Researchers identify a molecule critical to functional brain rejuvenation
(Advanced Science Research Center, GC/CUNY) A new study from a CUNY ASRC Neuroscience Initiative team has identified a molecule called ten-eleven-translocation 1 (TET1) as a necessary component in the repair of myelin, which protects nerves and facilitates accurate transmission of electrical signals. The discovery could have important implications in treating neurodegenerative diseases and for molecular rejuvenation of aging brains in healthy individuals. (Source: EurekAlert! - Social and Behavioral Science)
Source: EurekAlert! - Social and Behavioral Science - June 7, 2021 Category: International Medicine & Public Health Source Type: news

Genomics-informed decisions can help save species from extinction
(Lund University) Researchers in Lund, Copenhagen and Norwich have shown that harmful mutations present in the DNA play an important - yet neglected - role in the conservation and translocation programs of threatened species. (Source: EurekAlert! - Biology)
Source: EurekAlert! - Biology - June 4, 2021 Category: Biology Source Type: news

Accurate evaluation of CRISPR genome editing
(Bar-Ilan University) A multidisciplinary team of researchers from the Interdisciplinary Center Herzliya and Bar-Ilan University report in the May 24th issue of the journal Nature Communications the development of a new software tool to detect, evaluate and quantify off-target editing activity, including adverse translocation events that can cause cancer. The software is based on input taken from a standard measurement assay, involving multiplexed PCR amplification and Next-Generation Sequencing (NGS). (Source: EurekAlert! - Medicine and Health)
Source: EurekAlert! - Medicine and Health - May 24, 2021 Category: International Medicine & Public Health Source Type: news

Getting to the core of HIV replication
(University of Texas at Austin, Texas Advanced Computing Center) Mechanism found for how HIV-1 virus imports nucleotides into its core that fuel DNA synthesis, a key step in its replication. Supercomputer molecular dynamics simulations helped test translocation and free energy calculations. Research supported by the NSF-funded XSEDE through TACC Stampede2 and PSC Bridges. HIV-1 capsid research provides potential for new drug targets for therapeutic development such as improved anti-retroviral drugs. (Source: EurekAlert! - Biology)
Source: EurekAlert! - Biology - March 31, 2021 Category: Biology 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

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

Genetic Mutations May Add to Racial Disparity in Child B - ALL
Increased incidence of IKZF1 deletion and IGH - CRLF2 translocation seen in Hispanic/Latino children with B - ALL (Source: The Doctors Lounge - Oncology)
Source: The Doctors Lounge - Oncology - February 19, 2021 Category: Cancer & Oncology Tags: Oncology, Pathology, Pediatrics, Journal, Source Type: news

Genetic Mutations May Add to Racial Disparity in Child B-ALL
FRIDAY, Feb. 19, 2021 -- Hispanic/Latino (H/L) children with B-cell acute lymphoblastic leukemia (B-ALL) have an increased incidence of IKZF1 deletion and IGH-CRLF2 translocation, according to a letter to the editor published online Feb. 2 in... (Source: Drugs.com - Pharma News)
Source: Drugs.com - Pharma News - February 19, 2021 Category: Pharmaceuticals Source Type: news

Mechanism of spliceosome remodeling by the ATPase/helicase Prp2 and its coactivator Spp2
Spliceosome remodeling, executed by conserved adenosine triphosphatase (ATPase)/helicases including Prp2, enables precursor messenger RNA (pre-mRNA) splicing. However, the structural basis for the function of the ATPase/helicases remains poorly understood. Here, we report atomic structures of Prp2 in isolation, Prp2 complexed with its coactivator Spp2, and Prp2-loaded activated spliceosome and the results of structure-guided biochemical analysis. Prp2 weakly associates with the spliceosome and cannot function without Spp2, which stably associates with Prp2 and anchors on the spliceosome, thus tethering Prp2 to the activate...
Source: ScienceNOW - January 7, 2021 Category: Science Authors: Bai, R., Wan, R., Yan, C., Jia, Q., Lei, J., Shi, Y. Tags: Biochemistry, Online Only r-articles Source Type: news

Novel method identifies areas most suitable for conservation of black lion tamarin
(Funda ç ã o de Amparo à Pesquisa do Estado de S ã o Paulo) The researchers used modeling to show which areas are suitable in terms of forest cover and climate for occupation by the endangered species, which is endemic to the state of S ã o Paulo. Their study is a contribution to translocation initiatives that move groups of these animals to areas from which the species has disappeared. (Source: EurekAlert! - Biology)
Source: EurekAlert! - Biology - January 5, 2021 Category: Biology Source Type: news

Steps toward translocation-independent RNA polymerase inactivation by terminator ATPase {rho}
Factor-dependent transcription termination mechanisms are poorly understood. We determined a series of cryo–electron microscopy structures portraying the hexameric adenosine triphosphatase (ATPase) on a pathway to terminating NusA/NusG-modified elongation complexes. An open ring contacts NusA, NusG, and multiple regions of RNA polymerase, trapping and locally unwinding proximal upstream DNA. NusA wedges into the ring, initially sequestering RNA. Upon deflection of distal upstream DNA over the RNA polymerase zinc-binding domain, NusA rotates underneath one capping subunit, which subsequently captures RNA. After detach...
Source: ScienceNOW - December 31, 2020 Category: Science Authors: Said, N., Hilal, T., Sunday, N. D., Khatri, A., Bürger, J., Mielke, T., Belogurov, G. A., Loll, B., Sen, R., Artsimovitch, I., Wahl, M. C. Tags: Biochemistry, Online Only r-articles Source Type: news

Gene could help predict response to cervical cancer treatment
FINDINGSUCLA researchers have identified a potential diagnostic marker that could help predict how likely someone with cervical cancer is to respond to the standard treatment of chemotherapy and radiation.The scientists found that PACS-1, a gene that resides on a small segment of the long arm of chromosome 11, is overexpressed in cancer tissues, which can result in cancer growth and spread.  Further, they discovered that translocation of the PACS-1 protein from outside to inside the cell nucleus — a function required for normal cell growth — plays a role in the development of cervical cancer that is r...
Source: UCLA Newsroom: Health Sciences - December 11, 2020 Category: Universities & Medical Training Source Type: news

High genomic variability predicts success in desert tortoise refugees; could inform conservation
(American Association for the Advancement of Science) Tortoise refugees with the highest genetic variation are far more likely to survive conservation translocation than tortoises whose genetic diversity is lower, according to a new study. (Source: EurekAlert! - Biology)
Source: EurekAlert! - Biology - November 26, 2020 Category: Biology Source Type: news

Individual heterozygosity predicts translocation success in threatened desert tortoises
Anthropogenic environmental modification is placing as many as 1 million species at risk of extinction. One management action for reducing extinction risk is translocation of individuals to locations from which they have disappeared or to new locations where biologists hypothesize they have a good chance of surviving. To maximize this survival probability, the standard practice is to move animals from the closest possible populations that contain presumably related individuals. In an empirical test of this conventional wisdom, we analyzed a genomic dataset for 166 translocated desert tortoises (Gopherus agassizii) that eit...
Source: ScienceNOW - November 26, 2020 Category: Science Authors: Scott, P. A., Allison, L. J., Field, K. J., Averill-Murray, R. C., Shaffer, H. B. Tags: Ecology reports Source Type: news

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

Revealing the identity of the last unknown protein of autophagy
(Japan Science and Technology Agency) Japanese scientists discovered that Atg9, one of the proteins that function to mediate autophagy, has phospholipid-translocation activity (the lipid scramblase activity) between the two layers of the lipid bilayer?and elucidated that the protein's activity brings about autophagosome membrane expansion. The artificial control of autophagy is expected to promote the research and development of treating and preventing various diseases. (Source: EurekAlert! - Biology)
Source: EurekAlert! - Biology - November 4, 2020 Category: Biology Source Type: news

The coupling mechanism of mammalian respiratory complex I
Mitochondrial complex I couples NADH:ubiquinone oxidoreduction to proton pumping by an unknown mechanism. Here, we present cryo–electron microscopy structures of ovine complex I in five different conditions, including turnover, at resolutions up to 2.3 to 2.5 angstroms. Resolved water molecules allowed us to experimentally define the proton translocation pathways. Quinone binds at three positions along the quinone cavity, as does the inhibitor rotenone that also binds within subunit ND4. Dramatic conformational changes around the quinone cavity couple the redox reaction to proton translocation during open-to-closed s...
Source: ScienceNOW - October 29, 2020 Category: Science Authors: Kampjut, D., Sazanov, L. A. Tags: Biochemistry, Online Only r-articles Source Type: news

Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy
In this study, we isolated three bacterial species—Bifidobacterium pseudolongum, Lactobacillus johnsonii, and Olsenella species—that significantly enhanced efficacy of immune checkpoint inhibitors in four mouse models of cancer. We found that intestinal B. pseudolongum modulated enhanced immunotherapy response through production of the metabolite inosine. Decreased gut barrier function induced by immunotherapy increased systemic translocation of inosine and activated antitumor T cells. The effect of inosine was dependent on T cell expression of the adenosine A2A receptor and required costimulation. Collectively...
Source: ScienceNOW - September 16, 2020 Category: Science Authors: Mager, L. F., Burkhard, R., Pett, N., Cooke, N. C. A., Brown, K., Ramay, H., Paik, S., Stagg, J., Groves, R. A., Gallo, M., Lewis, I. A., Geuking, M. B., McCoy, K. D. Tags: Immunology, Medicine, Diseases reports Source Type: news

The gut as a hidden source of sepsis
From the initial hypothesis considering 30 years ago the gut as the " motor " of multiple organ failure (MOF) related to an induced hyperpermeability leading to bacterial translocation into the systemic circulation, the reality becomes significantly more complex. The gut contains three interplaying components - the epithelium, the microbiome, and the immune system - that have to cooperate to maintain two opposite function: adsorption of nutrients and maintenance of a barrier to prevent the crossing of intraluminal microbes or their products to avoid host response. Many critical illnesses are altering such a funct...
Source: Current Awareness Service for Health (CASH) - September 3, 2020 Category: Consumer Health News Source Type: news

Degradation of 5hmC-marked stalled replication forks by APE1 causes genomic instability
Synthetic lethality between poly(ADP-ribose) polymerase (PARP) inhibition and BRCA deficiency is exploited to treat breast and ovarian tumors. However, resistance to PARP inhibitors (PARPis) is common. To identify potential resistance mechanisms, we performed a genome-wide RNAi screen in BRCA2-deficient mouse embryonic stem cells and validation in KB2P1.21 mouse mammary tumor cells. We found that resistance to multiple PARPi emerged with reduced expression of TET2 (ten-eleven translocation), which promotes DNA demethylation by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethycytosine (5hmC) and other products. TET2 knockd...
Source: Signal Transduction Knowledge Environment - August 17, 2020 Category: Science Authors: Kharat, S. S., Ding, X., Swaminathan, D., Suresh, A., Singh, M., Sengodan, S. K., Burkett, S., Marks, H., Pamala, C., He, Y., Fox, S. D., Buehler, E. C., Muegge, K., Martin, S. E., Sharan, S. K. Tags: STKE Research Articles Source Type: news

Cognitive map-based navigation in wild bats revealed by a new high-throughput tracking system
Seven decades of research on the "cognitive map," the allocentric representation of space, have yielded key neurobiological insights, yet field evidence from free-ranging wild animals is still lacking. Using a system capable of tracking dozens of animals simultaneously at high accuracy and resolution, we assembled a large dataset of 172 foraging Egyptian fruit bats comprising>18 million localizations collected over 3449 bat-nights across 4 years. Detailed track analysis, combined with translocation experiments and exhaustive mapping of fruit trees, revealed that wild bats seldom exhibit random search but inste...
Source: ScienceNOW - July 8, 2020 Category: Science Authors: Toledo, S., Shohami, D., Schiffner, I., Lourie, E., Orchan, Y., Bartan, Y., Nathan, R. Tags: Ecology reports Source Type: news

A PI3K- and GTPase-independent Rac1-mTOR mechanism mediates MET-driven anchorage-independent cell growth but not migration
Receptor tyrosine kinases (RTKs) are often overexpressed or mutated in cancers and drive tumor growth and metastasis. In the current model of RTK signaling, including that of MET, downstream phosphatidylinositol 3-kinase (PI3K) mediates both cell proliferation and cell migration, whereas the small guanosine triphosphatase (GTPase) Rac1 mediates cell migration. However, in cultured NIH3T3 and glioblastoma cells, we found that class I PI3K mediated oncogenic MET–induced cell migration but not anchorage-independent growth. In contrast, Rac1 regulated both processes in distinct ways. Downstream of PI3K, Rac1 mediated cel...
Source: Signal Transduction Knowledge Environment - June 22, 2020 Category: Science Authors: Hervieu, A., Heuss, S. F., Zhang, C., Barrow-McGee, R., Joffre, C., Menard, L., Clarke, P. A., Kermorgant, S. Tags: STKE Research Articles Source Type: news

Nutrient transporter translocation to the plasma membrane via Golgi bypass in Aspergillus nidulans
Conference abstracts (Source: The Aspergillus Website - updates)
Source: The Aspergillus Website - updates - June 20, 2020 Category: Respiratory Medicine Authors: MeganB Source Type: news

IGF-1 receptor activity in the Golgi of migratory cancer cells depends on adhesion-dependent phosphorylation of Tyr1250 and Tyr1251
Although insulin-like growth factor 1 (IGF-1) signaling promotes tumor growth and cancer progression, therapies that target the IGF-1 receptor (IGF-1R) have shown poor clinical efficacy. To address IGF-1R activity in cancer cells and how it differs from that of the closely related insulin receptor (IR), we focused on two tyrosines in the IGF-1R C-terminal tail that are not present in the IR and are essential for IGF-1–mediated cancer cell survival, migration, and tumorigenic growth. We found that Tyr1250 and Tyr1251 (Tyr1250/1251) were autophosphorylated in a cell adhesion–dependent manner. To investigate the c...
Source: Signal Transduction Knowledge Environment - May 25, 2020 Category: Science Authors: Rieger, L., OShea, S., Godsmark, G., Stanicka, J., Kelly, G., OConnor, R. Tags: STKE Research Articles Source Type: news

Diacylglycerol kinase {zeta} promotes actin cytoskeleton remodeling and mechanical forces at the B cell immune synapse
Diacylglycerol kinases (DGKs) limit antigen receptor signaling in immune cells by consuming the second messenger diacylglycerol (DAG) to generate phosphatidic acid (PA). Here, we showed that DGK promotes lymphocyte function–associated antigen 1 (LFA-1)–mediated adhesion and F-actin generation at the immune synapse of B cells with antigen-presenting cells (APCs), mostly in a PA-dependent manner. Measurement of single-cell mechanical force generation indicated that DGK-deficient B cells exerted lower forces at the immune synapse than did wild-type B cells. Nonmuscle myosin activation and translocation of the micr...
Source: Signal Transduction Knowledge Environment - April 13, 2020 Category: Science Authors: Merino-Cortes, S. V., Gardeta, S. R., Roman-Garcia, S., Martinez-Riano, A., Pineau, J., Liebana, R., Merida, I., Dumenil, A.-M. L., Pierobon, P., Husson, J., Alarcon, B., Carrasco, Y. R. Tags: STKE Research Articles Source Type: news

Noncanonical STAT1 phosphorylation expands its transcriptional activity into promoting LPS-induced IL-6 and IL-12p40 production
The lipopolysaccharide (LPS)–induced endocytosis of Toll-like receptor 4 (TLR4) is an essential step in the production of interferon-β (IFN-β), which activates the transcription of antiviral response genes by STAT1 phosphorylated at Tyr701. Here, we showed that STAT1 regulated proinflammatory cytokine production downstream of TLR4 endocytosis independently of IFN-β signaling and the key proinflammatory regulator NF-B. In human macrophages, TLR4 endocytosis activated a noncanonical phosphorylation of STAT1 at Thr749, which subsequently promoted the production of interleukin-6 (IL-6) and IL-12p40 through...
Source: Signal Transduction Knowledge Environment - March 23, 2020 Category: Science Authors: Metwally, H., Tanaka, T., Li, S., Parajuli, G., Kang, S., Hanieh, H., Hashimoto, S., Chalise, J. P., Gemechu, Y., Standley, D. M., Kishimoto, T. Tags: STKE Research Articles Source Type: news

Improving success of giraffe translocations
(Penn State) In two new studies, an international team of researchers identifies the ideal composition of a group of giraffes to be translocated for conservation purposes and provides guidelines for all aspects of the translocation process. (Source: EurekAlert! - Biology)
Source: EurekAlert! - Biology - March 19, 2020 Category: Biology Source Type: news

PTPN22 phosphorylation acts as a molecular rheostat for the inhibition of TCR signaling
The hematopoietic-specific protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is encoded by a major autoimmunity risk gene. PTPN22 inhibits T cell activation by dephosphorylating substrates involved in proximal T cell receptor (TCR) signaling. Here, we found by mass spectrometry that PTPN22 was phosphorylated at Ser751 by PKCα in Jurkat and primary human T cells activated with phorbol ester/ionomycin or antibodies against CD3/CD28. The phosphorylation of PTPN22 at Ser751 prolonged its half-life by inhibiting K48-linked ubiquitination and impairing recruitment of the phosphatase to the plasma membrane, which is...
Source: Signal Transduction Knowledge Environment - March 16, 2020 Category: Science Authors: Yang, S., Svensson, M. N. D., Harder, N. H. O., Hsieh, W.-C., Santelli, E., Kiosses, W. B., Moresco, J. J., Yates, J. R., King, C. C., Liu, L., Stanford, S. M., Bottini, N. Tags: STKE Research Articles Source Type: news

Clostridium perfringens enterotoxin induces claudin-4 to activate YAP in oral squamous cell
(Impact Journals LLC) Oncotarget Volume 11, Issue 4: Treatment of human oral squamous cell carcinoma cell lines HSC3 and HSC4 with Clostridium perfringens enterotoxin, induced CLDN4 nuclear translocation to enhance epithelial-mesenchymal transition, stemness, cell proliferation, and invasive ability. (Source: EurekAlert! - Cancer)
Source: EurekAlert! - Cancer - February 4, 2020 Category: Cancer & Oncology Source Type: news

The parkin-coregulated gene product PACRG promotes TNF signaling by stabilizing LUBAC
The Parkin-coregulated gene (PACRG), which encodes a protein of unknown function, shares a bidirectional promoter with Parkin (PRKN), which encodes an E3 ubiquitin ligase. Because PRKN is important in mitochondrial quality control and protection against stress, we tested whether PACRG also affected these pathways in various cultured human cell lines and in mouse embryonic fibroblasts. PACRG did not play a role in mitophagy but did play a role in tumor necrosis factor (TNF) signaling. Similarly to Parkin, PACRG promoted nuclear factor B (NF-B) activation in response to TNF. TNF-induced nuclear translocation of the NF-B subu...
Source: Signal Transduction Knowledge Environment - February 3, 2020 Category: Science Authors: Meschede, J., Sadic, M., Furthmann, N., Miedema, T., Sehr, D. A., Müller-Rischart, A. K., Bader, V., Berlemann, L. A., Pilsl, A., Schlierf, A., Barkovits, K., Kachholz, B., Rittinger, K., Ikeda, F., Marcus, K., Schaefer, L., Tatzelt, J., Winklhofe Tags: STKE Research Articles Source Type: news

Dynamic palmitoylation controls the microdomain localization of the DKK1 receptors CKAP4 and LRP6
Dickkopf1 (DKK1) was originally identified as an antagonist of Wnt signaling that binds to and induces the clathrin-mediated endocytosis of the Wnt coreceptors low-density lipoprotein receptor–related proteins 5 and 6 (LRP5/6). DKK1 also binds to cytoskeleton-associated protein 4 (CKAP4), which was originally identified as an endoplasmic reticulum (ER) protein but also functions at the plasma membrane as a receptor for various ligands. The DKK1-CKAP4 pathway is activated in several human cancers and promotes cell proliferation by activating signaling through the kinases PI3K and AKT. We found that both CKAP4 and LRP6...
Source: Signal Transduction Knowledge Environment - November 18, 2019 Category: Science Authors: Sada, R., Kimura, H., Fukata, Y., Fukata, M., Yamamoto, H., Kikuchi, A. Tags: STKE Research Articles Source Type: news

Structure of the RSC complex bound to the nucleosome
The RSC complex remodels chromatin structure and regulates gene transcription. We used cryo–electron microscopy to determine the structure of yeast RSC bound to the nucleosome. RSC is delineated into the adenosine triphosphatase motor, the actin-related protein module, and the substrate recruitment module (SRM). RSC binds the nucleosome mainly through the motor, with the auxiliary subunit Sfh1 engaging the H2A-H2B acidic patch to enable nucleosome ejection. SRM is organized into three substrate-binding lobes poised to bind their respective nucleosomal epitopes. The relative orientations of the SRM and the motor on th...
Source: ScienceNOW - November 13, 2019 Category: Science Authors: Ye, Y., Wu, H., Chen, K., Clapier, C. R., Verma, N., Zhang, W., Deng, H., Cairns, B. R., Gao, N., Chen, Z. Tags: Biochemistry r-articles Source Type: news

Translocation of TRPV4-PI3K{gamma} complexes to the plasma membrane drives myofibroblast transdifferentiation
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 myofibroblast transdifferentiation and in vivo fibrosis through its mechanosensitivity to extracellular matrix stiffness. Here, we showed that TRPV4 promoted the transdifferentiation of human and mouse lung fibroblasts through its interaction with phosphoinositide 3-kinase (PI...
Source: Signal Transduction Knowledge Environment - November 11, 2019 Category: Science Authors: Grove, L. M., Mohan, M. L., Abraham, S., Scheraga, R. G., Southern, B. D., Crish, J. F., Naga Prasad, S. V., Olman, M. A. Tags: STKE Research Articles Source Type: news

Structural basis for the docking of mTORC1 on the lysosomal surface
The mTORC1 (mechanistic target of rapamycin complex 1) protein kinase regulates growth in response to nutrients and growth factors. Nutrients promote its translocation to the lysosomal surface, where its Raptor subunit interacts with the Rag guanosine triphosphatase (GTPase)–Ragulator complex. Nutrients switch the heterodimeric Rag GTPases among four different nucleotide-binding states, only one of which (RagA/B•GTP–RagC/D•GDP) permits mTORC1 association. We used cryo–electron microscopy to determine the structure of the supercomplex of Raptor with Rag-Ragulator at a resolution of 3.2 angstroms....
Source: ScienceNOW - October 23, 2019 Category: Science Authors: Rogala, K. B., Gu, X., Kedir, J. F., Abu-Remaileh, M., Bianchi, L. F., Bottino, A. M. S., Dueholm, R., Niehaus, A., Overwijn, D., Fils, A.-C. P., Zhou, S. X., Leary, D., Laqtom, N. N., Brignole, E. J., Sabatini, D. M. Tags: Biochemistry r-articles Source Type: news

Structural basis for client recognition and activity of Hsp40 chaperones
Hsp70 and Hsp40 chaperones work synergistically in a wide range of biological processes including protein synthesis, membrane translocation, and folding. We used nuclear magnetic resonance spectroscopy to determine the solution structure and dynamic features of an Hsp40 in complex with an unfolded client protein. Atomic structures of the various binding sites in the client complexed to the binding domains of the Hsp40 reveal the recognition pattern. Hsp40 engages the client in a highly dynamic fashion using a multivalent binding mechanism that alters the folding properties of the client. Different Hsp40 family members have...
Source: ScienceNOW - September 18, 2019 Category: Science Authors: Jiang, Y., Rossi, P., Kalodimos, C. G. Tags: Biochemistry reports Source Type: news

Tumor-derived TGF-{beta} inhibits mitochondrial respiration to suppress IFN-{gamma} production by human CD4+ T cells
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 survival. However, TGF-β also has tumor-suppressive activity; thus, dissecting cell type–specific molecular effects may inform therapeutic strategies targeting this cytokine. Here, using human peripheral and tumor-associated lymphocytes, we investigated how tumor-derived TGF-β suppresses a key antitumor function of...
Source: Signal Transduction Knowledge Environment - September 16, 2019 Category: Science Authors: Dimeloe, S., Gubser, P., Loeliger, J., Frick, C., Develioglu, L., Fischer, M., Marquardsen, F., Bantug, G. R., Thommen, D., Lecoultre, Y., Zippelius, A., Langenkamp, A., Hess, C. Tags: STKE Research Articles Source Type: news

Cryo-EM structures capture the transport cycle of the P4-ATPase flippase
In eukaryotic membranes, type IV P-type adenosine triphosphatases (P4-ATPases) mediate the translocation of phospholipids from the outer to the inner leaflet and maintain lipid asymmetry, which is critical for membrane trafficking and signaling pathways. Here, we report the cryo–electron microscopy structures of six distinct intermediates of the human ATP8A1-CDC50a heterocomplex at resolutions of 2.6 to 3.3 angstroms, elucidating the lipid translocation cycle of this P4-ATPase. ATP-dependent phosphorylation induces a large rotational movement of the actuator domain around the phosphorylation site in the phosphorylati...
Source: ScienceNOW - September 11, 2019 Category: Science Authors: Hiraizumi, M., Yamashita, K., Nishizawa, T., Nureki, O. Tags: Biochemistry r-articles Source Type: news

Structure and conformational plasticity of the intact Thermus thermophilus V/A-type ATPase
V (vacuolar)/A (archaeal)-type adenosine triphosphatases (ATPases), found in archaea and eubacteria, couple ATP hydrolysis or synthesis to proton translocation across the plasma membrane using the rotary-catalysis mechanism. They belong to the V-type ATPase family, which differs from the mitochondrial/chloroplast F-type ATP synthases in overall architecture. We solved cryo–electron microscopy structures of the intact Thermus thermophilus V/A-ATPase, reconstituted into lipid nanodiscs, in three rotational states and two substates. These structures indicate substantial flexibility between V1 and Vo in a working enzyme,...
Source: ScienceNOW - August 21, 2019 Category: Science Authors: Zhou, L., Sazanov, L. A. Tags: Biochemistry, Online Only r-articles Source Type: news

Nuclear hnRNPA2B1 initiates and amplifies the innate immune response to DNA viruses
We report that heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) recognizes pathogenic DNA and amplifies interferon-α/β (IFN-α/β) production. Upon DNA virus infection, nuclear-localized hnRNPA2B1 senses viral DNA, homodimerizes, and is then demethylated at arginine-226 by the arginine demethylase JMJD6. This results in hnRNPA2B1 translocation to the cytoplasm where it activates the TANK-binding kinase 1–interferon regulatory factor 3 (TBK1–IRF3) pathway, leading to IFN-α/β production. Additionally, hnRNPA2B1 facilitates N6-methyladenosine (m6A) modification and nucleocyto...
Source: ScienceNOW - August 14, 2019 Category: Science Authors: Wang, L., Wen, M., Cao, X. Tags: Immunology, Molecular Biology, Online Only r-articles Source Type: news

Structure of the Cdc48 segregase in the act of unfolding an authentic substrate
The cellular machine Cdc48 functions in multiple biological pathways by segregating its protein substrates from a variety of stable environments such as organelles or multi-subunit complexes. Despite extensive studies, the mechanism of Cdc48 has remained obscure, and its reported structures are inconsistent with models of substrate translocation proposed for other AAA+ ATPases (adenosine triphosphatases). Here, we report a 3.7-angstrom–resolution structure of Cdc48 in complex with an adaptor protein and a native substrate. Cdc48 engages substrate by adopting a helical configuration of substrate-binding residues that ...
Source: ScienceNOW - July 31, 2019 Category: Science Authors: Cooney, I., Han, H., Stewart, M. G., Carson, R. H., Hansen, D. T., Iwasa, J. H., Price, J. C., Hill, C. P., Shen, P. S. Tags: Biochemistry reports Source Type: news

Understanding social structure is important to rewilding
(San Diego Zoo Global) Increasing the success of wildlife translocations is critical, given the escalating global threats to wildlife. The study highlights the influence of a species' social structure on translocation success, and it provides a template for incorporating social information in the rehabilitation and release planning process. Using elephants as a model, the study highlights the need to include animal social structure as an integral part of conservation plans, in order to assure better animal welfare and program success. (Source: EurekAlert! - Social and Behavioral Science)
Source: EurekAlert! - Social and Behavioral Science - June 13, 2019 Category: International Medicine & Public Health Source Type: news

Flotillin-mediated endocytosis and ALIX-syntenin-1-mediated exocytosis protect the cell membrane from damage caused by necroptosis
Necroptosis is a form of regulated necrosis that is implicated in various human diseases including Alzheimer’s disease. Necroptosis requires the translocation of the pseudokinase MLKL from the cytosol to the plasma membrane after its phosphorylation by the kinase RIPK3. Using protein cross-linking followed by affinity purification, we detected the lipid raft–associated proteins flotillin-1 and flotillin-2 and the ESCRT-associated proteins ALIX and syntenin-1 in membrane-localized MLKL immunoprecipitates. Phosphorylated MLKL was removed from membranes through either flotillin-mediated endocytosis followed by lys...
Source: Signal Transduction Knowledge Environment - May 27, 2019 Category: Science Authors: Fan, W., Guo, J., Gao, B., Zhang, W., Ling, L., Xu, T., Pan, C., Li, L., Chen, S., Wang, H., Zhang, J., Wang, X. Tags: STKE Research Articles Source Type: news

Miro2 is a Parkin receptor for selective removal of damaged mitochondria
(Science China Press) Defects in mitophagy are linked to a variety of human diseases including Parkinson's and cardiac disorders. At present, how the damaged mitochondria are selectively recognized and targeted by Parkin is not fully understood. Miro2, a mitochondrial outer membrane protein, has been identified as a platform for Parkin translocation to damaged mitochondria. Miro2 senses both the depolarization and the Ca2+ release from mitochondria to ensure that only damaged mitochondria are targeted by Parkin for mitophagic clearance. (Source: EurekAlert! - Biology)
Source: EurekAlert! - Biology - May 16, 2019 Category: Biology Source Type: news

p62 and Nrf2 are essential for exercise-mediated enhancement of antioxidant protein in muscle
(Nagoya City University) Regular exercise prevents oxidative stress-induced muscle wasting, at least partially by improving the antioxidant defense system. In the present study, we found that regular endurance exercise enhances the expression of p62/SQSTM1 (p62) and its phosphorylation at Ser 351 thereby dissociating nuclear factor erythroid 2-related factor 2 (Nrf2) from Keap1, which results in increased Nrf2 nuclear translocation and DNA binding activity. These findings suggest that Ser 351 phosphorylation of p62 plays a critical role in this regulation. (Source: EurekAlert! - Biology)
Source: EurekAlert! - Biology - April 25, 2019 Category: Biology Source Type: news

TRPV1 promotes opioid analgesia during inflammation
Pain and inflammation are inherently linked responses to injury, infection, or chronic diseases. Given that acute inflammation in humans or mice enhances the analgesic properties of opioids, there is much interest in determining the inflammatory transducers that prime opioid receptor signaling in primary afferent nociceptors. Here, we found that activation of the transient receptor potential vanilloid type 1 (TRPV1) channel stimulated a mitogen-activated protein kinase (MAPK) signaling pathway that was accompanied by the shuttling of the scaffold protein β-arrestin2 to the nucleus. The nuclear translocation of β-...
Source: Signal Transduction Knowledge Environment - April 1, 2019 Category: Science Authors: Basso, L., Aboushousha, R., Fan, C. Y., Iftinca, M., Melo, H., Flynn, R., Agosti, F., Hollenberg, M. D., Thompson, R., Bourinet, E., Trang, T., Altier, C. Tags: STKE Research Articles Source Type: news

Translocation of bighorn sheep in Arizona has positive genetic outcomes
(University of Wyoming) Research shows it is possible to re-establish bighorn sheep populations without a reduction of genetic diversity over a short period and without erosion of ancestral lineage. (Source: EurekAlert! - Medicine and Health)
Source: EurekAlert! - Medicine and Health - March 6, 2019 Category: International Medicine & Public Health Source Type: news

Immunometabolism regulates TCR recycling and iNKT cell functions
Invariant natural killer T (iNKT) cells are innate-like T lymphocytes that express an invariant T cell receptor (TCR), which recognizes glycolipid antigens presented on CD1d molecules. These cells are phenotypically and functionally distinct from conventional T cells. When we characterized the metabolic activity of iNKT cells, consistent with their activated phenotype, we found that they had much less mitochondrial respiratory capacity but increased glycolytic activity in comparison to naìˆve conventional CD4+ T cells. After TCR engagement, iNKT cells further increased aerobic glycolysis, which was important for the expre...
Source: Signal Transduction Knowledge Environment - February 26, 2019 Category: Science Authors: Fu, S., Zhu, S., Tian, C., Bai, S., Zhang, J., Zhan, C., Xie, D., Wang, L., Li, Z., Li, J., Zhang, H., Zhou, R., Tian, Z., Xu, T., Bai, L. Tags: STKE Research Articles Source Type: news

Structure of the posttranslational Sec protein-translocation channel complex from yeast
The Sec61 protein-conducting channel mediates transport of many proteins, such as secretory proteins, across the endoplasmic reticulum (ER) membrane during or after translation. Posttranslational transport is enabled by two additional membrane proteins associated with the channel, Sec63 and Sec62, but its mechanism is poorly understood. We determined a structure of the Sec complex (Sec61-Sec63-Sec71-Sec72) from Saccharomyces cerevisiae by cryo–electron microscopy (cryo-EM). The structure shows that Sec63 tightly associates with Sec61 through interactions in cytosolic, transmembrane, and ER-luminal domains, prying ope...
Source: ScienceNOW - January 3, 2019 Category: Science Authors: Itskanov, S., Park, E. Tags: Biochemistry reports Source Type: news

The {beta}4 subunit of Cav1.2 channels is required for an optimal interferon response in cardiac muscle cells
The auxiliary β4 subunit of the cardiac Cav1.2 channel plays a poorly understood role in gene transcription. Here, we characterized the regulatory effects of the β4 subunit in H9c2 rat cardiac cells on the abundances of Ifnb mRNA [which encodes interferon-β (IFN-β)] and of the IFN-β–related genes Ddx58, Ifitm3, Irf7, Stat2, Ifih1, and Mx1, as well as on the abundances of the antiviral proteins DDX58, IRF7, STAT2, and IFITM3. Knocking down the β4 subunit in H9c2 cells reduced the expression of IFN-β–stimulated genes. In response to inhibition of the kinase JAK1, the abundances ...
Source: Signal Transduction Knowledge Environment - December 11, 2018 Category: Science Authors: Tammineni, E. R., Carrillo, E. D., Soto-Acosta, R., Angel-Ambrocio, A. H., Garcia, M. C., Bautista-Carbajal, P., del Angel, R. M., Sanchez, J. A. Tags: STKE Research Articles Source Type: news

Restricting mitochondrial GRK2 post-ischemia confers cardioprotection by reducing myocyte death and maintaining glucose oxidation
Increased abundance of GRK2 [G protein–coupled receptor (GPCR) kinase 2] is associated with poor cardiac function in heart failure patients. In animal models, GRK2 contributes to the pathogenesis of heart failure after ischemia-reperfusion (IR) injury. In addition to its role in down-regulating activated GPCRs, GRK2 also localizes to mitochondria both basally and post-IR injury, where it regulates cellular metabolism. We previously showed that phosphorylation of GRK2 at Ser670 is essential for the translocation of GRK2 to the mitochondria of cardiomyocytes post-IR injury in vitro and that this localization promotes c...
Source: Signal Transduction Knowledge Environment - December 11, 2018 Category: Science Authors: Sato, P. Y., Chuprun, J. K., Grisanti, L. A., Woodall, M. C., Brown, B. R., Roy, R., Traynham, C. J., Ibetti, J., Lucchese, A. M., Yuan, A., Drosatos, K., Tilley, D. G., Gao, E., Koch, W. J. Tags: STKE Research Articles Source Type: news