Functional coupling of GABAA/B receptors and the channel TRPV4 mediates rapid progesterone signaling in the oviduct
We report a rapid response to P4 and agonists of -aminobutyric acid receptors A and B (GABAA/B) in the mouse oviduct that was characterized by oscillatory Ca2+ signals and increased ciliary beat frequency (CBF). Pharmacological manipulation, genetic ablation, and siRNA-mediated knockdown in oviductal cells, as well as overexpression experiments in HEK 293T cells, confirmed the participation of the cationic channel TRPV4, different subunits of GABAA (α1 to α3, β2, and β3), and GABAB1 in P4-induced responses. TRPV4-mediated Ca2+ entry in close proximity to the inositol trisphosphate receptor was require...
Source: Signal Transduction Knowledge Environment - August 14, 2018 Category: Science Authors: Jung, C., Fernandez-Duenas, V., Plata, C., Garcia-Elias, A., Ciruela, F., Fernandez-Fernandez, J. M., Valverde, M. A. Tags: STKE Research Articles Source Type: news

Aurora-PLK1 cascades as key signaling modules in the regulation of mitosis
Mitosis is controlled by reversible protein phosphorylation involving specific kinases and phosphatases. A handful of major mitotic protein kinases, such as the cyclin B–CDK1 complex, the Aurora kinases, and Polo-like kinase 1 (PLK1), cooperatively regulate distinct mitotic processes. Research has identified proteins and mechanisms that integrate these kinases into signaling cascades that guide essential mitotic events. These findings have important implications for our understanding of the mechanisms of mitotic regulation and may advance the development of novel antimitotic drugs. We review collected evidence that i...
Source: Signal Transduction Knowledge Environment - August 14, 2018 Category: Science Authors: Joukov, V., De Nicolo, A. Tags: STKE Reviews Source Type: news

Mitotic phosphorylation regulates Hsp72 spindle localization by uncoupling ATP binding from substrate release
Hsp72 is a member of the 70-kDa heat shock family of molecular chaperones (Hsp70s) that comprise a nucleotide-binding domain (NBD) and a substrate-binding domain (SBD) connected by a linker that couples the exchange of adenosine diphosphate (ADP) for adenosine triphosphate (ATP) with the release of the protein substrate. Mitotic phosphorylation of Hsp72 by the kinase NEK6 at Thr66 located in the NBD promotes the localization of Hsp72 to the mitotic spindle and is required for efficient spindle assembly and chromosome congression and segregation. We determined the crystal structure of the Hsp72 NBD containing a genetically ...
Source: Signal Transduction Knowledge Environment - August 14, 2018 Category: Science Authors: Mukherjee, M., Sabir, S., ORegan, L., Sampson, J., Richards, M. W., Huguenin-Dezot, N., Ault, J. R., Chin, J. W., Zhuravleva, A., Fry, A. M., Bayliss, R. Tags: STKE Research Articles Source Type: news

Inflammasome SUMOylation
NLRP3 inflammasome activity is inhibited by SUMOylation. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - August 14, 2018 Category: Science Authors: Williams, E. R. Tags: STKE Editors ' Choice Source Type: news

Identification of Toll-like receptor signaling inhibitors based on selective activation of hierarchically acting signaling proteins
Toll-like receptors (TLRs) recognize various pathogen- and host tissue–derived molecules and initiate inflammatory immune responses. Exaggerated or prolonged TLR activation, however, can lead to etiologically diverse diseases, such as bacterial sepsis, metabolic and autoimmune diseases, or stroke. Despite the apparent medical need, no small-molecule drugs against TLR pathways are clinically available. This may be because of the complex signaling mechanisms of TLRs, which are governed by a series of protein-protein interactions initiated by Toll/interleukin-1 receptor homology domains (TIR) found in TLRs and the cytop...
Source: Signal Transduction Knowledge Environment - August 14, 2018 Category: Science Authors: Ippagunta, S. K., Pollock, J. A., Sharma, N., Lin, W., Chen, T., Tawaratsumida, K., High, A. A., Min, J., Chen, Y., Guy, R. K., Redecke, V., Katzenellenbogen, J. A., Häcker, H. Tags: STKE Research Resources Source Type: news

Starving cancer cells to death
Cisplatin-resistant cancer cells are particularly susceptible to starvation-induced death. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - August 7, 2018 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news

Profiling the origin, dynamics, and function of traction force in B cell activation
B lymphocytes use B cell receptors (BCRs) to recognize membrane-bound antigens to further initiate cell spreading and contraction responses during B cell activation. We combined traction force microscopy and live-cell imaging to profile the origin, dynamics, and function of traction force generation in these responses. We showed that B cell activation required the generation of 10 to 20 nN of traction force when encountering antigens presented by substrates with stiffness values from 0.5 to 1 kPa, which mimic the rigidity of antigen-presenting cells in vivo. Perturbation experiments revealed that F-actin remodeling and myo...
Source: Signal Transduction Knowledge Environment - August 7, 2018 Category: Science Authors: Wang, J., Lin, F., Wan, Z., Sun, X., Lu, Y., Huang, J., Wang, F., Zeng, Y., Chen, Y.-H., Shi, Y., Zheng, W., Li, Z., Xiong, C., Liu, W. Tags: STKE Research Articles Source Type: news

The acid-sensing ion channel ASIC1a mediates striatal synapse remodeling and procedural motor learning
Acid-sensing ion channel 1a (ASIC1a) is abundant in multiple brain regions, including the striatum, which serves as the input nucleus of the basal ganglia and is critically involved in procedural learning and motor memory. We investigated the functional role of ASIC1a in striatal neurons. We found that ASIC1a was critical for striatum-dependent motor coordination and procedural learning by regulating the synaptic plasticity of striatal medium spiny neurons. Global deletion of Asic1a in mice led to increased dendritic spine density but impaired spine morphology and postsynaptic architecture, which were accompanied by the de...
Source: Signal Transduction Knowledge Environment - August 7, 2018 Category: Science Authors: Yu, Z., Wu, Y.-J., Wang, Y.-Z., Liu, D.-S., Song, X.-L., Jiang, Q., Li, Y., Zhang, S., Xu, N.-J., Zhu, M. X., Li, W.-G., Xu, T.-L. Tags: STKE Research Articles Source Type: news

G protein signaling-biased agonism at the {kappa}-opioid receptor is maintained in striatal neurons
Biased agonists of G protein–coupled receptors may present a means to refine receptor signaling in a way that separates side effects from therapeutic properties. Several studies have shown that agonists that activate the -opioid receptor (KOR) in a manner that favors G protein coupling over β-arrestin2 recruitment in cell culture may represent a means to treat pain and itch while avoiding sedation and dysphoria. Although it is attractive to speculate that the bias between G protein signaling and β-arrestin2 recruitment is the reason for these divergent behaviors, little evidence has emerged to show that the...
Source: Signal Transduction Knowledge Environment - August 7, 2018 Category: Science Authors: Ho, J.-H., Stahl, E. L., Schmid, C. L., Scarry, S. M., Aube, J., Bohn, L. M. Tags: STKE Research Articles Source Type: news

Supplementing leukemia therapy
Increasing the amount of dietary histidine enhances the sensitivity of leukemia xenografts in mice to methotrexate. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - July 31, 2018 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

CDK12-mediated transcriptional regulation of noncanonical NF-{kappa}B components is essential for signaling
Members of the family of nuclear factor B (NF-B) transcription factors are critical for multiple cellular processes, including regulating innate and adaptive immune responses, cell proliferation, and cell survival. Canonical NF-B complexes are retained in the cytoplasm by the inhibitory protein IBα, whereas noncanonical NF-B complexes are retained by p100. Although activation of canonical NF-B signaling through the IBα kinase complex is well studied, few regulators of the NF-B–inducing kinase (NIK)–dependent processing of noncanonical p100 to p52 and the subsequent nuclear translocation of p52 have ...
Source: Signal Transduction Knowledge Environment - July 31, 2018 Category: Science Authors: Henry, K. L., Kellner, D., Bajrami, B., Anderson, J. E., Beyna, M., Bhisetti, G., Cameron, T., Capacci, A. G., Bertolotti-Ciarlet, A., Feng, J., Gao, B., Hopkins, B., Jenkins, T., Li, K., May-Dracka, T., Murugan, P., Wei, R., Zeng, W., Allaire, N., Buckle Tags: STKE Research Articles Source Type: news

Editorial retraction
(Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - July 31, 2018 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

Cholesterol sulfate is a DOCK2 inhibitor that mediates tissue-specific immune evasion in the eye
Although immune responses are essential to protect the body from infection, they can also harm tissues. Certain tissues and organs, including the eye, constitute specialized microenvironments that locally inhibit immune reactivity. Dedicator of cytokinesis protein 2 (DOCK2) is a Rac-specific guanine nucleotide exchange factor (GEF) that is predominantly found in hematopoietic cells. DOCK2 plays a key role in immune surveillance because it is essential for the activation and migration of leukocytes. DOCK2 mutations cause severe immunodeficiency in humans. We found that DOCK2-mediated Rac activation and leukocyte migration w...
Source: Signal Transduction Knowledge Environment - July 31, 2018 Category: Science Authors: Sakurai, T., Uruno, T., Sugiura, Y., Tatsuguchi, T., Yamamura, K., Ushijima, M., Hattori, Y., Kukimoto-Niino, M., Mishima-Tsumagari, C., Watanabe, M., Suematsu, M., Fukui, Y. Tags: STKE Research Articles Source Type: news

Caught in the "Akt": Cross-talk between EphA2 and EGFR through the Akt-PIKfyve axis maintains cellular sensitivity to EGF
Activation of EGFR (epidermal growth factor receptor) and Eph receptor often exerts opposing effects on cell functions. In this issue of Science Signaling, Stallaert et al. reveal how cells maintain sustained response to EGF stimulation by replenishing EGFR at the plasma membrane and how conflicting signals from the EphA-ephrin system and EGFR are integrated to coordinate cellular responses, including cell migration and proliferation. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - July 31, 2018 Category: Science Authors: Shi, X., Wang, B. Tags: STKE Focus Source Type: news

Contact inhibitory Eph signaling suppresses EGF-promoted cell migration by decoupling EGFR activity from vesicular recycling
The ability of cells to adapt their response to growth factors in relation to their environment is an essential aspect of tissue development and homeostasis. We found that signaling mediated by the Eph family of receptor tyrosine kinases from cell-cell contacts changed the cellular response to the growth factor EGF by modulating the vesicular trafficking of its receptor, EGFR. Eph receptor activation trapped EGFR in Rab5-positive early endosomes by inhibiting Akt-dependent vesicular recycling. By altering the spatial distribution of EGFR activity, EGF-promoted Akt signaling from the plasma membrane was suppressed, thereby ...
Source: Signal Transduction Knowledge Environment - July 31, 2018 Category: Science Authors: Stallaert, W., Brüggemann, Y., Sabet, O., Baak, L., Gattiglio, M., Bastiaens, P. I. H. Tags: STKE Research Articles Source Type: news

Lysosomes on an acid trip
Acidic environments cause lysosomes to redistribute to the cell periphery, suppressing mTORC1, translation, and circadian oscillations. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - July 24, 2018 Category: Science Authors: Wong, W. Tags: STKE Editors ' Choice Source Type: news

Quantitative analysis of competitive cytokine signaling predicts tissue thresholds for the propagation of macrophage activation
Toll-like receptor (TLR) signaling regulates macrophage activation and effector cytokine propagation in the constrained environment of a tissue. In macrophage populations, TLR4 stimulates the dose-dependent transcription of nuclear factor B (NF-B) target genes. However, using single-RNA counting, we found that individual cells exhibited a wide range (three orders of magnitude) of expression of the gene encoding the proinflammatory cytokine tumor necrosis factor–α (TNF-α). The TLR4-induced TNFA transcriptional response correlated with the extent of NF-B signaling in the cells and their size. We compared th...
Source: Signal Transduction Knowledge Environment - July 24, 2018 Category: Science Authors: Bagnall, J., Boddington, C., England, H., Brignall, R., Downton, P., Alsoufi, Z., Boyd, J., Rowe, W., Bennett, A., Walker, C., Adamson, A., Patel, N. M. X., OCualain, R., Schmidt, L., Spiller, D. G., Jackson, D. A., Müller, W., Muldoon, M., White, Tags: STKE Research Articles Source Type: news

The transcription factor Lef1 switches partners from {beta}-catenin to Smad3 during muscle stem cell quiescence
Skeletal muscle stem cells (MuSCs), also known as satellite cells, persist in adult mammals by entering a state of quiescence (G0) during the early postnatal period. Quiescence is reversed during damage-induced regeneration and re-established after regeneration. Entry of cultured myoblasts into G0 is associated with a specific, reversible induction of Wnt target genes, thus implicating members of the Tcf and Lef1 (Tcf/Lef) transcription factor family, which mediate transcriptional responses to Wnt signaling, in the initiation of quiescence. We found that the canonical Wnt effector β-catenin, which cooperates with Tcf/...
Source: Signal Transduction Knowledge Environment - July 24, 2018 Category: Science Authors: Aloysius, A., DasGupta, R., Dhawan, J. Tags: STKE Research Articles Source Type: news

Mechanisms of inside-out signaling of the high-affinity IgG receptor Fc{gamma}RI
Fc receptors (FcRs) are an important bridge between the innate and adaptive immune system. Fc gamma receptor I (FcRI; CD64), the high-affinity receptor for immunoglobulin G (IgG), plays roles in inflammation, autoimmune responses, and immunotherapy. Stimulation of myeloid cells with cytokines, such as tumor necrosis factor–α ( TNFα) and interferon- ( IFN), increases the binding of FcRI to immune complexes (ICs), such as antibody-opsonized pathogens or tumor cells, through a process known as "inside-out" signaling. Using super-resolution imaging, we found that stimulation of cells with IL-3 also ...
Source: Signal Transduction Knowledge Environment - July 24, 2018 Category: Science Authors: Brandsma, A. M., Schwartz, S. L., Wester, M. J., Valley, C. C., Blezer, G. L. A., Vidarsson, G., Lidke, K. A., ten Broeke, T., Lidke, D. S., Leusen, J. H. W. Tags: STKE Research Articles Source Type: news

Modeling chemotherapy-induced stress to identify rational combination therapies in the DNA damage response pathway
Cells respond to DNA damage by activating complex signaling networks that decide cell fate, promoting not only DNA damage repair and survival but also cell death. We have developed a multiscale computational model that quantitatively links chemotherapy-induced DNA damage response signaling to cell fate. The computational model was trained and calibrated on extensive data from U2OS osteosarcoma cells, including the cell cycle distribution of the initial cell population, signaling data measured by Western blotting, and cell fate data in response to chemotherapy treatment measured by time-lapse microscopy. The resulting mecha...
Source: Signal Transduction Knowledge Environment - July 24, 2018 Category: Science Authors: Alkan, O., Schoeberl, B., Shah, M., Koshkaryev, A., Heinemann, T., Drummond, D. C., Yaffe, M. B., Raue, A. Tags: STKE Research Articles Source Type: news

Multisite phosphorylation is required for sustained interaction with GRKs and arrestins during rapid {mu}-opioid receptor desensitization
We report how specific multisite phosphorylation controlled the dynamics of GRK and β-arrestin interactions with MOR and show how such phosphorylation mediated receptor desensitization. We showed that GRK2/3 was recruited more quickly than was β-arrestin to a DAMGO-activated MOR. β-Arrestin recruitment required GRK2 activity and MOR phosphorylation, but GRK recruitment also depended on the phosphorylation sites in the C-terminal tail, specifically four serine and threonine residues within the 370TREHPSTANT379 motif. Our results also suggested that other residues outside this motif participated in the initial...
Source: Signal Transduction Knowledge Environment - July 17, 2018 Category: Science Authors: Miess, E., Gondin, A. B., Yousuf, A., Steinborn, R., Mösslein, N., Yang, Y., Göldner, M., Ruland, J. G., Bünemann, M., Krasel, C., Christie, M. J., Halls, M. L., Schulz, S., Canals, M. Tags: STKE Research Articles Source Type: news

CRISPR, cancer, and p53
CRISPR-Cas9 genome editing is most efficient in cells lacking functional p53 protein, a phenotype common to cancer cells. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - July 17, 2018 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

Synthetic lethality of TNK2 inhibition in PTPN11-mutant leukemia
The protein tyrosine phosphatase PTPN11 is implicated in the pathogenesis of juvenile myelomonocytic leukemia (JMML), acute myeloid leukemia (AML), and other malignancies. Activating mutations in PTPN11 increase downstream proliferative signaling and cell survival. We investigated the signaling upstream of PTPN11 in JMML and AML cells and found that PTPN11 was activated by the nonreceptor tyrosine/serine/threonine kinase TNK2 and that PTPN11-mutant JMML and AML cells were sensitive to TNK2 inhibition. In cultured human cell–based assays, PTPN11 and TNK2 interacted directly, enabling TNK2 to phosphorylate PTPN11, whic...
Source: Signal Transduction Knowledge Environment - July 17, 2018 Category: Science Authors: Jenkins, C., Luty, S. B., Maxson, J. E., Eide, C. A., Abel, M. L., Togiai, C., Nemecek, E. R., Bottomly, D., McWeeney, S. K., Wilmot, B., Loriaux, M., Chang, B. H., Tyner, J. W. Tags: STKE Research Articles Source Type: news

Unique BIR domain sets determine inhibitor of apoptosis protein-driven cell death and NOD2 complex signal specificity
The mammalian IAPs, X-linked inhibitor of apoptosis protein (XIAP) and cellular inhibitor of apoptosis protein 1 and 2 (cIAP1 and cIAP2), play pivotal roles in innate immune signaling and inflammatory homeostasis, often working in parallel or in conjunction at a signaling complex. IAPs direct both nucleotide-binding oligomerization domain-containing 2 (NOD2) signaling complexes and cell death mechanisms to appropriately regulate inflammation. Although it is known that XIAP is critical for NOD2 signaling and that the loss of cIAP1 and cIAP2 blunts NOD2 activity, it is unclear whether these three highly related proteins can ...
Source: Signal Transduction Knowledge Environment - July 17, 2018 Category: Science Authors: Chirieleison, S. M., Rathkey, J. K., Abbott, D. W. Tags: STKE Research Articles Source Type: news

IKK promotes cytokine-induced and cancer-associated AMPK activity and attenuates phenformin-induced cell death in LKB1-deficient cells
The 5' AMP-activated protein kinase (AMPK) is an energy sensor that is activated upon phosphorylation of Thr172 in its activation loop by the kinase LKB1, CAMKK2, or TAK1. TAK1-dependent AMPK phosphorylation of Thr172 is less well characterized than phosphorylation of this site by LKB1 or CAMKK2. An important target of TAK1 is IB kinase (IKK), which controls the activation of the transcription factor NF-B. We tested the hypothesis that IKK acted downstream of TAK1 to activate AMPK by phosphorylating Thr172. IKK was required for the phosphorylation of Thr172 in AMPK in response to treatment with the inflammatory cytokine IL...
Source: Signal Transduction Knowledge Environment - July 10, 2018 Category: Science Authors: Antonia, R. J., Baldwin, A. S. Tags: STKE Research Articles Source Type: news

The costimulatory molecule CD226 signals through VAV1 to amplify TCR signals and promote IL-17 production by CD4+ T cells
The activation of T cells requires the guanine nucleotide exchange factor VAV1. Using mice in which a tag for affinity purification was attached to endogenous VAV1 molecules, we analyzed by quantitative mass spectrometry the signaling complex that assembles around activated VAV1. Fifty VAV1-binding partners were identified, most of which had not been previously reported to participate in VAV1 signaling. Among these was CD226, a costimulatory molecule of immune cells. Engagement of CD226 induced the tyrosine phosphorylation of VAV1 and synergized with T cell receptor (TCR) signals to specifically enhance the production of i...
Source: Signal Transduction Knowledge Environment - July 10, 2018 Category: Science Authors: Gaud, G., Roncagalli, R., Chaoui, K., Bernard, I., Familiades, J., Colacios, C., Kassem, S., Monsarrat, B., Burlet-Schiltz, O., de Peredo, A. G., Malissen, B., Saoudi, A. Tags: STKE Research Articles Source Type: news

New connections: Putting the brakes on inflammation
By targeting multiple pathways, microRNAs limit inflammation during sepsis. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - July 10, 2018 Category: Science Authors: Williams, E. R. Tags: STKE Editors ' Choice Source Type: news

Mitochondrial redox sensing by the kinase ATM maintains cellular antioxidant capacity
Mitochondria are integral to cellular energy metabolism and ATP production and are involved in regulating many cellular processes. Mitochondria produce reactive oxygen species (ROS), which not only can damage cellular components but also participate in signal transduction. The kinase ATM, which is mutated in the neurodegenerative, autosomal recessive disease ataxia-telangiectasia (A-T), is a key player in the nuclear DNA damage response. However, ATM also performs a redox-sensing function mediated through formation of ROS-dependent disulfide-linked dimers. We found that mitochondria-derived hydrogen peroxide promoted ATM d...
Source: Signal Transduction Knowledge Environment - July 10, 2018 Category: Science Authors: Zhang, Y., Lee, J.-H., Paull, T. T., Gehrke, S., DAlessandro, A., Dou, Q., Gladyshev, V. N., Schroeder, E. A., Steyl, S. K., Christian, B. E., Shadel, G. S. Tags: STKE Research Articles Source Type: news

Nuclear import pathway key to rescuing dominant progerin phenotypes
In this issue of Science Signaling, Larrieu et al. show that an acetyltransferase inhibitor that rescues many dominant nuclear phenotypes caused by progerin, a truncated form of lamin A, does so by releasing the specialized nuclear import receptor TNPO1 from sequestration by microtubules. This release enables TNPO1-dependent import of specific cargoes, including the nuclear pore protein Nup153 and the heterogeneous nuclear ribonucleoprotein hnRNPA1, thus restoring the functionality of nuclear pore complexes, rebalancing the nucleocytoplasmic Ran gradient, and normalizing gene expression. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - July 3, 2018 Category: Science Authors: Wilson, K. L. Tags: STKE Focus Source Type: news

Sunshine for your mind
Moderate exposure to ultraviolet light stimulates glutamate synthesis in the brain and improves learning and memory. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - July 3, 2018 Category: Science Authors: VanHook, A. M. Tags: STKE Editors ' Choice Source Type: news

Inhibition of the acetyltransferase NAT10 normalizes progeric and aging cells by rebalancing the Transportin-1 nuclear import pathway
This study identifies a nuclear import pathway affected in aging and underscores the potential for NAT10 inhibition as a possible therapeutic strategy for HGPS and perhaps also for pathologies associated with normal aging. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - July 3, 2018 Category: Science Authors: Larrieu, D., Vire, E., Robson, S., Breusegem, S. Y., Kouzarides, T., Jackson, S. P. Tags: STKE Research Articles Source Type: news

Tomosyn functions as a PKC{delta}-regulated fusion clamp in mast cell degranulation
Soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) family proteins mediate membrane fusion critical for vesicular transport and cellular secretion. Mast cells rely on SNARE-mediated membrane fusion for degranulation stimulated by crosslinking of immunoglobulin E (IgE) bound to the Fc receptor (FcRI). We investigated the mechanisms downstream of receptor activation that control degranulation. We found that the SNARE binding protein tomosyn-1 (also known as STXBP5) inhibited FcRI-stimulated degranulation of mast cells. After mast cell activation, tomosyn-1 was phosphorylated on serine and thr...
Source: Signal Transduction Knowledge Environment - July 3, 2018 Category: Science Authors: Madera-Salcedo, I. K., Danelli, L., Tiwari, N., Dema, B., Pacreau, E., Vibhushan, S., Birnbaum, J., Agabriel, C., Liabeuf, V., Klingebiel, C., Menasche, G., Macias-Silva, M., Benhamou, M., Charles, N., Gonzalez-Espinosa, C., Vitte, J., Blank, U. Tags: STKE Research Articles Source Type: news

Proteomic analysis of S-nitrosylated nuclear proteins in rat cortical neurons
Neurons modulate gene expression in response to extrinsic signals to enable brain development, cognition, and learning and to process stimuli that regulate systemic physiological functions. This signal-to-gene communication is facilitated by posttranslational modifications such as S-nitrosylation, the covalent attachment of a nitric oxide (NO) moiety to cysteine thiols. In the cerebral cortex, S-nitrosylation of histone deacetylase 2 (HDAC2) is required for gene transcription during neuronal development, but few other nuclear targets of S-nitrosylation have been identified to date. We used S-nitrosothiol resin-assisted cap...
Source: Signal Transduction Knowledge Environment - July 3, 2018 Category: Science Authors: Smith, J. G., Aldous, S. G., Andreassi, C., Cuda, G., Gaspari, M., Riccio, A. Tags: STKE Research Resources Source Type: news

Evolution of human, chicken, alligator, frog, and zebrafish mineralocorticoid receptors: Allosteric influence on steroid specificity
Although multiple steroid ligands of the glucocorticoid, mineralocorticoid, and progestin families bind to and regulate the activity of mineralocorticoid receptors (MRs), the responses to these ligands differ across species. To understand how the different domains of MRs contribute to the ligand-induced activation or inhibition of MR activity, we studied the response to eight steroids (aldosterone, 11-deoxycorticosterone, 11-deoxycortisol, cortisol, corticosterone, progesterone, 19-norprogesterone, and spironolactone) of human, chicken, alligator, frog, and zebrafish full-length MRs and truncated MRs, which lacked the N-te...
Source: Signal Transduction Knowledge Environment - July 3, 2018 Category: Science Authors: Katsu, Y., Oka, K., Baker, M. E. Tags: STKE Research Articles Source Type: news

Thyroid hormone receptor and ERR{alpha} coordinately regulate mitochondrial fission, mitophagy, biogenesis, and function
Thyroid hormone receptor β1 (THRB1) and estrogen-related receptor α (ESRRA; also known as ERRα) both play important roles in mitochondrial activity. To understand their potential interactions, we performed transcriptome and ChIP-seq analyses and found that many genes that were co-regulated by both THRB1 and ESRRA were involved in mitochondrial metabolic pathways. These included oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, and β-oxidation of fatty acids. TH increased ESRRA expression and activity in a THRB1-dependent manner through the induction of the transcriptional coactiv...
Source: Signal Transduction Knowledge Environment - June 26, 2018 Category: Science Authors: Singh, B. K., Sinha, R. A., Tripathi, M., Mendoza, A., Ohba, K., Sy, J. A. C., Xie, S. Y., Zhou, J., Ho, J. P., Chang, C.-y., Wu, Y., Giguere, V., Bay, B.-H., Vanacker, J.-M., Ghosh, S., Gauthier, K., Hollenberg, A. N., McDonnell, D. P., Yen, P. M. Tags: STKE Research Articles Source Type: news

New connections: Reprogramming B cell metabolism
Two key regulators of B cell metabolism are required for effective immune responses. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - June 26, 2018 Category: Science Authors: Foley, J. F. Tags: STKE Editors ' Choice Source Type: news

The plant cell wall integrity maintenance and immune signaling systems cooperate to control stress responses in Arabidopsis thaliana
Cell walls surround all plant cells, and their composition and structure are modified in a tightly controlled, adaptive manner to meet sometimes opposing functional requirements during growth and development. The plant cell wall integrity (CWI) maintenance mechanism controls these functional modifications, as well as responses to cell wall damage (CWD). We investigated how the CWI system mediates responses to CWD in Arabidopsis thaliana. CWD induced by cell wall–degrading enzymes or an inhibitor of cellulose biosynthesis elicited similar, turgor-sensitive stress responses. Phenotypic clustering with 27 genotypes iden...
Source: Signal Transduction Knowledge Environment - June 26, 2018 Category: Science Authors: Engelsdorf, T., Gigli-Bisceglia, N., Veerabagu, M., McKenna, J. F., Vaahtera, L., Augstein, F., Van der Does, D., Zipfel, C., Hamann, T. Tags: STKE Research Articles Source Type: news

MEG3-4 is a miRNA decoy that regulates IL-1{beta} abundance to initiate and then limit inflammation to prevent sepsis during lung infection
Long noncoding RNAs (lncRNAs) regulate gene expression. We investigated the role of lncRNAs in the inflammatory response to bacterial infection in the lungs. We identified the lncRNA MEG3 as a tissue-specific modulator of inflammatory responses during bacterial infection. Among the 10 transcript isoforms of MEG3, transcript 4 (referred to as MEG3-4) encodes the isoform with the lowest abundance in mouse lungs. Nonetheless, we found that MEG3-4 bound to the microRNA miR-138 in a competitive manner with mRNA encoding the proinflammatory cytokine interleukin-1β (IL-1β), thereby increasing IL-1β abundance and in...
Source: Signal Transduction Knowledge Environment - June 26, 2018 Category: Science Authors: Li, R., Fang, L., Pu, Q., Bu, H., Zhu, P., Chen, Z., Yu, M., Li, X., Weiland, T., Bansal, A., Ye, S. Q., Wei, Y., Jiang, J., Wu, M. Tags: STKE Research Articles Source Type: news

PARP12 suppresses Zika virus infection through PARP-dependent degradation of NS1 and NS3 viral proteins
Zika virus infection stimulates a type I interferon (IFN) response in host cells, which suppresses viral replication. Type I IFNs exert antiviral effects by inducing the expression of hundreds of IFN-stimulated genes (ISGs). To screen for antiviral ISGs that restricted Zika virus replication, we individually knocked out 21 ISGs in A549 lung cancer cells and identified PARP12 as a strong inhibitor of Zika virus replication. Our findings suggest that PARP12 mediated the ADP-ribosylation of NS1 and NS3, nonstructural viral proteins that are involved in viral replication and modulating host defense responses. This modification...
Source: Signal Transduction Knowledge Environment - June 19, 2018 Category: Science Authors: Li, L., Zhao, H., Liu, P., Li, C., Quanquin, N., Ji, X., Sun, N., Du, P., Qin, C.-F., Lu, N., Cheng, G. Tags: STKE Research Articles Source Type: news

New connections: Engineering DNA repair vulnerability to treat cancer
Drugs that impair DNA repair broaden cancer sensitivity to common therapies. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - June 19, 2018 Category: Science Authors: Ferrarelli, L. K. Tags: STKE Editors ' Choice Source Type: news

Oligomerization of MrgC11 and {mu}-opioid receptors in sensory neurons enhances morphine analgesia
The μ-opioid receptor (MOR) agonist morphine is commonly used for pain management, but it has severe adverse effects and produces analgesic tolerance. Thus, alternative ways of stimulating MOR activity are needed. We found that MrgC11, a sensory neuron–specific G protein–coupled receptor, may form heteromeric complexes with MOR. Peptide-mediated activation of MrgC11 enhanced MOR recycling by inducing coendocytosis and sorting of MOR for membrane reinsertion. MrgC11 activation also inhibited the coupling of MOR to β-arrestin-2 and enhanced the morphine-dependent inhibition of cAMP production. Intrathecal...
Source: Signal Transduction Knowledge Environment - June 19, 2018 Category: Science Authors: He, S.-Q., Xu, Q., Tiwari, V., Yang, F., Anderson, M., Chen, Z., Grenald, S. A., Raja, S. N., Dong, X., Guan, Y. Tags: STKE Research Articles Source Type: news

Inhibition of somatosensory mechanotransduction by annexin A6
Mechanically activated, slowly adapting currents in sensory neurons have been linked to noxious mechanosensation. The conotoxin NMB-1 (noxious mechanosensation blocker-1) blocks such currents and inhibits mechanical pain. Using a biotinylated form of NMB-1 in mass spectrometry analysis, we identified 67 binding proteins in sensory neurons and a sensory neuron–derived cell line, of which the top candidate was annexin A6, a membrane-associated calcium-binding protein. Annexin A6–deficient mice showed increased sensitivity to mechanical stimuli. Sensory neurons from these mice showed increased activity of the cati...
Source: Signal Transduction Knowledge Environment - June 19, 2018 Category: Science Authors: Raouf, R., Lolignier, S., Sexton, J. E., Millet, Q., Santana-Varela, S., Biller, A., Fuller, A. M., Pereira, V., Choudhary, J. S., Collins, M. O., Moss, S. E., Lewis, R., Tordo, J., Henckaerts, E., Linden, M., Wood, J. N. Tags: STKE Research Articles Source Type: news

Regulation of thymocyte trafficking by Tagap, a GAP domain protein linked to human autoimmunity
Multiple autoimmune pathologies are associated with single-nucleotide polymorphisms of the human gene TAGAP, which encodes TAGAP, a guanosine triphosphatase (GTPase)–activating protein. We showed in mice that Tagap-mediated signaling by the sema3E/plexin-D1 ligand-receptor complex attenuates thymocytes’ adhesion to the cortex through their β1-containing integrins. By promoting thymocyte detachment within the cortex of the thymus, Tagap-mediated signaling enabled their translocation to the medulla, which is required for continued thymic selection. Tagap physically interacted with the cytoplasmic domain of p...
Source: Signal Transduction Knowledge Environment - June 12, 2018 Category: Science Authors: Duke-Cohan, J. S., Ishikawa, Y., Yoshizawa, A., Choi, Y.-I., Lee, C.-N., Acuto, O., Kissler, S., Reinherz, E. L. Tags: STKE Research Articles Source Type: news

A coupled-clock system drives the automaticity of human sinoatrial nodal pacemaker cells
The spontaneous rhythmic action potentials generated by the sinoatrial node (SAN), the primary pacemaker in the heart, dictate the regular and optimal cardiac contractions that pump blood around the body. Although the heart rate of humans is substantially slower than that of smaller experimental animals, current perspectives on the biophysical mechanisms underlying the automaticity of sinoatrial nodal pacemaker cells (SANCs) have been gleaned largely from studies of animal hearts. Using human SANCs, we demonstrated that spontaneous rhythmic local Ca2+ releases generated by a Ca2+ clock were coupled to electrogenic surface ...
Source: Signal Transduction Knowledge Environment - June 12, 2018 Category: Science Authors: Tsutsui, K., Monfredi, O. J., Sirenko-Tagirova, S. G., Maltseva, L. A., Bychkov, R., Kim, M. S., Ziman, B. D., Tarasov, K. V., Tarasova, Y. S., Zhang, J., Wang, M., Maltsev, A. V., Brennan, J. A., Efimov, I. R., Stern, M. D., Maltsev, V. A., Lakatta, E. G Tags: STKE Research Articles Source Type: news

A painful takedown of host defenses
A flesh-eating bacterium disables host defenses by inducing pain-sensing neurons to release a neutrophil-inhibiting peptide. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - June 12, 2018 Category: Science Authors: Wong, W. Tags: STKE Editors ' Choice Source Type: news

"Disruptor" residues in the regulator of G protein signaling (RGS) R12 subfamily attenuate the inactivation of G{alpha} subunits
Understanding the molecular basis of interaction specificity between RGS (regulator of G protein signaling) proteins and heterotrimeric (αβ) G proteins would enable the manipulation of RGS-G protein interactions, explore their functions, and effectively target them therapeutically. RGS proteins are classified into four subfamilies (R4, R7, RZ, and R12) and function as negative regulators of G protein signaling by inactivating Gα subunits. We found that the R12 subfamily members RGS10 and RGS14 had lower activity than most R4 subfamily members toward the Gi subfamily member Gαo. Using structure-based ...
Source: Signal Transduction Knowledge Environment - June 12, 2018 Category: Science Authors: Asli, A., Sadiya, I., Avital-Shacham, M., Kosloff, M. Tags: STKE Research Articles Source Type: news

SOCE mediated by STIM and Orai is essential for pacemaker activity in the interstitial cells of Cajal in the gastrointestinal tract
Electrical pacemaker activity generates phasic contractions and motility patterns such as segmentation and peristalsis in the gastrointestinal tract. Pacemaker currents are generated in interstitial cells of Cajal (ICC), which release Ca2+ from intracellular stores that stimulates Ca2+-activated Cl– channels (CaCCs) in the plasma membrane. Thus, Ca2+ stores must be maintained to sustain pacemaker activity. Store-operated Ca2+ entry (SOCE) facilitates the refilling of Ca2+ stores by a mechanism dependent upon interactions between STIM and Orai proteins. We investigated the role of SOCE in ICC pacemaker activity. Reint...
Source: Signal Transduction Knowledge Environment - June 12, 2018 Category: Science Authors: Zheng, H., Drumm, B. T., Earley, S., Sung, T. S., Koh, S. D., Sanders, K. M. Tags: STKE Research Articles Source Type: news

K63-linked polyubiquitin chains bind to DNA to facilitate DNA damage repair
Polyubiquitylation is canonically viewed as a posttranslational modification that governs protein stability or protein-protein interactions, in which distinct polyubiquitin linkages ultimately determine the fate of modified protein(s). We explored whether polyubiquitin chains have any nonprotein-related function. Using in vitro pull-down assays with synthetic materials, we found that polyubiquitin chains with the Lys63 (K63) linkage bound to DNA through a motif we called the "DNA-interacting patch" (DIP), which is composed of the adjacent residues Thr9, Lys11, and Glu34. Upon DNA damage, the binding of K63-linked...
Source: Signal Transduction Knowledge Environment - June 5, 2018 Category: Science Authors: Liu, P., Gan, W., Su, S., Hauenstein, A. V., Fu, T.-m., Brasher, B., Schwerdtfeger, C., Liang, A. C., Xu, M., Wei, W. Tags: STKE Research Articles Source Type: news

The channel-kinase TRPM7 regulates antigen gathering and internalization in B cells
Members of the transient receptor potential (TRP) family of ion channels are cellular sensors involved in numerous physiological and pathological processes. We identified the TRP subfamily M member 7 (TRPM7) channel-kinase as a previously uncharacterized regulator of B cell activation. We showed that TRPM7 played a critical role in the early events of B cell activation through both its ion channel and kinase functions. DT40 B cells deficient in TRPM7 or expressing a kinase-deficient mutant of TRPM7 showed defective gathering of antigen and prolonged B cell receptor (BCR) signaling. We showed that lipid metabolism was alter...
Source: Signal Transduction Knowledge Environment - June 5, 2018 Category: Science Authors: Krishnamoorthy, M., Wasim, L., Buhari, F. H. M., Zhao, T., Mahtani, T., Ho, J., Kang, S., Deason-Towne, F., Perraud, A.-L., Schmitz, C., Treanor, B. Tags: STKE Research Articles Source Type: news

Highlight: Distinct functions of the ion channel-kinase TRPM7
Two studies in this week’s issue of Science Signaling identify distinct activities of the ion channel–kinase TRPM7 that control discrete functions in B cells. (Source: Signal Transduction Knowledge Environment)
Source: Signal Transduction Knowledge Environment - June 5, 2018 Category: Science Authors: Williams, E. Tags: STKE Editors ' Choice Source Type: news