Phosphorylated G{beta} is a directional cue during yeast gradient tracking
Budding yeast cells interpret shallow pheromone gradients from cells of the opposite mating type, polarize their growth toward the pheromone source, and fuse at the chemotropic growth site. We previously proposed a deterministic, gradient-sensing model that explains how yeast cells switch from the intrinsically positioned default polarity site (DS) to the gradient-aligned chemotropic site (CS) at the plasma membrane. Because phosphorylation of the mating-specific Gβ subunit is thought to be important for this process, we developed a biosensor that bound to phosphorylated but not unphosphorylated Gβ and monitored ...
Source: Signal Transduction Knowledge Environment - May 11, 2021 Category: Science Authors: Abdul-Ganiyu, R., Venegas, L. A., Wang, X., Puerner, C., Arkowitz, R. A., Kay, B. K., Stone, D. E. Tags: STKE Research Articles Source Type: news

Cloaked by mutant p53
Mutant p53 takes the STING out of antitumor immunity. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - May 11, 2021 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

ERK phosphorylation is RAF independent in naïve and activated B cells but RAF dependent in plasma cell differentiation
Members of the RAF family of serine-threonine kinases are intermediates in the mitogen-activated protein kinase and extracellular signal–regulated kinase (MAPK-ERK) signaling pathway, which controls key differentiation processes in B cells. By analyzing mice with B cell–specific deletion of Raf1, Braf, or both, we showed that Raf-1 and B-Raf acted together in mediating the positive selection of pre-B and transitional B cells as well as in initiating plasma cell differentiation. However, genetic or chemical inactivation of RAFs led to increased ERK phosphorylation in mature B cells. ERK activation in the absence...
Source: Signal Transduction Knowledge Environment - May 11, 2021 Category: Science Authors: Scheffler, L., Feicht, S., Babushku, T., Kuhn, L. B., Ehrenberg, S., Frankenberger, S., Lehmann, F. M., Hobeika, E., Jungnickel, B., Baccarini, M., Bornkamm, G. W., Strobl, L. J., Zimber-Strobl, U. Tags: STKE Research Articles Source Type: news

Remodeling of the Homer-Shank interactome mediates homeostatic plasticity
Neurons maintain stable levels of excitability using homeostatic synaptic scaling, which adjusts the strength of a neuron’s postsynaptic inputs to compensate for extended changes in overall activity. Here, we investigated whether prolonged changes in activity affect network-level protein interactions at the synapse. We assessed a glutamatergic synapse protein interaction network (PIN) composed of 380 binary associations among 21 protein members in mouse neurons. Manipulating the activation of cultured mouse cortical neurons induced widespread bidirectional PIN alterations that reflected rapid rearrangements of glutam...
Source: Signal Transduction Knowledge Environment - May 4, 2021 Category: Science Authors: Heavner, W. E., Lautz, J. D., Speed, H. E., Gniffke, E. P., Immendorf, K. B., Welsh, J. P., Baertsch, N. A., Smith, S. E. P. Tags: STKE Research Resources Source Type: news

Structural analysis of the PTEN:P-Rex2 signaling complex reveals how cancer-associated mutations coordinate to hyperactivate Rac1
The dual-specificity phosphatase PTEN functions as a tumor suppressor by hydrolyzing PI(3,4,5)P3 to PI(4,5)P2 to inhibit PI3K-AKT signaling and cellular proliferation. P-Rex2 is a guanine nucleotide exchange factor for Rho GTPases and can be activated by Gβ subunits downstream of G protein–coupled receptor signaling and by PI(3,4,5)P3 downstream of receptor tyrosine kinases. The PTEN:P-Rex2 complex is a commonly mutated signaling node in metastatic cancer. Assembly of the PTEN:P-Rex2 complex inhibits the activity of both proteins, and its dysregulation can drive PI3K-AKT signaling and cellular proliferation. Her...
Source: Signal Transduction Knowledge Environment - May 4, 2021 Category: Science Authors: DAndrea, L., Lucato, C. M., Marquez, E. A., Chang, Y.-G., Civciristov, S., Mastos, C., Lupton, C. J., Huang, C., Elmlund, H., Schittenhelm, R. B., Mitchell, C. A., Whisstock, J. C., Halls, M. L., Ellisdon, A. M. Tags: STKE Research Articles Source Type: news

Polyamines determine dispersal
Monitoring of environmental polyamines controls the dispersal of Vibrio cholerae biofilms. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - May 4, 2021 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news

Pinpointing cysteine oxidation sites by high-resolution proteomics reveals a mechanism of redox-dependent inhibition of human STING
Protein function is regulated by posttranslational modifications (PTMs), among which reversible oxidation of cysteine residues has emerged as a key regulatory mechanism of cellular responses. Given the redox regulation of virus-host interactions, the identification of oxidized cysteine sites in cells is essential to understand the underlying mechanisms involved. Here, we present a proteome-wide identification of reversibly oxidized cysteine sites in oxidant-treated cells using a maleimide-based bioswitch method coupled to mass spectrometry analysis. We identified 2720 unique oxidized cysteine sites within 1473 proteins wit...
Source: Signal Transduction Knowledge Environment - April 27, 2021 Category: Science Authors: Zamorano Cuervo, N., Fortin, A., Caron, E., Chartier, S., Grandvaux, N. Tags: STKE Research Articles Source Type: news

Select hyperactivating NLRP3 ligands enhance the TH1- and TH17-inducing potential of human type 2 conventional dendritic cells
The detection of microorganisms and danger signals by pattern recognition receptors on dendritic cells (DCs) and the consequent formation of inflammasomes are pivotal for initiating protective immune responses. Although the activation of inflammasomes leading to secretion of the cytokine IL-1β is typically accompanied by pyroptosis (an inflammatory form of lytic programmed cell death), some cells can survive and exist in a state of hyperactivation. Here, we found that the conventional type 2 DC (cDC2) subset is the major human DC subset that is transcriptionally and functionally poised for inflammasome formation and r...
Source: Signal Transduction Knowledge Environment - April 27, 2021 Category: Science Authors: Hatscher, L., Lehmann, C. H. K., Purbojo, A., Onderka, C., Liang, C., Hartmann, A., Cesnjevar, R., Bruns, H., Gross, O., Nimmerjahn, F., Ivanovic-Burmazovic, I., Kunz, M., Heger, L., Dudziak, D. Tags: STKE Research Articles Source Type: news

Exercising for future generations
A placenta-to-fetus pathway transmits the benefits of maternal exercise on the metabolic health of offspring. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - April 27, 2021 Category: Science Authors: Wong, W. Tags: STKE Editors ' Choice Source Type: news

A leukotriene-dependent spleen-liver axis drives TNF production in systemic inflammation
Production of the proinflammatory cytokine tumor necrosis factor (TNF) must be precisely regulated for effective host immunity without the induction of collateral tissue damage. Here, we showed that TNF production was driven by a spleen-liver axis in a rat model of systemic inflammation induced by bacterial lipopolysaccharide (LPS). Analysis of cytokine expression and secretion in combination with splenectomy and hepatectomy revealed that the spleen generated not only TNF but also factors that enhanced TNF production by the liver, the latter of which accounted for nearly half of the TNF secreted into the circulation. Using...
Source: Signal Transduction Knowledge Environment - April 20, 2021 Category: Science Authors: Fonseca, M. T., Moretti, E. H., Marques, L. M. M., Machado, B. F., Brito, C. F., Guedes, J. T., Komegae, E. N., Vieira, T. S., Festuccia, W. T., Lopes, N. P., Steiner, A. A. Tags: STKE Research Articles Source Type: news

Aging and autoimmunity
Cytoplasmic DNA sensing by the KU complex enhances CD4+ T cell activation and contributes to aging-induced autoimmunity. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - April 20, 2021 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

CLIC1 and CLIC4 mediate endothelial S1P receptor signaling to facilitate Rac1 and RhoA activity and function
Chloride intracellular channels 1 (CLIC1) and 4 (CLIC4) are expressed in endothelial cells and regulate angiogenic behaviors in vitro, and the expression of Clic4 is important for vascular development and function in mice. Here, we found that CLIC1 and CLIC4 in endothelial cells regulate critical G protein–coupled receptor (GPCR) pathways associated with vascular development and disease. In cultured endothelial cells, we found that CLIC1 and CLIC4 transiently translocated to the plasma membrane in response to sphingosine 1-phosphate (S1P). Both CLIC1 and CLIC4 were essential for mediating S1P-induced activation of th...
Source: Signal Transduction Knowledge Environment - April 20, 2021 Category: Science Authors: Mao, D. Y., Kleinjan, M. L., Jilishitz, I., Swaminathan, B., Obinata, H., Komarova, Y. A., Bayless, K. J., Hla, T., Kitajewski, J. K. Tags: STKE Research Articles Source Type: news

Connect-the-DOT from early stress to depression
Targeting the epigenetic enzyme DOT1L may reverse some behavioral effects of early-life stress. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - April 13, 2021 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

DDAH2 suppresses RLR-MAVS-mediated innate antiviral immunity by stimulating nitric oxide-activated, Drp1-induced mitochondrial fission
The RIG-I–like receptor (RLR) signaling pathway is pivotal for innate immunity against invading viruses, and dysregulation of this molecular cascade has been linked to various diseases. Here, we identified dimethylarginine dimethylaminohydrolase 2 (DDAH2) as a potent regulator of the RLR-mediated antiviral response in human and mouse. Overexpression of DDAH2 attenuated RLR signaling, whereas loss of DDAH2 function enhanced RLR signaling and suppressed viral replication ex vivo and in mice. Upon viral infection, DDAH2 relocated to mitochondria, where it induced the production of nitric oxide (NO) and the activation of...
Source: Signal Transduction Knowledge Environment - April 13, 2021 Category: Science Authors: Huang, S., Li, Z., Wu, Z., Liu, C., Yu, M., Wen, M., Zhang, L., Wang, X. Tags: STKE Research Articles Source Type: news

mTORC2 controls the activity of PKC and Akt by phosphorylating a conserved TOR interaction motif
The complex mTORC2 is accepted to be the kinase that controls the phosphorylation of the hydrophobic motif, a key regulatory switch for AGC kinases, although whether mTOR directly phosphorylates this motif remains controversial. Here, we identified an mTOR-mediated phosphorylation site that we termed the TOR interaction motif (TIM; F-x3-F-pT), which controls the phosphorylation of the hydrophobic motif of PKC and Akt and the activity of these kinases. The TIM is invariant in mTORC2-dependent AGC kinases, is evolutionarily conserved, and coevolved with mTORC2 components. Mutation of this motif in Akt1 and PKCβII abolis...
Source: Signal Transduction Knowledge Environment - April 13, 2021 Category: Science Authors: Baffi, T. R., Lorden, G., Wozniak, J. M., Feichtner, A., Yeung, W., Kornev, A. P., King, C. C., Del Rio, J. C., Limaye, A. J., Bogomolovas, J., Gould, C. M., Chen, J., Kennedy, E. J., Kannan, N., Gonzalez, D. J., Stefan, E., Taylor, S. S., Newton, A. C. Tags: STKE Research Articles Source Type: news

ARC unleashes elastase
An antiapoptotic cytoplasmic protein becomes a proapoptotic nuclear protein in diabetes. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - April 6, 2021 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news

Myeloid cell-derived HOCl is a paracrine effector that trans-inhibits IKK/NF-{kappa}B in melanoma cells and limits early tumor progression
The myeloperoxidase (MPO) system of myeloid-derived cells (MDCs) is central to cellular innate immunity. Upon MDC activation, MPO is secreted into phagosomes where it catalyzes the production of hypochlorous acid (HOCl), a potent chlorinating oxidant. Here, we demonstrated that the myeloid lineage–restricted MPO-HOCl system had antitumor effects in early melanoma growth in aged mice. Orthotopic melanomas grew more slowly in immunocompetent MPO+/+ host mice compared to age-matched syngeneic MPO–/– mice. Real-time intravital tumor imaging in vivo and in cell cocultures revealed a cell-cell proximity-depende...
Source: Signal Transduction Knowledge Environment - April 6, 2021 Category: Science Authors: Liu, T. W., Gammon, S. T., Yang, P., Fuentes, D., Piwnica-Worms, D. Tags: STKE Research Articles Source Type: news

Input-specific regulation of glutamatergic synaptic transmission in the medial prefrontal cortex by mGlu2/mGlu4 receptor heterodimers
Metabotropic glutamate receptors (mGluRs) are G protein–coupled receptors that regulate various aspects of central nervous system processing in normal physiology and in disease. They are thought to function as disulfide-linked homodimers, but studies have suggested that mGluRs can form functional heterodimers in cell lines. Using selective allosteric ligands, ex vivo brain slice electrophysiology, and optogenetic approaches, we found that two mGluR subtypes—mGluR2 and mGluR4 (or mGlu2 and mGlu4)—exist as functional heterodimers that regulate excitatory transmission in a synapse-specific manner within the ...
Source: Signal Transduction Knowledge Environment - April 6, 2021 Category: Science Authors: Xiang, Z., Lv, X., Lin, X., OBrien, D. E., Altman, M. K., Lindsley, C. W., Javitch, J. A., Niswender, C. M., Conn, P. J. Tags: STKE Research Articles Source Type: news

Biased ligands at opioid receptors: Current status and future directions
The opioid crisis represents a major worldwide public health crisis that has accelerated the search for safer and more effective opioids. Over the past few years, the identification of biased opioid ligands capable of eliciting selective functional responses has provided an alternative avenue to develop novel therapeutics without the side effects of current opioid medications. However, whether biased agonism or other pharmacological properties, such as partial agonism (or low efficacy), account for the therapeutic benefits remains questionable. Here, we provide a summary of the current status of biased opioid ligands that ...
Source: Signal Transduction Knowledge Environment - April 6, 2021 Category: Science Authors: Che, T., Dwivedi-Agnihotri, H., Shukla, A. K., Roth, B. L. Tags: STKE Reviews Source Type: news

A cancerous connection for creatine
Obesity induces adipocytes to release creatine that is used by nearby breast cancer cells to fuel growth. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - March 30, 2021 Category: Science Authors: Wong, W. Tags: STKE Editors ' Choice Source Type: news

A peptide of the N terminus of GRK5 attenuates pressure-overload hypertrophy and heart failure
Aberrant changes in gene expression underlie the pathogenesis and progression of pressure-overload heart failure, leading to maladaptive cardiac hypertrophy, ventricular remodeling, and contractile dysfunction. Signaling through the G protein Gq triggers maladaptation and heart failure, in part through the activation of G protein–coupled receptor kinase 5 (GRK5). Hypertrophic stimuli induce the accumulation of GRK5 in the nuclei of cardiomyocytes, where it regulates pathological gene expression through multiple transcription factors including NFAT. The nuclear targeting of GRK5 is mediated by an amino-terminal (NT) d...
Source: Signal Transduction Knowledge Environment - March 30, 2021 Category: Science Authors: Coleman, R. C., Eguchi, A., Lieu, M., Roy, R., Barr, E. W., Ibetti, J., Lucchese, A.-M., Peluzzo, A. M., Gresham, K., Chuprun, J. K., Koch, W. J. Tags: STKE Research Articles Source Type: news

Inositol 1,4,5-trisphosphate 3-kinase B promotes Ca2+ mobilization and the inflammatory activity of dendritic cells
Innate immune responses to Gram-negative bacteria depend on the recognition of lipopolysaccharide (LPS) by a receptor complex that includes CD14 and TLR4. In dendritic cells (DCs), CD14 enhances the activation not only of TLR4 but also that of the NFAT family of transcription factors, which suppresses cell survival and promotes the production of inflammatory mediators. NFAT activation requires Ca2+ mobilization. In DCs, Ca2+ mobilization in response to LPS depends on phospholipase C 2 (PLC2), which produces inositol 1,4,5-trisphosphate (IP3). Here, we showed that the IP3 receptor 3 (IP3R3) and ITPKB, a kinase that converts...
Source: Signal Transduction Knowledge Environment - March 30, 2021 Category: Science Authors: Marongiu, L., Mingozzi, F., Cigni, C., Marzi, R., Di Gioia, M., Garre, M., Parazzoli, D., Sironi, L., Collini, M., Sakaguchi, R., Morii, T., Crosti, M., Moro, M., Schurmans, S., Catelani, T., Rotem, R., Colombo, M., Shears, S., Prosperi, D., Zanoni, I., G Tags: STKE Research Articles Source Type: news

Sensing mitochondrial damage
Detection of cytosolic mitochondrial RNA resulting from mitochondrial DNA breaks triggers a type I interferon response. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - March 23, 2021 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

HN1L/JPT2: A signaling protein that connects NAADP generation to Ca2+ microdomain formation
NAADP-evoked Ca2+ release through type 1 ryanodine receptors (RYR1) is a major mechanism underlying the earliest signals in T cell activation, which are the formation of Ca2+ microdomains. In our characterization of the molecular machinery underlying NAADP action, we identified an NAADP-binding protein, called hematological and neurological expressed 1–like protein (HN1L) [also known as Jupiter microtubule-associated homolog 2 (JPT2)]. Gene deletion of Hn1l/Jpt2 in human Jurkat and primary rat T cells resulted in decreased numbers of initial Ca2+ microdomains and delayed the onset and decreased the amplitude of globa...
Source: Signal Transduction Knowledge Environment - March 23, 2021 Category: Science Authors: Roggenkamp, H. G., Khansahib, I., Hernandez C., L. C., Zhang, Y., Lodygin, D., Krüger, A., Gu, F., Möckl, F., Löhndorf, A., Wolters, V., Woike, D., Rosche, A., Bauche, A., Schetelig, D., Werner, R., Schlüter, H., Failla, A. Tags: STKE Research Articles Source Type: news

Essential requirement for JPT2 in NAADP-evoked Ca2+ signaling
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a second messenger that releases Ca2+ from acidic organelles through the activation of two-pore channels (TPCs) to regulate endolysosomal trafficking events. NAADP action is mediated by NAADP-binding protein(s) of unknown identity that confer NAADP sensitivity to TPCs. Here, we used a "clickable" NAADP-based photoprobe to isolate human NAADP-binding proteins and identified Jupiter microtubule-associated homolog 2 (JPT2) as a TPC accessory protein required for endogenous NAADP-evoked Ca2+ signaling. JPT2 was also required for the translocation of a severe ac...
Source: Signal Transduction Knowledge Environment - March 23, 2021 Category: Science Authors: Gunaratne, G. S., Brailoiu, E., He, S., Unterwald, E. M., Patel, S., Slama, J. T., Walseth, T. F., Marchant, J. S. Tags: STKE Research Articles Source Type: news

TMEM16F mediates bystander TCR-CD3 membrane dissociation at the immunological synapse and potentiates T cell activation
This study establishes the molecular basis for the role of TMEM16F in bystander TCR–induced signal amplification and identifies enhancement of TMEM16F function as a potential therapeutic strategy for promoting T cell activation. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - March 23, 2021 Category: Science Authors: Connolly, A., Panes, R., Tual, M., Lafortune, R., Bellemare-Pelletier, A., Gagnon, E. Tags: STKE Research Articles Source Type: news

Teaming with NAADP
NAADP is a potent Ca2+-mobilizing messenger linked to numerous Ca2+-dependent effects across the natural world. On 18 February 2021, delegates attended a virtual symposium to discuss studies of the mechanisms of action of NAADP, including the work of Gunaratne et al. and Roggenkamp et al. in this issue of Science Signaling. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - March 23, 2021 Category: Science Authors: Patel, S., Gregori, M., Yuan, Y. Tags: STKE Focus Source Type: news

Targeting metastatic NETs
Blocking tumor-to-neutrophil cross-talk by cathepsin C may prevent lung metastasis. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - March 16, 2021 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

A ligand-receptor interactome platform for discovery of pain mechanisms and therapeutic targets
In the peripheral nervous system, ligand-receptor interactions between cells and neurons shape sensory experience, including pain. We set out to identify the potential interactions between sensory neurons and peripheral cell types implicated in disease-associated pain. Using mouse and human RNA sequencing datasets and computational analysis, we created interactome maps between dorsal root ganglion (DRG) sensory neurons and an array of normal cell types, as well as colitis-associated glial cells, rheumatoid arthritis–associated synovial macrophages, and pancreatic tumor tissue. These maps revealed a common correlation...
Source: Signal Transduction Knowledge Environment - March 16, 2021 Category: Science Authors: Wangzhou, A., Paige, C., Neerukonda, S. V., Naik, D. K., Kume, M., David, E. T., Dussor, G., Ray, P. R., Price, T. J. Tags: STKE Research Resources Source Type: news

Interleukin-7 protects CD8+ T cells from adenosine-mediated immunosuppression
The nucleoside adenosine accumulates extracellularly in solid tumors and inhibits CD8+ T cells by activating adenosine receptors. The cytokine interleukin-7 (IL-7), which is produced by various tissues and tumors, promotes the survival and maintenance of T cells. Adenosine and IL-7 signaling are being clinically targeted separately or in combination with other therapies for solid tumor indications. Here, we found that IL-7 signaling promoted the accumulation of tumor-associated CD8+ T cells, in part, by preventing adenosine-mediated immunosuppression. Inhibition of the transcription factor FoxO1 downstream of IL-7 receptor...
Source: Signal Transduction Knowledge Environment - March 16, 2021 Category: Science Authors: Koyas, A., Tucer, S., Kayhan, M., Savas, A. C., Akdemir, I., Cekic, C. Tags: STKE Research Articles Source Type: news

The cytosolic DNA sensor cGAS recognizes neutrophil extracellular traps
Neutrophil extracellular traps (NETs) are structures consisting of chromatin and antimicrobial molecules that are released by neutrophils during a form of regulated cell death called NETosis. NETs trap invading pathogens, promote coagulation, and activate myeloid cells to produce type I interferons (IFNs), proinflammatory cytokines that regulate the immune system. Here, we showed that macrophages and other myeloid cells phagocytosed NETs. Once in phagosomes, NETs translocated to the cytosol, where the DNA backbones of these structures activated the innate immune sensor cyclic GMP-AMP synthase (cGAS) and induced type I IFN ...
Source: Signal Transduction Knowledge Environment - March 9, 2021 Category: Science Authors: Apel, F., Andreeva, L., Knackstedt, L. S., Streeck, R., Frese, C. K., Goosmann, C., Hopfner, K.-P., Zychlinsky, A. Tags: STKE Research Articles Source Type: news

Identification of human immune cell subtypes most responsive to IL-1{beta}-induced inflammatory signaling using mass cytometry
IL-1β is a key mediator of the cytokine storm linked to high morbidity and mortality from COVID-19, and IL-1β blockade with anakinra and canakinumab during COVID-19 infection has entered clinical trials. Using mass cytometry of human peripheral blood mononuclear cells, we identified effector memory CD4+ T cells and CD4–CD8low/–CD161+ T cells, specifically those positive for the chemokine receptor CCR6, as the circulating immune subtypes with the greatest response to IL-1β. This response manifested as increased phosphorylation and, thus, activation of the proinflammatory transcription factor NF-B ...
Source: Signal Transduction Knowledge Environment - March 9, 2021 Category: Science Authors: Kothari, H., Williams, C. M., McSkimming, C., Drago, F., Marshall, M. A., Garmey, J., Vigneshwar, M., Zunder, E. R., McNamara, C. A. Tags: STKE Research Articles Source Type: news

Autophagy chokes on SARS-CoV-2
SARS-CoV-2 ORF3a prevents autophagosome-lysosome fusion. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - March 9, 2021 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news

Endogenous modification of the chemoattractant CXCL5 alters receptor usage and enhances its activity toward neutrophils and monocytes
The inflammatory human chemokine CXCL5 interacts with the G protein–coupled receptor CXCR2 to induce chemotaxis and activation of neutrophils. CXCL5 also has weak agonist activity toward CXCR1. The N-terminus of CXCL5 can be modified by proteolytic cleavage or deimination of Arg9 to citrulline (Cit), and these modifications can occur separately or together. Here, we chemically synthesized native CXCL5(1–78), truncated CXCL5 [CXCL5(9–78)], and the citrullinated (Cit9) versions and characterized their functions in vitro and in vivo. Compared with full-length CXCL5, N-terminal truncation resulted in enhanced...
Source: Signal Transduction Knowledge Environment - March 9, 2021 Category: Science Authors: Metzemaekers, M., Mortier, A., Vacchini, A., Boff, D., Yu, K., Janssens, R., Farina, F. M., Milanesi, S., Berghmans, N., Pörtner, N., Van Damme, J., Allegretti, M., Teixeira, M. M., Locati, M., Borroni, E. M., Amaral, F. A., Proost, P. Tags: STKE Research Articles Source Type: news

SOX9 is required for kidney fibrosis and activates NAV3 to drive renal myofibroblast function
Renal fibrosis is a common end point for kidney injury and many chronic kidney diseases. Fibrogenesis depends on the sustained activation of myofibroblasts, which deposit the extracellular matrix that causes progressive scarring and organ failure. Here, we showed that the transcription factor SOX9 was associated with kidney fibrosis in humans and required for experimentally induced kidney fibrosis in mice. From genome-wide analysis, we identified Neuron navigator 3 (NAV3) as acting downstream of SOX9 in kidney fibrosis. NAV3 increased in abundance and colocalized with SOX9 after renal injury in mice, and both SOX9 and NAV3...
Source: Signal Transduction Knowledge Environment - March 2, 2021 Category: Science Authors: Raza, S., Jokl, E., Pritchett, J., Martin, K., Su, K., Simpson, K., Birchall, L., Mullan, A. F., Athwal, V. S., Doherty, D. T., Zeef, L., Henderson, N. C., Kalra, P. A., Hanley, N. A., Piper Hanley, K. Tags: STKE Research Articles Source Type: news

A venous-specific purinergic signaling cascade initiated by Pannexin 1 regulates TNF{alpha}-induced increases in endothelial permeability
The endothelial cell barrier regulates the passage of fluid between the bloodstream and underlying tissues, and barrier function impairment exacerbates the severity of inflammatory insults. To understand how inflammation alters vessel permeability, we studied the effects of the proinflammatory cytokine TNFα on transendothelial permeability and electrophysiology in ex vivo murine veins and arteries. We found that TNFα specifically decreased the barrier function of venous endothelium without affecting that of arterial endothelium. On the basis of RNA expression profiling and protein analysis, we found that claudi...
Source: Signal Transduction Knowledge Environment - March 2, 2021 Category: Science Authors: Maier-Begandt, D., Comstra, H. S., Molina, S. A., Krüger, N., Ruddiman, C. A., Chen, Y.-L., Chen, X., Biwer, L. A., Johnstone, S. R., Lohman, A. W., Good, M. E., DeLalio, L. J., Hong, K., Bacon, H. M., Yan, Z., Sonkusare, S. K., Koval, M., Isakson Tags: STKE Research Articles Source Type: news

Messaging by mitochondria
Intercellular mitochondrial transfer promotes metabolic homeostasis and stimulates wound healing. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - March 2, 2021 Category: Science Authors: Wong, W. Tags: STKE Editors ' Choice Source Type: news

Control of ribosomal protein synthesis by the Microprocessor complex
Ribosome biogenesis in eukaryotes requires the coordinated production and assembly of 80 ribosomal proteins and four ribosomal RNAs (rRNAs), and its rate must be synchronized with cellular growth. Here, we showed that the Microprocessor complex, which mediates the first step of microRNA processing, potentiated the transcription of ribosomal protein genes by eliminating DNA/RNA hybrids known as R-loops. Nutrient deprivation triggered the nuclear export of Drosha, a key component of the Microprocessor complex, and its subsequent degradation by the E3 ubiquitin ligase Nedd4, thereby reducing ribosomal protein production and p...
Source: Signal Transduction Knowledge Environment - February 23, 2021 Category: Science Authors: Jiang, X., Prabhakar, A., Van der Voorn, S. M., Ghatpande, P., Celona, B., Venkataramanan, S., Calviello, L., Lin, C., Wang, W., Black, B. L., Floor, S. N., Lagna, G., Hata, A. Tags: STKE Research Articles Source Type: news

A TRAIL from gut to brain
Natural killer cells licensed by gut microbiota drive a population of TRAIL+ astrocytes to limit inflammation in the brain. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - February 23, 2021 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

Plasmodesmata-localized proteins and ROS orchestrate light-induced rapid systemic signaling in Arabidopsis
Systemic signaling and systemic acquired acclimation (SAA) are key to the survival of plants during episodes of abiotic stress. These processes depend on a continuous chain of cell-to-cell signaling events that extends from the initial tissue that senses the stress (the local tissue) to the entire plant (systemic tissues). Reactive oxygen species (ROS) and Ca2+ are key signaling molecules thought to be involved in this cell-to-cell mechanism. Here, we report that the systemic response of Arabidopsis thaliana to a local treatment of high light stress, which resulted in local ROS accumulation, required ROS generated by respi...
Source: Signal Transduction Knowledge Environment - February 23, 2021 Category: Science Authors: Fichman, Y., Myers, R. J., Grant, D. G., Mittler, R. Tags: STKE Research Articles Source Type: news

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