Hypusine biosynthesis in β cells links polyamine metabolism to facultative cellular proliferation to maintain glucose homeostasis.
Hypusine biosynthesis in β cells links polyamine metabolism to facultative cellular proliferation to maintain glucose homeostasis. Sci Signal. 2019 Dec 03;12(610): Authors: Levasseur EM, Yamada K, Piñeros AR, Wu W, Syed F, Orr KS, Anderson-Baucum E, Mastracci TL, Maier B, Mosley AL, Liu Y, Bernal-Mizrachi E, Alonso LC, Scott D, Garcia-Ocaña A, Tersey SA, Mirmira RG Abstract 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 ...
Source: Science Signaling - December 3, 2019 Category: Biomedical Science Authors: Levasseur EM, Yamada K, Piñeros AR, Wu W, Syed F, Orr KS, Anderson-Baucum E, Mastracci TL, Maier B, Mosley AL, Liu Y, Bernal-Mizrachi E, Alonso LC, Scott D, Garcia-Ocaña A, Tersey SA, Mirmira RG Tags: Sci Signal Source Type: research

Biased M1 receptor-positive allosteric modulators reveal role of phospholipase D in M1-dependent rodent cortical plasticity.
Abstract 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 (P...
Source: Science Signaling - December 3, 2019 Category: Biomedical Science Authors: Moran SP, Xiang Z, Doyle CA, Maksymetz J, Lv X, Faltin S, Fisher NM, Niswender CM, Rook JM, Lindsley CW, Conn PJ Tags: Sci Signal Source Type: research

The interaction of ceramide 1-phosphate with group IVA cytosolic phospholipase A2 coordinates acute wound healing and repair.
Abstract 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 i...
Source: Science Signaling - December 3, 2019 Category: Biomedical Science Authors: MacKnight HP, Stephenson DJ, Hoeferlin LA, Benusa SD, DeLigio JT, Maus KD, Ali AN, Wayne JS, Park MA, Hinchcliffe EH, Brown RE, Ryan JJ, Diegelmann RF, Chalfant CE Tags: Sci Signal Source Type: research

The human secretome.
ring;nberg A, Dodig-Crnkovic T, Pin E, Zwahlen M, Oksvold P, von Feilitzen K, Häussler RS, Hong MG, Lindskog C, Ponten F, Katona B, Vuu J, Lindström E, Nielsen J, Robinson J, Ayoglu B, Mahdessian D, Sullivan D, Thul P, Danielsson F, Stadler C, Lundberg E, Bergström G, Gummesson A, Voldborg BG, Tegel H, Hober S, Forsström B, Schwenk JM, Fagerberg L, Sivertsson Å Abstract 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 diagnosti...
Source: Science Signaling - November 26, 2019 Category: Biomedical Science Authors: Uhlén M, Karlsson MJ, Hober A, Svensson AS, 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, Lundqvist M, Malm M, Volk AL, Nilsson P, Månberg A, Tags: Sci Signal Source Type: research

Thiol-based direct threat sensing by the stress-activated protein kinase Hog1.
Abstract 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 Ho...
Source: Science Signaling - November 26, 2019 Category: Biomedical Science Authors: Guerra-Moreno A, Prado MA, Ang J, Schnell HM, Micoogullari Y, Paulo JA, Finley D, Gygi SP, Hanna J Tags: Sci Signal Source Type: research

PKR-dependent cytosolic cGAS foci are necessary for intracellular DNA sensing.
Abstract 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 interfer...
Source: Science Signaling - November 26, 2019 Category: Biomedical 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: Sci Signal Source Type: research

Sequential activation of STIM1 links Ca2+ with luminal domain unfolding.
Abstract 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...
Source: Science Signaling - November 19, 2019 Category: Biomedical 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 PB, Romanin C, Ettrich RH, Schindl R Tags: Sci Signal Source Type: research

Dynamic palmitoylation controls the microdomain localization of the DKK1 receptors CKAP4 and LRP6.
Abstract 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 CK...
Source: Science Signaling - November 19, 2019 Category: Biomedical Science Authors: Sada R, Kimura H, Fukata Y, Fukata M, Yamamoto H, Kikuchi A Tags: Sci Signal Source Type: research

Translocation of TRPV4-PI3K γ complexes to the plasma membrane drives myofibroblast transdifferentiation.
Translocation of TRPV4-PI3Kγ complexes to the plasma membrane drives myofibroblast transdifferentiation. Sci Signal. 2019 Nov 12;12(607): Authors: Grove LM, Mohan ML, Abraham S, Scheraga RG, Southern BD, Crish JF, Naga Prasad SV, Olman MA Abstract Myofibroblasts are key contributors to pathological fibrotic conditions of several major organs. The transdifferentiation of fibroblasts into myofibroblasts requires both a mechanical signal and transforming growth factor-β (TGF-β) signaling. The cation channel transient receptor potential vanilloid 4 (TRPV4) is a critical mediator of myofibr...
Source: Science Signaling - November 12, 2019 Category: Biomedical Science Authors: Grove LM, Mohan ML, Abraham S, Scheraga RG, Southern BD, Crish JF, Naga Prasad SV, Olman MA Tags: Sci Signal Source Type: research

The ALK-1/SMAD/ATOH8 axis attenuates hypoxic responses and protects against the development of pulmonary arterial hypertension.
Abstract Dysregulated bone morphogenetic protein (BMP) signaling in endothelial cells (ECs) is implicated in vascular diseases such as pulmonary arterial hypertension (PAH). Here, we showed that the transcription factor ATOH8 was a direct target of SMAD1/5 and was induced in a manner dependent on BMP but independent of Notch, another critical signaling pathway in ECs. In zebrafish and mice, inactivation of Atoh8 did not cause an arteriovenous malformation-like phenotype, which may arise because of dysregulated Notch signaling. In contrast, Atoh8-deficient mice exhibited a phenotype mimicking PAH, which included in...
Source: Science Signaling - November 12, 2019 Category: Biomedical Science Authors: Morikawa M, Mitani Y, Holmborn K, Kato T, Koinuma D, Maruyama J, Vasilaki E, Sawada H, Kobayashi M, Ozawa T, Morishita Y, Bessho Y, Maeda S, Ledin J, Aburatani H, Kageyama R, Maruyama K, Heldin CH, Miyazono K Tags: Sci Signal Source Type: research

Amino acid starvation enhances vaccine efficacy by augmenting neutralizing antibody production.
Abstract Specific reduction in the intake of proteins or amino acids (AAs) offers enormous health benefits, including increased life span, protection against age-associated disorders, and improved metabolic fitness and immunity. Cells respond to conditions of AA starvation by activating the amino acid starvation response (AAR). Here, we showed that mimicking AAR with halofuginone (HF) enhanced the magnitude and affinity of neutralizing, antigen-specific antibody responses in mice immunized with dengue virus envelope domain III protein (DENVrEDIII), a potent vaccine candidate against DENV. HF enhanced the formation...
Source: Science Signaling - November 12, 2019 Category: Biomedical Science Authors: Afroz S, Shama, Battu S, Matin S, Solouki S, Elmore JP, Minhas G, Huang W, August A, Khan N Tags: Sci Signal Source Type: research

TFEB drives PGC-1 α expression in adipocytes to protect against diet-induced metabolic dysfunction.
In this study, we sought to characterize the role of TFEB in adipocyte and adipose tissue physiology and evaluate the therapeutic potential of adipocyte-specific TFEB overexpression in obesity. We demonstrated that mice with adipocyte-specific TFEB overexpression (Adipo-TFEB) were protected from diet-induced obesity, insulin resistance, and metabolic sequelae. Adipo-TFEB mice were lean primarily through increased metabolic rate, suggesting a role for adipose tissue browning and enhanced nonshivering thermogenesis in fat. Transcriptional characterization revealed that TFEB targeted genes involved in adipose tissue browning ...
Source: Science Signaling - November 5, 2019 Category: Biomedical Science Authors: Evans TD, Zhang X, Jeong SJ, He A, Song E, Bhattacharya S, Holloway KB, Lodhi IJ, Razani B Tags: Sci Signal Source Type: research

Extension of the Notch intracellular domain ankyrin repeat stack by NRARP promotes feedback inhibition of Notch signaling.
Abstract Canonical Notch signaling relies on regulated proteolysis of the receptor Notch to generate a nuclear effector that induces the transcription of Notch-responsive genes. In higher organisms, one Notch-responsive gene that is activated in many different cell types encodes the Notch-regulated ankyrin repeat protein (NRARP), which acts as a negative feedback regulator of Notch responses. Here, we showed that NRARP inhibited the growth of Notch-dependent T cell acute lymphoblastic leukemia (T-ALL) cell lines and bound directly to the core Notch transcriptional activation complex (NTC), requiring both the trans...
Source: Science Signaling - November 5, 2019 Category: Biomedical Science Authors: Jarrett SM, Seegar TCM, Andrews M, Adelmant G, Marto JA, Aster JC, Blacklow SC Tags: Sci Signal Source Type: research

Nucleotide exchange-dependent and nucleotide exchange-independent functions of plant heterotrimeric GTP-binding proteins.
Abstract Heterotrimeric guanine nucleotide-binding proteins (G proteins), which are composed of α, β, and γ subunits, are versatile, guanine nucleotide-dependent, molecular on-off switches. In animals and fungi, the exchange of GDP for GTP on Gα controls G protein activation and is crucial for normal cellular responses to diverse extracellular signals. The model plant Arabidopsis thaliana has a single canonical Gα subunit, AtGPA1. We found that, in planta, the constitutively active, GTP-bound AtGPA1(Q222L) mutant and the nucleotide-free AtGPA1(S52C) mutant interacted with Gβ&gamma...
Source: Science Signaling - November 5, 2019 Category: Biomedical Science Authors: Maruta N, Trusov Y, Chakravorty D, Urano D, Assmann SM, Botella JR Tags: Sci Signal Source Type: research

iRhom2 and TNF: Partners or enemies?
Abstract iRhom2 is an essential cofactor for ADAM17, the metalloprotease that sheds both the proinflammatory cytokine tumor necrosis factor-α (TNF-α) and TNF receptors (TNFRs) from the cell surface. In this issue of Science Signaling, Sundaram et al. demonstrate a protective role for iRhom2 in promoting ADAM17-mediated shedding of TNFRs in hepatic stellate cells, which reduces TNFR signaling and liver fibrosis in response to injury. PMID: 31662485 [PubMed - in process] (Source: Science Signaling)
Source: Science Signaling - October 29, 2019 Category: Biomedical Science Authors: Badenes M, Adrain C Tags: Sci Signal Source Type: research

iRhom2 inhibits bile duct obstruction-induced liver fibrosis.
AA, Lang KS, Lang PA Abstract Chronic liver disease can induce prolonged activation of hepatic stellate cells, which may result in liver fibrosis. Inactive rhomboid protein 2 (iRhom2) is required for the maturation of A disintegrin and metalloprotease 17 (ADAM17, also called TACE), which is responsible for the cleavage of membrane-bound tumor necrosis factor-α (TNF-α) and its receptors (TNFRs). Here, using the murine bile duct ligation (BDL) model, we showed that the abundance of iRhom2 and activation of ADAM17 increased during liver fibrosis. Consistent with this, concentrations of ADAM17 substrates ...
Source: Science Signaling - October 29, 2019 Category: Biomedical Science Authors: Sundaram B, Behnke K, Belancic A, Al-Salihi MA, Thabet Y, Polz R, Pellegrino R, Zhuang Y, Shinde PV, Xu HC, Vasilevska J, Longerich T, Herebian D, Mayatepek E, Bock HH, May P, Kordes C, Aghaeepour N, Mak TW, Keitel V, Häussinger D, Scheller J, Pandyra AA Tags: Sci Signal Source Type: research

TLR7 and TLR8 activate distinct pathways in monocytes during RNA virus infection.
Abstract Human blood CD14+ monocytes are bone marrow-derived white blood cells that sense and respond to pathogens. Although innate immune activation by RNA viruses preferentially occurs through intracellular RIG-I-like receptors, other nucleic acid recognition receptors, such as Toll-like receptors (TLRs), play a role in finely programming the final outcome of virus infection. Here, we dissected how human monocytes respond to infection with either Coxsackie (CV), encephalomyocarditis (EMCV), influenza A (IAV), measles (MV), Sendai (SV), or vesicular stomatitis (VSV) virus. We found that in monocytes, type I inter...
Source: Science Signaling - October 29, 2019 Category: Biomedical Science Authors: de Marcken M, Dhaliwal K, Danielsen AC, Gautron AS, Dominguez-Villar M Tags: Sci Signal Source Type: research

An engineered pathway for N-hydroxy-pipecolic acid synthesis enhances systemic acquired resistance in tomato.
Abstract Systemic acquired resistance (SAR) is a powerful immune response that triggers broad-spectrum disease resistance throughout a plant. In the model plant Arabidopsis thaliana, long-distance signaling and SAR activation in uninfected tissues occur without circulating immune cells and instead rely on the metabolite N-hydroxy-pipecolic acid (NHP). Engineering SAR in crop plants would enable external control of a plant's ability to mount a global defense response upon sudden changes in the environment. Such a metabolite-engineering approach would require the molecular machinery for producing and responding to N...
Source: Science Signaling - October 22, 2019 Category: Biomedical Science Authors: Holmes EC, Chen YC, Sattely ES, Mudgett MB Tags: Sci Signal Source Type: research

Induction of metabolic quiescence defines the transitional to follicular B cell switch.
Abstract Transitional B cells must actively undergo selection for self-tolerance before maturing into their resting follicular B cell successors. We found that metabolic quiescence was acquired at the follicular B cell stage in both humans and mice. In follicular B cells, the expression of genes involved in ribosome biogenesis, aerobic respiration, and mammalian target of rapamycin complex 1 (mTORC1) signaling was reduced when compared to that in transitional B cells. Functional metabolism studies, profiling of whole-cell metabolites, and analysis of cell surface proteins in human B cells suggested that this trans...
Source: Science Signaling - October 22, 2019 Category: Biomedical Science Authors: Farmer JR, Allard-Chamard H, Sun N, Ahmad M, Bertocchi A, Mahajan VS, Aicher T, Arnold J, Benson MD, Morningstar J, Barmettler S, Yuen G, Murphy SJH, Walter JE, Ghebremichael M, Shalek AK, Batista F, Gerszten R, Pillai S Tags: Sci Signal Source Type: research

CD45 functions as a signaling gatekeeper in T cells.
Abstract T cells require the protein tyrosine phosphatase CD45 to detect and respond to antigen because it activates the Src family kinase Lck, which phosphorylates the T cell antigen receptor (TCR) complex. CD45 activates Lck by opposing the negative regulatory kinase Csk. Paradoxically, CD45 has also been implicated in suppressing TCR signaling by dephosphorylating the same signaling motifs within the TCR complex upon which Lck acts. We sought to reconcile these observations using chemical and genetic perturbations of the Csk/CD45 regulatory axis incorporated with computational analyses. Specifically, we titrate...
Source: Science Signaling - October 22, 2019 Category: Biomedical Science Authors: Courtney AH, Shvets AA, Lu W, Griffante G, Mollenauer M, Horkova V, Lo WL, Yu S, Stepanek O, Chakraborty AK, Weiss A Tags: Sci Signal Source Type: research

Impaired regulation of KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathology.
Abstract KCC2 is a vital neuronal K+/Cl- cotransporter that is implicated in the etiology of numerous neurological diseases. In normal cells, KCC2 undergoes developmental dephosphorylation at Thr906 and Thr1007 We engineered mice with heterozygous phosphomimetic mutations T906E and T1007E (KCC2E/+ ) to prevent the normal developmental dephosphorylation of these sites. Immature (postnatal day 15) but not juvenile (postnatal day 30) KCC2E/+ mice exhibited altered GABAergic inhibition, an increased glutamate/GABA synaptic ratio, and greater susceptibility to seizure. KCC2E/+ mice also had abnormal ultrasonic vocaliza...
Source: Science Signaling - October 15, 2019 Category: Biomedical Science Authors: Pisella LI, Gaiarsa JL, Diabira D, Zhang J, Khalilov I, Duan J, Kahle KT, Medina I Tags: Sci Signal Source Type: research

Tuning the regulator: Phosphorylation of KCC2 at two specific sites is critical for neurodevelopment.
Abstract The K+/Cl- cotransporter KCC2 is a molecular switch between excitatory and inhibitory effects of GABAergic inputs into neurons. In a pair of exciting studies, Watanabe et al. and Pisella et al. elucidate the role of KCC2 dephosphorylation in this process and reveal its consequences for neurodevelopment and nervous system pathology. PMID: 31615900 [PubMed - in process] (Source: Science Signaling)
Source: Science Signaling - October 15, 2019 Category: Biomedical Science Authors: Zamponi GW Tags: Sci Signal Source Type: research

Developmentally regulated KCC2 phosphorylation is essential for dynamic GABA-mediated inhibition and survival.
Abstract Despite its importance for γ-aminobutyric acid (GABA) inhibition and involvement in neurodevelopmental disease, the regulatory mechanisms of the K+/Cl- cotransporter KCC2 (encoded by SLC12A5) during maturation of the central nervous system (CNS) are not entirely understood. Here, we applied quantitative phosphoproteomics to systematically map sites of KCC2 phosphorylation during CNS development in the mouse. KCC2 phosphorylation at Thr906 and Thr1007, which inhibits KCC2 activity, underwent dephosphorylation in parallel with the GABA excitatory-inhibitory sequence in vivo. Knockin mice expressing th...
Source: Science Signaling - October 15, 2019 Category: Biomedical Science Authors: Watanabe M, Zhang J, Mansuri MS, Duan J, Karimy JK, Delpire E, Alper SL, Lifton RP, Fukuda A, Kahle KT Tags: Sci Signal Source Type: research

The Ca2+ export pump PMCA clears near-membrane Ca2+ to facilitate store-operated Ca2+ entry and NFAT activation.
Abstract Ca2+ signals, which facilitate pluripotent changes in cell fate, reflect the balance between cation entry and export. We found that overexpression of either isoform of the Ca2+-extruding plasma membrane calcium ATPase 4 (PMCA4) pump in Jurkat T cells unexpectedly increased activation of the Ca2+-dependent transcription factor nuclear factor of activated T cells (NFAT). Coexpression of the endoplasmic reticulum-resident Ca2+ sensor stromal interaction molecule 1 (STIM1) with the PMCA4b splice variant further enhanced NFAT activity; however, coexpression with PMCA4a depressed NFAT. No PMCA4 splice variant d...
Source: Science Signaling - October 8, 2019 Category: Biomedical Science Authors: Go CK, Hooper R, Aronson MR, Schultz B, Cangoz T, Nemani N, Zhang Y, Madesh M, Soboloff J Tags: Sci Signal Source Type: research

CARD9 mediates dendritic cell-induced development of Lyn deficiency-associated autoimmune and inflammatory diseases.
Abstract CARD9 is an immune adaptor protein in myeloid cells that is involved in C-type lectin signaling and antifungal immunity. CARD9 is implicated in autoimmune and inflammatory-related diseases, such as rheumatoid arthritis, IgA nephropathy, ankylosing spondylitis, and inflammatory bowel disease (IBD). Given that Lyn-deficient (Lyn-/-) mice are susceptible to both autoimmunity and IBD, we investigated the immunological role of CARD9 in the development of these diseases using the Lyn-/- mouse model. We found that genetic deletion of CARD9 was sufficient to reduce the development of both spontaneous autoimmune d...
Source: Science Signaling - October 8, 2019 Category: Biomedical Science Authors: Ma J, Abram CL, Hu Y, Lowell CA Tags: Sci Signal Source Type: research

T cell-derived soluble glycoprotein GPIb α mediates PGE2 production in human monocytes activated with the vaccine adjuvant MDP.
T cell-derived soluble glycoprotein GPIbα mediates PGE2 production in human monocytes activated with the vaccine adjuvant MDP. Sci Signal. 2019 Oct 08;12(602): Authors: Liu F, Endo Y, Romantseva T, Wu WW, Akue A, Shen RF, Golding H, Zaitseva M Abstract Vaccine adjuvants containing analogs of microbial products activate pattern recognition receptors (PRRs) on antigen-presenting cells, including monocytes and macrophages, which can cause prostaglandin E2 (PGE2) release and consequently undesired inflammatory responses and fever in vaccine recipients. Here, we studied the mechanism of PGE2 producti...
Source: Science Signaling - October 8, 2019 Category: Biomedical Science Authors: Liu F, Endo Y, Romantseva T, Wu WW, Akue A, Shen RF, Golding H, Zaitseva M Tags: Sci Signal Source Type: research

HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species.
Abstract Inactivation of the VHL tumor suppressor gene is the signature initiating event in clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, and causes the accumulation of hypoxia-inducible factor 2α (HIF-2α). HIF-2α inhibitors are effective in some ccRCC cases, but both de novo and acquired resistance have been observed in the laboratory and in the clinic. Here, we identified synthetic lethality between decreased activity of cyclin-dependent kinases 4 and 6 (CDK4/6) and VHL inactivation in two species (human and Drosophila) and across diverse human ccRCC cell lines...
Source: Science Signaling - October 1, 2019 Category: Biomedical Science Authors: Nicholson HE, Tariq Z, Housden BE, Jennings RB, Stransky LA, Perrimon N, Signoretti S, Kaelin WG Tags: Sci Signal Source Type: research

LGP2 binds to PACT to regulate RIG-I- and MDA5-mediated antiviral responses.
We described a point mutation within LGP2 that disrupted the LGP2-PACT interaction and led to the loss of LGP2-mediated regulation of RIG-I and MDA5 signaling. These results suggest a model in which the LGP2-PACT interaction regulates the inflammatory responses mediated by RIG-I and MDA5 and enables the cellular RNA-silencing machinery to coordinate with the innate immune response. PMID: 31575732 [PubMed - in process] (Source: Science Signaling)
Source: Science Signaling - October 1, 2019 Category: Biomedical Science Authors: Sanchez David RY, Combredet C, Najburg V, Millot GA, Beauclair G, Schwikowski B, Léger T, Camadro JM, Jacob Y, Bellalou J, Jouvenet N, Tangy F, Komarova AV Tags: Sci Signal Source Type: research

Brain-derived neurotrophic factor stimulation of T-type Ca2+ channels in sensory neurons contributes to increased peripheral pain sensitivity.
Abstract Although brain-derived neurotrophic factor (BDNF) is implicated in the nociceptive signaling of peripheral sensory neurons, the underlying mechanisms remain largely unknown. Here, we elucidated the effects of BDNF on the neuronal excitability of trigeminal ganglion (TG) neurons and the pain sensitivity of rats mediated by T-type Ca2+ channels. BDNF reversibly and dose-dependently enhanced T-type channel currents through the activation of tropomyosin receptor kinase B (TrkB). Antagonism of phosphatidylinositol 3-kinase (PI3K) but not of its downstream target, the kinase AKT, abolished the BDNF-induced T-ty...
Source: Science Signaling - September 24, 2019 Category: Biomedical Science Authors: Wang H, Wei Y, Pu Y, Jiang D, Jiang X, Zhang Y, Tao J Tags: Sci Signal Source Type: research

A systems mechanism for KRAS mutant allele-specific responses to targeted therapy.
Abstract Cancer treatment decisions are increasingly guided by which specific genes are mutated within each patient's tumor. For example, agents inhibiting the epidermal growth factor receptor (EGFR) benefit many colorectal cancer (CRC) patients, with the general exception of those whose tumor includes a KRAS mutation. However, among the various KRAS mutations, that which encodes the G13D mutant protein (KRASG13D) behaves differently; for unknown reasons, KRASG13D CRC patients benefit from the EGFR-blocking antibody cetuximab. Controversy surrounds this observation, because it contradicts the well-established mech...
Source: Science Signaling - September 24, 2019 Category: Biomedical Science Authors: McFall T, Diedrich JK, Mengistu M, Littlechild SL, Paskvan KV, Sisk-Hackworth L, Moresco JJ, Shaw AS, Stites EC Tags: Sci Signal Source Type: research

Full focus on calcium.
Abstract Intracellular calcium (Ca2+) signals are of prime importance for cellular function and behavior and are underpinned by a plethora of Ca2+ channels, pumps, transporters, and binding proteins that are regulated in complex ways. A series of biennial meetings, the International Meetings of the European Calcium Society (ECS), focuses on a better understanding of these complex mechanisms in the framework of cellular and organismal (patho)physiology. PMID: 31530730 [PubMed - in process] (Source: Science Signaling)
Source: Science Signaling - September 17, 2019 Category: Biomedical Science Authors: Parys JB, Guse AH Tags: Sci Signal Source Type: research

Tumor-derived TGF- β inhibits mitochondrial respiration to suppress IFN-γ production by human CD4+ T cells.
Tumor-derived TGF-β inhibits mitochondrial respiration to suppress IFN-γ production by human CD4+ T cells. Sci Signal. 2019 Sep 17;12(599): Authors: Dimeloe S, Gubser P, Loeliger J, Frick C, Develioglu L, Fischer M, Marquardsen F, Bantug GR, Thommen D, Lecoultre Y, Zippelius A, Langenkamp A, Hess C Abstract Transforming growth factor-β (TGF-β) is produced by tumors, and increased amounts of this cytokine in the tumor microenvironment and serum are associated with poor patient survival. TGF-β-mediated suppression of antitumor T cell responses contributes to tumor growth and su...
Source: Science Signaling - September 17, 2019 Category: Biomedical Science Authors: Dimeloe S, Gubser P, Loeliger J, Frick C, Develioglu L, Fischer M, Marquardsen F, Bantug GR, Thommen D, Lecoultre Y, Zippelius A, Langenkamp A, Hess C Tags: Sci Signal Source Type: research

Targeting of host cell receptor tyrosine kinases by intracellular pathogens.
Abstract Intracellular pathogens use complex and tightly regulated processes to enter host cells. Upon initial interactions with signaling proteins at the surface of target cells, intracellular microbes activate and co-opt specific host signaling pathways that mediate cell surface-cytosol communications to facilitate pathogen internalization. Here, we discuss the roles of host receptor tyrosine kinases (RTKs) in the establishment of productive infections by major intracellular pathogens. We evaluate the gaps in the current understanding of this process and propose a comprehensive approach for assessing the role of...
Source: Science Signaling - September 17, 2019 Category: Biomedical Science Authors: Haqshenas G, Doerig C Tags: Sci Signal Source Type: research

Engineering γδT cells limits tonic signaling associated with chimeric antigen receptors.
Engineering γδT cells limits tonic signaling associated with chimeric antigen receptors. Sci Signal. 2019 Sep 10;12(598): Authors: Fisher J, Sharma R, Don DW, Barisa M, Hurtado MO, Abramowski P, Porter L, Day W, Borea R, Inglott S, Anderson J, Pe'er D Abstract Despite the benefits of chimeric antigen receptor (CAR)-T cell therapies against lymphoid malignancies, responses in solid tumors have been more limited and off-target toxicities have been more marked. Among the possible design limitations of CAR-T cells for cancer are unwanted tonic (antigen-independent) signaling and off-target act...
Source: Science Signaling - September 10, 2019 Category: Biomedical Science Authors: Fisher J, Sharma R, Don DW, Barisa M, Hurtado MO, Abramowski P, Porter L, Day W, Borea R, Inglott S, Anderson J, Pe'er D Tags: Sci Signal Source Type: research

Kinetics of CXCL12 binding to atypical chemokine receptor 3 reveal a role for the receptor N terminus in chemokine binding.
Abstract Chemokines bind to membrane-spanning chemokine receptors, which signal through G proteins and promote cell migration. However, atypical chemokine receptor 3 (ACKR3) does not appear to couple to G proteins, and instead of directly promoting cell migration, it regulates the extracellular concentration of chemokines that it shares with the G protein-coupled receptors (GPCRs) CXCR3 and CXCR4, thereby influencing the responses of these receptors. Understanding how these receptors bind their ligands is important for understanding these different processes. Here, we applied association and dissociation kinetic m...
Source: Science Signaling - September 10, 2019 Category: Biomedical Science Authors: Gustavsson M, Dyer DP, Zhao C, Handel TM Tags: Sci Signal Source Type: research

Inflammation induces stress erythropoiesis through heme-dependent activation of SPI-C.
Abstract Inflammation alters bone marrow hematopoiesis to favor the production of innate immune effector cells at the expense of lymphoid cells and erythrocytes. Furthermore, proinflammatory cytokines inhibit steady-state erythropoiesis, which leads to the development of anemia in diseases with chronic inflammation. Acute anemia or hypoxic stress induces stress erythropoiesis, which generates a wave of new erythrocytes to maintain erythroid homeostasis until steady-state erythropoiesis can resume. Although hypoxia-dependent signaling is a key component of stress erythropoiesis, we found that inflammation also indu...
Source: Science Signaling - September 10, 2019 Category: Biomedical Science Authors: Bennett LF, Liao C, Quickel MD, Yeoh BS, Vijay-Kumar M, Hankey-Giblin P, Prabhu KS, Paulson RF Tags: Sci Signal Source Type: research

Diacylglycerol kinase ζ promotes allergic airway inflammation and airway hyperresponsiveness through distinct mechanisms.
Diacylglycerol kinase ζ promotes allergic airway inflammation and airway hyperresponsiveness through distinct mechanisms. Sci Signal. 2019 Sep 03;12(597): Authors: Singh BK, Lu W, Schmidt Paustian AM, Ge MQ, Koziol-White CJ, Flayer CH, Killingbeck SS, Wang N, Dong X, Riese MJ, Deshpande DA, Panettieri RA, Haczku A, Kambayashi T Abstract Asthma is a chronic allergic inflammatory airway disease caused by aberrant immune responses to inhaled allergens, which leads to airway hyperresponsiveness (AHR) to contractile stimuli and airway obstruction. Blocking T helper 2 (TH2) differentiation represents a...
Source: Science Signaling - September 3, 2019 Category: Biomedical Science Authors: Singh BK, Lu W, Schmidt Paustian AM, Ge MQ, Koziol-White CJ, Flayer CH, Killingbeck SS, Wang N, Dong X, Riese MJ, Deshpande DA, Panettieri RA, Haczku A, Kambayashi T Tags: Sci Signal Source Type: research

Structure-function guided modeling of chemokine-GPCR specificity for the chemokine XCL1 and its receptor XCR1.
Abstract Chemokines interact with their G protein-coupled receptors (GPCRs) through a two-step, two-site mechanism and, through this interaction, mediate various homeostatic and immune response mechanisms. Upon initial recognition of the chemokine by the receptor, the amino terminus of the chemokine inserts into the orthosteric pocket of the GPCR, causing conformational changes that trigger intracellular signaling. There is considerable structural and functional evidence to suggest that the amino acid composition and length of the chemokine amino terminus is critical for GPCR activation, complementing the size and...
Source: Science Signaling - September 3, 2019 Category: Biomedical Science Authors: Fox JC, Thomas MA, Dishman AF, Larsen O, Nakayama T, Yoshie O, Rosenkilde MM, Volkman BF Tags: Sci Signal Source Type: research

The induction of HAD-like phosphatases by multiple signaling pathways confers resistance to the metabolic inhibitor 2-deoxyglucose.
eacute;on S Abstract Anti-cancer strategies that target the glycolytic metabolism of tumors have been proposed. The glucose analog 2-deoxyglucose (2DG) is imported into cells and, after phosphorylation, becomes 2DG-6-phosphate, a toxic by-product that inhibits glycolysis. Using yeast as a model, we performed an unbiased mass spectrometry-based approach to probe the cellular effects of 2DG on the proteome and study resistance mechanisms to 2DG. We found that two phosphatases that target 2DG-6-phosphate were induced upon exposure to 2DG and participated in 2DG detoxification. Dog1 and Dog2 are HAD (haloacid dehaloge...
Source: Science Signaling - September 3, 2019 Category: Biomedical Science Authors: Defenouillère Q, Verraes A, Laussel C, Friedrich A, Schacherer J, Léon S Tags: Sci Signal Source Type: research

SMAC mimetics promote NIK-dependent inhibition of CD4+ TH17 cell differentiation.
Abstract Second mitochondria-derived activator of caspase (SMAC) mimetics (SMs) are selective antagonists of the inhibitor of apoptosis proteins (IAPs), which activate noncanonical NF-κB signaling and promote tumor cell death. Through gene expression analysis, we found that treatment of CD4+ T cells with SMs during T helper 17 (TH17) cell differentiation disrupted the balance between two antagonistic transcription factor modules. Moreover, proteomics analysis revealed that SMs altered the abundance of proteins associated with cell cycle, mitochondrial activity, and the balance between canonical and noncanoni...
Source: Science Signaling - August 27, 2019 Category: Biomedical Science Authors: Rizk J, Kaplinsky J, Agerholm R, Kadekar D, Ivars F, Agace WW, Wong WW, Szucs MJ, Myers SA, Carr SA, Waisman A, Bekiaris V Tags: Sci Signal Source Type: research

SMAC mimetics throw a molecular switch to control TH17 responses.
Abstract IL-17 produced by TH17 cells plays a central role in numerous protective and pathologic immune responses. In this issue of Science Signaling, Rizk et al. define a molecular switch controlled by the cellular inhibitor of apoptosis proteins that regulates TH17 immunity. PMID: 31455724 [PubMed - in process] (Source: Science Signaling)
Source: Science Signaling - August 27, 2019 Category: Biomedical Science Authors: Dougan SK, Dougan M Tags: Sci Signal Source Type: research

Therapeutic blockade of activin-A improves NK cell function and antitumor immunity.
Abstract Natural killer (NK) cells are innate lymphocytes that play a major role in immunosurveillance against tumor initiation and metastatic spread. The signals and checkpoints that regulate NK cell fitness and function in the tumor microenvironment are not well defined. Transforming growth factor-β (TGF-β) is a suppressor of NK cells that inhibits interleukin-15 (IL-15)-dependent signaling events and increases the abundance of receptors that promote tissue residency. Here, we showed that NK cells express the type I activin receptor ALK4, which, upon binding to its ligand activin-A, phosphorylated SMAD...
Source: Science Signaling - August 27, 2019 Category: Biomedical Science Authors: Rautela J, Dagley LF, de Oliveira CC, Schuster IS, Hediyeh-Zadeh S, Delconte RB, Cursons J, Hennessy R, Hutchinson DS, Harrison C, Kita B, Vivier E, Webb AI, Degli-Esposti MA, Davis MJ, Huntington ND, Souza-Fonseca-Guimaraes F Tags: Sci Signal Source Type: research

Reverse signaling by semaphorin 4C elicits SMAD1/5- and ID1/3-dependent invasive reprogramming in cancer cells.
Abstract Semaphorins are a family of molecular signals that guide cell migration and are implicated in the regulation of cancer cells. In particular, transmembrane semaphorins are postulated to act as both ligands ("forward" mode) and signaling receptors ("reverse" mode); however, reverse semaphorin signaling in cancer is relatively less understood. Here, we identified a previously unknown function of transmembrane semaphorin 4C (Sema4C), acting in reverse mode, to elicit nonconventional TGF-β/BMP receptor activation and selective SMAD1/5 phosphorylation. Sema4C coimmunoprecipitated with T...
Source: Science Signaling - August 20, 2019 Category: Biomedical Science Authors: Gurrapu S, Franzolin G, Fard D, Accardo M, Medico E, Sarotto I, Sapino A, Isella C, Tamagnone L Tags: Sci Signal Source Type: research

Targeting tumor phenotypic plasticity and metabolic remodeling in adaptive cross-drug tolerance.
Abstract Metastable phenotypic state transitions in cancer cells can lead to the development of transient adaptive resistance or tolerance to chemotherapy. Here, we report that the acquisition of a phenotype marked by increased abundance of CD44 (CD44Hi) by breast cancer cells as a tolerance response to routinely used cytotoxic drugs, such as taxanes, activated a metabolic switch that conferred tolerance against unrelated standard-of-care chemotherapeutic agents, such as anthracyclines. We characterized the sequence of molecular events that connected the induced CD44Hi phenotype to increased activity of both the g...
Source: Science Signaling - August 20, 2019 Category: Biomedical Science Authors: Goldman A, Khiste S, Freinkman E, Dhawan A, Majumder B, Mondal J, Pinkerton AB, Eton E, Medhi R, Chandrasekar V, Rahman MM, Ichimura T, Gopinath KS, Majumder P, Kohandel M, Sengupta S Tags: Sci Signal Source Type: research

Dynamics of drug response informs rational combination regimens.
Abstract Metabolic plasticity in cancer has been linked to the development of drug-tolerant populations. In this issue of Science Signaling, Goldman et al integrate metabolic plasticity with phenotypic state transitions to examine how this reprogramming can be therapeutically exploited. PMID: 31431544 [PubMed - in process] (Source: Science Signaling)
Source: Science Signaling - August 20, 2019 Category: Biomedical Science Authors: Paudel BB, Quaranta V Tags: Sci Signal Source Type: research

Muscle-generated BDNF is a sexually dimorphic myokine that controls metabolic flexibility.
Abstract The ability of skeletal muscle to switch between lipid and glucose oxidation for ATP production during metabolic stress is pivotal for maintaining systemic energy homeostasis, and dysregulation of this metabolic flexibility is a dominant cause of several metabolic disorders. However, the molecular mechanism that governs fuel selection in muscle is not well understood. Here, we report that brain-derived neurotrophic factor (BDNF) is a fasting-induced myokine that controls metabolic reprograming through the AMPK/CREB/PGC-1α pathway in female mice. Female mice with a muscle-specific deficiency in BDNF ...
Source: Science Signaling - August 13, 2019 Category: Biomedical Science Authors: Yang X, Brobst D, Chan WS, Tse MCL, Herlea-Pana O, Ahuja P, Bi X, Zaw AM, Kwong ZSW, Jia WH, Zhang ZG, Zhang N, Chow SKH, Cheung WH, Louie JCY, Griffin TM, Nong W, Hui JHL, Du GH, Noh HL, Saengnipanthkul S, Chow BKC, Kim JK, Lee CW, Chan CB Tags: Sci Signal Source Type: research

Mitotic phosphorylation by NEK6 and NEK7 reduces the microtubule affinity of EML4 to promote chromosome congression.
Abstract EML4 is a microtubule-associated protein that promotes microtubule stability. We investigated its regulation across the cell cycle and found that EML4 was distributed as punctate foci along the microtubule lattice in interphase but exhibited reduced association with spindle microtubules in mitosis. Microtubule sedimentation and cryo-electron microscopy with 3D reconstruction revealed that the basic N-terminal domain of EML4 mediated its binding to the acidic C-terminal tails of α- and β-tubulin on the microtubule surface. The mitotic kinases NEK6 and NEK7 phosphorylated the EML4 N-terminal doma...
Source: Science Signaling - August 13, 2019 Category: Biomedical Science Authors: Adib R, Montgomery JM, Atherton J, O'Regan L, Richards MW, Straatman KR, Roth D, Straube A, Bayliss R, Moores CA, Fry AM Tags: Sci Signal Source Type: research

Emerging concepts in pseudoenzyme classification, evolution, and signaling.
Abstract The 21st century is witnessing an explosive surge in our understanding of pseudoenzyme-driven regulatory mechanisms in biology. Pseudoenzymes are proteins that have sequence homology with enzyme families but that are proven or predicted to lack enzyme activity due to mutations in otherwise conserved catalytic amino acids. The best-studied pseudoenzymes are pseudokinases, although examples from other families are emerging at a rapid rate as experimental approaches catch up with an avalanche of freely available informatics data. Kingdom-wide analysis in prokaryotes, archaea and eukaryotes reveals that betwe...
Source: Science Signaling - August 13, 2019 Category: Biomedical Science Authors: Ribeiro AJM, Das S, Dawson N, Zaru R, Orchard S, Thornton JM, Orengo C, Zeqiraj E, Murphy JM, Eyers PA Tags: Sci Signal Source Type: research

IRF6 and TAK1 coordinately promote the activation of HIPK2 to stimulate apoptosis during palate fusion.
Abstract Cleft palate is a common craniofacial defect caused by a failure in palate fusion. The palatal shelves migrate toward one another and meet at the embryonic midline, creating a seam. Transforming growth factor-β3 (TGF-β3)-induced apoptosis of the medial edge epithelium (MEE), the cells located along the seam, is required for completion of palate fusion. The transcription factor interferon regulatory factor 6 (IRF6) promotes TGF-β3-induced MEE cell apoptosis by stimulating the degradation of the transcription factor ΔNp63 and promoting the expression of the gene encoding the cyclin-depe...
Source: Science Signaling - August 6, 2019 Category: Biomedical Science Authors: Ke CY, Mei HH, Wong FH, Lo LJ Tags: Sci Signal Source Type: research

Disruption of SynGAP-dopamine D1 receptor complexes alters actin and microtubule dynamics and impairs GABAergic interneuron migration.
Abstract Disruption of γ-aminobutyric acid (GABA)-ergic interneuron migration is implicated in various neurodevelopmental disorders, including autism spectrum disorder and schizophrenia. The dopamine D1 receptor (D1R) promotes GABAergic interneuron migration, which is disrupted in various neurological disorders, some of which are also associated with mutations in the gene encoding synaptic Ras-guanosine triphosphatase-activating protein (SynGAP). Here, we explored the mechanisms underlying these associations and their possible connection. In prenatal mouse brain tissue, we found a previously unknown interact...
Source: Science Signaling - August 6, 2019 Category: Biomedical Science Authors: Su P, Lai TKY, Lee FHF, Abela AR, Fletcher PJ, Liu F Tags: Sci Signal Source Type: research