling, Schüchner et al. and Frohner et al. report that flanking amino acids and an underappreciated posttranslational modification perturb epitope affinity for two groups of widely used monoclonal antibodies. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - January 28, 2020 Category: Science Authors: Janes, K. A. Tags: STKE Focus Source Type: news

Antibodies recognizing the C terminus of PP2A catalytic subunit are unsuitable for evaluating PP2A activity and holoenzyme composition
The methyl-esterification of the C-terminal leucine of the protein phosphatase 2A (PP2A) catalytic (C) subunit is essential for the assembly of specific trimeric PP2A holoenzymes, and this region of the C subunit also contains two threonine and tyrosine phosphorylation sites. Most commercial antibodies—including the monoclonal antibody 1D6 that is part of a frequently used, commercial phosphatase assay kit—are directed toward the C terminus of the C subunit, raising questions as to their ability to recognize methylated and phosphorylated forms of the enzyme. Here, we tested several PP2A C antibodies, including ...
Source: Signal Transduction Knowledge Environment - January 28, 2020 Category: Science Authors: Frohner, I. E., Mudrak, I., Kronlachner, S., Schüchner, S., Ogris, E. Tags: STKE Research Resources Source Type: news

Plant chemokine mimics
Human immune cells migrate in response to plant chemokine orthologs that bind to and activate the chemokine receptor CXCR4. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - January 28, 2020 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

Acute O2 sensing through HIF2{alpha}-dependent expression of atypical cytochrome oxidase subunits in arterial chemoreceptors
We report that inactivation of Epas1 in adult mice resulted in selective abolition of glomus cell responsiveness to acute hypoxia and the hypoxic ventilatory response. Epas1 deficiency led to the decreased expression of atypical mitochondrial subunits in the carotid body, and genetic deletion of Cox4i2 mimicked the defective hypoxic responses of Epas1-null mice. These findings provide a mechanistic explanation for the acute O2 regulation of breathing, reveal an unanticipated role of HIF2α, and link acute and chronic adaptive responses to hypoxia. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - January 21, 2020 Category: Science Authors: Moreno-Dominguez, A., Ortega-Saenz, P., Gao, L., Colinas, O., Garcia-Flores, P., Bonilla-Henao, V., Aragones, J., Hüttemann, M., Grossman, L. I., Weissmann, N., Sommer, N., Lopez-Barneo, J. Tags: STKE Research Articles Source Type: news

Too much stretching is bad for the lungs
Excessive mechanical strain on alveolar stem cells induces TGF-β signaling and progressive lung fibrosis. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - January 21, 2020 Category: Science Authors: Wong, W. Tags: STKE Editors ' Choice Source Type: news

Ca2+ waves coordinate purinergic receptor-evoked integrin activation and polarization
In conclusion, spatial and temporal patterns of Ca2+ increase enable fine control of αIIbβ3 activation after cellular stimulation. P2Y1-stimulated Ca2+ transients coupled to αIIbβ3 activation only in the context of P2Y12 coactivation, thereby providing an additional temporal mechanism of synergy between these Gq- and Gi-coupled GPCRs. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - January 21, 2020 Category: Science Authors: Bye, A. P., Gibbins, J. M., Mahaut-Smith, M. P. Tags: STKE Research Articles Source Type: news

Spatial and temporal alterations in protein structure by EGF regulate cryptic cysteine oxidation
Stimulation of plasma membrane receptor tyrosine kinases (RTKs), such as the epidermal growth factor receptor (EGFR), locally increases the abundance of reactive oxygen species (ROS). These ROS then oxidize cysteine residues in proteins to potentiate downstream signaling. Spatial confinement of ROS is an important regulatory mechanism of redox signaling that enables the stimulation of different RTKs to oxidize distinct sets of downstream proteins. To uncover additional mechanisms that specify cysteines that are redox regulated by EGF stimulation, we performed time-resolved quantification of the EGF-dependent oxidation of 4...
Source: Signal Transduction Knowledge Environment - January 21, 2020 Category: Science Authors: Behring, J. B., van der Post, S., Mooradian, A. D., Egan, M. J., Zimmerman, M. I., Clements, J. L., Bowman, G. R., Held, J. M. Tags: STKE Research Articles Source Type: news

Genetic basis of oxygen sensing in the carotid body: HIF2{alpha} and an isoform switch in cytochrome c oxidase subunit 4
The mechanistic basis of the marked oxygen sensitivity of glomus cells in the carotid body has long puzzled physiologists. In this issue of Science Signaling, Moreno-Domínguez et al. show the critical importance of high levels of hypoxia-inducible factor, HIF2α/EPAS1, and the nuclear-encoded mitochondrial cytochrome c oxidase subunit, COX4I2, in glomus cell sensitivity to hypoxia. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - January 21, 2020 Category: Science Authors: Bishop, T., Ratcliffe, P. J. Tags: STKE Focus Source Type: news

The Vibrio cholerae MARTX toxin silences the inflammatory response to cytoskeletal damage before inducing actin cytoskeleton collapse
Multifunctional autoprocessing repeats-in-toxin (MARTX) toxins are pore-forming bacterial toxins that translocate multiple functionally independent effector domains into a target eukaryotic cell. Vibrio cholerae colonizes intestinal epithelial cells (IECs) and uses a MARTX toxin with three effector domains—an actin cross-linking domain (ACD), a Rho inactivation domain (RID), and an α/β hydrolase domain (ABH)—to suppress innate immunity and enhance colonization. We investigated whether these multiple catalytic enzymes delivered from a single toxin functioned in a coordinated manner to suppress intesti...
Source: Signal Transduction Knowledge Environment - January 14, 2020 Category: Science Authors: Woida, P. J., Satchell, K. J. F. Tags: STKE Research Articles Source Type: news

Predicting resistance to KRAS inhibitors
Studies identify common targets for preventing resistance to KRAS inhibitors. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - January 14, 2020 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

Single-molecule imaging reveals the oligomeric state of functional TNF{alpha}-induced plasma membrane TNFR1 clusters in cells
Ligand-induced tumor necrosis factor receptor 1 (TNFR1) activation controls nuclear factor -light-chain-enhancer of activated B cells (NF-B) signaling, cell proliferation, programmed cell death, and survival and is crucially involved in inflammation, autoimmune disorders, and cancer progression. Despite the relevance of TNFR1 clustering for signaling, oligomerization of ligand-free and ligand-activated TNFR1 remains controversial. At present, models range from ligand-independent receptor predimerization to ligand-induced oligomerization. Here, we used quantitative, single-molecule superresolution microscopy to study TNFR1 ...
Source: Signal Transduction Knowledge Environment - January 14, 2020 Category: Science Authors: Karathanasis, C., Medler, J., Fricke, F., Smith, S., Malkusch, S., Widera, D., Fulda, S., Wajant, H., van Wijk, S. J. L., Dikic, I., Heilemann, M. Tags: STKE Research Articles Source Type: news

Hereditary spastic paraplegia SPG8 mutations impair CAV1-dependent, integrin-mediated cell adhesion
Mutations in WASHC5 (also known as KIAA0196) cause autosomal dominant hereditary spastic paraplegia (HSP) type SPG8. WASHC5, commonly called strumpellin, is a core component of the Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex that activates actin nucleation at endosomes. Although various other cellular roles for strumpellin have also been described, none account for how SPG8-associated mutations lead to HSP. Here, we identified protein interactors of the WASH complex by immunoprecipitation and mass spectrometry and assessed the functions of strumpellin in cultured cells using both overexpression and RNA...
Source: Signal Transduction Knowledge Environment - January 7, 2020 Category: Science Authors: Lee, S., Park, H., Zhu, P.-P., Jung, S.-Y., Blackstone, C., Chang, J. Tags: STKE Research Articles Source Type: news

The GPCR accessory protein MRAP2 regulates both biased signaling and constitutive activity of the ghrelin receptor GHSR1a
Ghrelin is a hormone secreted by the stomach during fasting periods and acts through its receptor, the growth hormone secretagogue 1a (GHSR1a), to promote food intake and prevent hypoglycemia. As such, GHSR1a is an important regulator of energy and glucose homeostasis and a target for the treatment of obesity. Here, we showed that the accessory protein MRAP2 altered GHSR1a signaling by inhibiting its constitutive activity, as well as by enhancing its G protein–dependent signaling and blocking the recruitment and signaling of β-arrestin in response to ghrelin. In addition, the effects of MRAP2 on the Gαq an...
Source: Signal Transduction Knowledge Environment - January 7, 2020 Category: Science Authors: Rouault, A. A. J., Rosselli-Murai, L. K., Hernandez, C. C., Gimenez, L. E., Tall, G. G., Sebag, J. A. Tags: STKE Research Articles Source Type: news

Cracking the context-specific PI3K signaling code
Specificity in signal transduction is determined by the ability of cells to "encode" and subsequently "decode" different environmental signals. Akin to computer software, this "signaling code" governs context-dependent execution of cellular programs through modulation of signaling dynamics and can be corrupted by disease-causing mutations. Class IA phosphoinositide 3-kinase (PI3K) signaling is critical for normal growth and development and is dysregulated in human disorders such as benign overgrowth syndromes, cancer, primary immune deficiency, and metabolic syndrome. Despite decades of PI3K r...
Source: Signal Transduction Knowledge Environment - January 7, 2020 Category: Science Authors: Madsen, R. R., Vanhaesebroeck, B. Tags: STKE Reviews Source Type: news

Genetic diversity affects the nanoscale membrane organization and signaling of natural killer cell receptors
Genetic diversity in human natural killer (NK) cell receptors is linked to resistance and susceptibility to many diseases. Here, we tested the effect of this diversity on the nanoscale organization of killer cell immunoglobulin-like receptors (KIRs). Using superresolution microscopy, we found that inhibitory KIRs encoded by different genes and alleles were organized differently at the surface of primary human NK cells. KIRs that were found at low abundance assembled into smaller clusters than those formed by KIRs that were more highly abundant, and at low abundance, there was a greater proportion of KIRs in clusters. Upon ...
Source: Signal Transduction Knowledge Environment - December 17, 2019 Category: Science Authors: Kennedy, P. R., Barthen, C., Williamson, D. J., Pitkeathly, W. T. E., Hazime, K. S., Cumming, J., Stacey, K. B., Hilton, H. G., Carrington, M., Parham, P., Davis, D. M. Tags: STKE Research Articles Source Type: news

Signaling from mTOR to eIF2{alpha} mediates cell migration in response to the chemotherapeutic doxorubicin
After exposure to cytotoxic chemotherapeutics, tumor cells alter their translatome to promote cell survival programs through the regulation of eukaryotic initiation factor 4F (eIF4F) and ternary complex. Compounds that block mTOR signaling and eIF4F complex formation, such as rapamycin and its analogs, have been used in combination therapies to enhance cell killing, although their success has been limited. This is likely because the cross-talk between signaling pathways that coordinate eIF4F regulation with ternary complex formation after treatment with genotoxic therapeutics has not been fully explored. Here, we described...
Source: Signal Transduction Knowledge Environment - December 17, 2019 Category: Science Authors: Harvey, R. F., Pöyry, T. A. A., Stoneley, M., Willis, A. E. Tags: STKE Research Articles Source Type: news

Distinguishing friend from foe
Toxin-stimulated immune signaling helps neonatal mice distinguish between harmless skin colonizers and potential pathogens. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - December 17, 2019 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news

Hexokinase 2 couples glycolysis with the profibrotic actions of TGF-{beta}
Metabolic dysregulation in fibroblasts is implicated in the profibrotic actions of transforming growth factor–β (TGF-β). Here, we present evidence that hexokinase 2 (HK2) is important for mediating the fibroproliferative activity of TGF-β both in vitro and in vivo. Both Smad-dependent and Smad-independent TGF-β signaling induced HK2 accumulation in murine and human lung fibroblasts through induction of the transcription factor c-Myc. Knockdown of HK2 or pharmacological inhibition of HK2 activity with Lonidamine decreased TGF-β–stimulated fibrogenic processes, including profibrotic gene ...
Source: Signal Transduction Knowledge Environment - December 17, 2019 Category: Science Authors: Yin, X., Choudhury, M., Kang, J.-H., Schaefbauer, K. J., Jung, M.-Y., Andrianifahanana, M., Hernandez, D. M., Leof, E. B. Tags: STKE Research Articles Source Type: news

Retraction
(Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - December 17, 2019 Category: Science Authors: Coleman, J. L. J., Ngo, T., Schmidt, J., Mrad, N., Liew, C. K., Jones, N. M., Graham, R. M., Smith, N. J. Tags: STKE Retraction Source Type: news

Metabolic rewiring of the hypertensive kidney
Hypertension is a persistent epidemic across the developed world that is closely associated with kidney disease. Here, we applied a metabolomic, phosphoproteomic, and proteomic strategy to analyze the effect of hypertensive insults on kidneys. Our data revealed the metabolic aspects of hypertension-induced glomerular sclerosis, including lipid breakdown at early disease stages and activation of anaplerotic pathways to regenerate energy equivalents to counter stress. For example, branched-chain amino acids and proline, required for collagen synthesis, were depleted in glomeruli at early time points. Furthermore, indicators ...
Source: Signal Transduction Knowledge Environment - December 10, 2019 Category: Science Authors: Rinschen, M. M., Palygin, O., Guijas, C., Palermo, A., Palacio-Escat, N., Domingo-Almenara, X., Montenegro-Burke, R., Saez-Rodriguez, J., Staruschenko, A., Siuzdak, G. Tags: STKE Research Resources Source Type: news

A direct heterotypic interaction between the DIX domains of Dishevelled and Axin mediates signaling to {beta}-catenin
The Wnt–β-catenin signaling pathway regulates embryonic development and tissue homeostasis throughout the animal kingdom. Signaling through this pathway crucially depends on the opposing activities of two cytoplasmic multiprotein complexes: the Axin destruction complex, which destabilizes the downstream effector β-catenin, and the Dishevelled signalosome, which inactivates the Axin complex and thus enables β-catenin to accumulate and operate a transcriptional switch in the nucleus. These complexes are assembled by dynamic head-to-tail polymerization of the DIX domains of Axin or Dishevelled, respective...
Source: Signal Transduction Knowledge Environment - December 10, 2019 Category: Science Authors: Yamanishi, K., Fiedler, M., Terawaki, S.-i., Higuchi, Y., Bienz, M., Shibata, N. Tags: STKE Research Articles Source Type: news

Mutations that TANK a kinase
ALS-associated mutations in the kinase TBK1 with the same pathological outcome affect distinct signaling pathways. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - December 10, 2019 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

The interaction of ceramide 1-phosphate with group IVA cytosolic phospholipase A2 coordinates acute wound healing and repair
The sphingolipid ceramide 1-phosphate (C1P) directly binds to and activates group IVA cytosolic phospholipase A2 (cPLA2α) to stimulate the production of eicosanoids. Because eicosanoids are important in wound healing, we examined the repair of skin wounds in knockout (KO) mice lacking cPLA2α and in knock-in (KI) mice in which endogenous cPLA2α was replaced with a mutant form having an ablated C1P interaction site. Wound closure rate was not affected in the KO or KI mice, but wound maturation was enhanced in the KI mice compared to that in wild-type controls. Wounds in KI mice displayed increased infiltrat...
Source: Signal Transduction Knowledge Environment - December 3, 2019 Category: Science Authors: MacKnight, H. P., Stephenson, D. J., Hoeferlin, L. A., Benusa, S. D., DeLigio, J. T., Maus, K. D., Ali, A. N., Wayne, J. S., Park, M. A., Hinchcliffe, E. H., Brown, R. E., Ryan, J. J., Diegelmann, R. F., Chalfant, C. E. Tags: STKE Research Articles Source Type: news

The long and short of antiviral activity
Only short isoforms of the pseudoenzyme PARP13 inhibit interferon responses. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - December 3, 2019 Category: Science Authors: Williams, E. R. Tags: STKE Editors ' Choice Source Type: news

Erratum for the Research Article: "HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species" by H. E. Nicholson, Z. Tariq, B. E. Housden, R. B. Jennings, L. A. Stransky, N. Perrimon, S. Signoretti, W. G. Kaelin
(Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - December 3, 2019 Category: Science Tags: STKE Errata Source Type: news

Biased M1 receptor-positive allosteric modulators reveal role of phospholipase D in M1-dependent rodent cortical plasticity
Highly selective, positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach to potentially improve cognitive function in patients suffering from Alzheimer’s disease and schizophrenia. Discovery programs have produced a structurally diverse range of M1 receptor PAMs with distinct pharmacological properties, including different extents of agonist activity and differences in signal bias. This includes biased M1 receptor PAMs that can potentiate coupling of the receptor to activation of phospholipase C (PLC) but not phospholipase D (PLD). However...
Source: Signal Transduction Knowledge Environment - December 3, 2019 Category: Science Authors: Moran, S. P., Xiang, Z., Doyle, C. A., Maksymetz, J., Lv, X., Faltin, S., Fisher, N. M., Niswender, C. M., Rook, J. M., Lindsley, C. W., Conn, P. J. Tags: STKE Research Articles Source Type: news

Hypusine biosynthesis in {beta} cells links polyamine metabolism to facultative cellular proliferation to maintain glucose homeostasis
Deoxyhypusine synthase (DHPS) uses the polyamine spermidine to catalyze the hypusine modification of the mRNA translation factor eIF5A and promotes oncogenesis through poorly defined mechanisms. Because germline deletion of Dhps is embryonically lethal, its role in normal postnatal cellular function in vivo remains unknown. We generated a mouse model that enabled the inducible, postnatal deletion of Dhps specifically in postnatal islet β cells, which function to maintain glucose homeostasis. Removal of Dhps did not have an effect under normal physiologic conditions. However, upon development of insulin resistance, whi...
Source: Signal Transduction Knowledge Environment - December 3, 2019 Category: Science Authors: Levasseur, E. M., Yamada, K., Pineros, A. R., Wu, W., Syed, F., Orr, K. S., Anderson-Baucum, E., Mastracci, T. L., Maier, B., Mosley, A. L., Liu, Y., Bernal-Mizrachi, E., Alonso, L. C., Scott, D., Garcia-Ocana, A., Tersey, S. A., Mirmira, R. G. Tags: STKE Research Articles Source Type: news

PKR-dependent cytosolic cGAS foci are necessary for intracellular DNA sensing
Cyclic GMP-AMP synthase (cGAS) is a major sensor of cytosolic DNA from invading pathogens and damaged cellular organelles. Activation of cGAS promotes liquid-like phase separation and formation of membraneless cytoplasmic structures. Here, we found that cGAS bound G3BP1, a double-stranded nucleic acid helicase involved in the formation of stress granules. Loss of G3BP1 blocked subcellular cGAS condensation and suppressed the interferon response to intracellular DNA and DNA virus particles in cells. Furthermore, an RNA-dependent association with PKR promoted G3BP1 foci formation and cGAS-dependent interferon responses. Toge...
Source: Signal Transduction Knowledge Environment - November 26, 2019 Category: Science Authors: Hu, S., Sun, H., Yin, L., Li, J., Mei, S., Xu, F., Wu, C., Liu, X., Zhao, F., Zhang, D., Huang, Y., Ren, L., Cen, S., Wang, J., Liang, C., Guo, F. Tags: STKE Research Articles Source Type: news

Thiol-based direct threat sensing by the stress-activated protein kinase Hog1
The yeast stress-activated protein kinase Hog1 is best known for its role in mediating the response to osmotic stress, but it is also activated by various mechanistically distinct environmental stressors, including heat shock, endoplasmic reticulum stress, and arsenic. In the osmotic stress response, the signal is sensed upstream and relayed to Hog1 through a kinase cascade. Here, we identified a mode of Hog1 function whereby Hog1 senses arsenic through a direct physical interaction that requires three conserved cysteine residues located adjacent to the catalytic loop. These residues were essential for Hog1-mediated protec...
Source: Signal Transduction Knowledge Environment - November 26, 2019 Category: Science Authors: Guerra-Moreno, A., Prado, M. A., Ang, J., Schnell, H. M., Micoogullari, Y., Paulo, J. A., Finley, D., Gygi, S. P., Hanna, J. Tags: STKE Research Articles Source Type: news

Trauma promotes resilience
Wounding induces cytoprotective mechanisms that make cells more resistant to oxidative damage. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - November 26, 2019 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news

The human secretome
The proteins secreted by human cells (collectively referred to as the secretome) are important not only for the basic understanding of human biology but also for the identification of potential targets for future diagnostics and therapies. Here, we present a comprehensive analysis of proteins predicted to be secreted in human cells, which provides information about their final localization in the human body, including the proteins actively secreted to peripheral blood. The analysis suggests that a large number of the proteins of the secretome are not secreted out of the cell, but instead are retained intracellularly, where...
Source: Signal Transduction Knowledge Environment - November 26, 2019 Category: Science Authors: Uhlen, M., Karlsson, M. J., Hober, A., Svensson, A.-S., Scheffel, J., Kotol, D., Zhong, W., Tebani, A., Strandberg, L., Edfors, F., Sjöstedt, E., Mulder, J., Mardinoglu, A., Berling, A., Ekblad, S., Dannemeyer, M., Kanje, S., Rockberg, J., Lundqvi Tags: STKE Research Resources Source Type: news

Dynamic palmitoylation controls the microdomain localization of the DKK1 receptors CKAP4 and LRP6
Dickkopf1 (DKK1) was originally identified as an antagonist of Wnt signaling that binds to and induces the clathrin-mediated endocytosis of the Wnt coreceptors low-density lipoprotein receptor–related proteins 5 and 6 (LRP5/6). DKK1 also binds to cytoskeleton-associated protein 4 (CKAP4), which was originally identified as an endoplasmic reticulum (ER) protein but also functions at the plasma membrane as a receptor for various ligands. The DKK1-CKAP4 pathway is activated in several human cancers and promotes cell proliferation by activating signaling through the kinases PI3K and AKT. We found that both CKAP4 and LRP6...
Source: Signal Transduction Knowledge Environment - November 19, 2019 Category: Science Authors: Sada, R., Kimura, H., Fukata, Y., Fukata, M., Yamamoto, H., Kikuchi, A. Tags: STKE Research Articles Source Type: news

Sequential activation of STIM1 links Ca2+ with luminal domain unfolding
The stromal interaction molecule 1 (STIM1) has two important functions, Ca2+ sensing within the endoplasmic reticulum and activation of the store-operated Ca2+ channel Orai1, enabling plasma-membrane Ca2+ influx. We combined molecular dynamics (MD) simulations with live-cell recordings and determined the sequential Ca2+-dependent conformations of the luminal STIM1 domain upon activation. Furthermore, we identified the residues within the canonical and noncanonical EF-hand domains that can bind to multiple Ca2+ ions. In MD simulations, a single Ca2+ ion was sufficient to stabilize the luminal STIM1 complex. Ca2+ store deple...
Source: Signal Transduction Knowledge Environment - November 19, 2019 Category: Science Authors: Schober, R., Bonhenry, D., Lunz, V., Zhu, J., Krizova, A., Frischauf, I., Fahrner, M., Zhang, M., Waldherr, L., Schmidt, T., Derler, I., Stathopulos, P. B., Romanin, C., Ettrich, R. H., Schindl, R. Tags: STKE Research Articles Source Type: news