Heterogeneity in human hippocampal CaMKII transcripts reveals allosteric hub-dependent regulation.
Abstract Calcium/calmodulin-dependent protein kinase II (CaMKII) plays a central role in Ca2+ signaling throughout the body. In the hippocampus, CaMKII is required for learning and memory. Vertebrate genomes encode four CaMKII homologs: CaMKIIα, CaMKIIβ, CaMKIIγ, and CaMKIIδ. All CaMKIIs consist of a kinase domain, a regulatory segment, a variable linker region, and a hub domain, which is responsible for oligomerization. The four proteins differ primarily in linker length and composition because of extensive alternative splicing. Here, we report the heterogeneity of CaMKII transcripts in thr...
Source: Science Signaling - July 21, 2020 Category: Biomedical Science Authors: Sloutsky R, Dziedzic N, Dunn MJ, Bates RM, Torres-Ocampo AP, Boopathy S, Page B, Weeks JG, Chao LH, Stratton MM Tags: Sci Signal Source Type: research

Redox priming promotes Aurora A activation during mitosis.
In this study, x-ray crystal structures of the Aurora A kinase domain delineate redox-sensitive cysteine residues that, upon covalent modification, can allosterically regulate kinase activity and oligomerization state. We showed in both Xenopus laevis egg extracts and mammalian cells that a conserved cysteine residue within the Aurora A activation loop is crucial for Aurora A activation by autophosphorylation. We further showed that covalent disulfide adducts of this residue promote autophosphorylation of the Aurora A kinase domain. These findings reveal a potential mechanistic link between Aurora A activation and changes ...
Source: Science Signaling - July 21, 2020 Category: Biomedical Science Authors: Lim DC, Joukov V, Rettenmaier TJ, Kumagai A, Dunphy WG, Wells JA, Yaffe MB Tags: Sci Signal Source Type: research

Fusobacterium nucleatum host-cell binding and invasion induces IL-8 and CXCL1 secretion that drives colorectal cancer cell migration.
de DJ Abstract Fusobacterium nucleatum is implicated in accelerating colorectal cancer (CRC) and is found within metastatic CRC cells in patient biopsies. Here, we found that bacterial invasion of CRC cells and cocultured immune cells induced a differential cytokine secretion that may contribute to CRC metastasis. We used a modified galactose kinase markerless gene deletion approach and found that F. nucleatum invaded cultured HCT116 CRC cells through the bacterial surface adhesin Fap2. In turn, Fap2-dependent invasion induced the secretion of the proinflammatory cytokines IL-8 and CXCL1, which are associated with...
Source: Science Signaling - July 21, 2020 Category: Biomedical Science Authors: Casasanta MA, Yoo CC, Udayasuryan B, Sanders BE, Umaña A, Zhang Y, Peng H, Duncan AJ, Wang Y, Li L, Verbridge SS, Slade DJ Tags: Sci Signal Source Type: research

Cancer cells with defective oxidative phosphorylation require endoplasmic reticulum-to-mitochondria Ca2+ transfer for survival.
tt JK Abstract Spontaneous Ca2+ signaling from the InsP3R intracellular Ca2+ release channel to mitochondria is essential for optimal oxidative phosphorylation (OXPHOS) and ATP production. In cells with defective OXPHOS, reductive carboxylation replaces oxidative metabolism to maintain amounts of reducing equivalents and metabolic precursors. To investigate the role of mitochondrial Ca2+ uptake in regulating bioenergetics in these cells, we used OXPHOS-competent and OXPHOS-defective cells. Inhibition of InsP3R activity or mitochondrial Ca2+ uptake increased α-ketoglutarate (αKG) abundance and the NAD+/...
Source: Science Signaling - July 14, 2020 Category: Biomedical Science Authors: Cardenas C, Lovy A, Silva-Pavez E, Urra F, Mizzoni C, Ahumada-Castro U, Bustos G, Jaňa F, Cruz P, Farias P, Mendoza E, Huerta H, Murgas P, Hunter M, Rios M, Cerda O, Georgakoudi I, Zakarian A, Molgó J, Foskett JK Tags: Sci Signal Source Type: research

Two glutamate- and pH-regulated Ca2+ channels are required for systemic wound signaling in Arabidopsis.
Abstract Plants defend against herbivores and nematodes by rapidly sending signals from the wounded sites to the whole plant. We investigated how plants generate and transduce these rapidly moving, long-distance signals referred to as systemic wound signals. We developed a system for measuring systemic responses to root wounding in Arabidopsis thaliana We found that root wounding or the application of glutamate to wounded roots was sufficient to trigger root-to-shoot Ca2+ waves and slow wave potentials (SWPs). Both of these systemic signals were inhibited by either disruption of both GLR3.3 and GLR3.6, which encod...
Source: Science Signaling - July 14, 2020 Category: Biomedical Science Authors: Shao Q, Gao Q, Lhamo D, Zhang H, Luan S Tags: Sci Signal Source Type: research

Functional anatomy of the full-length CXCR4-CXCL12 complex systematically dissected by quantitative model-guided mutagenesis.
Abstract Because of their prominent roles in development, cancer, and HIV, the chemokine receptor CXCR4 and its ligand CXCL12 have been the subject of numerous structural and functional studies, but the determinants of ligand binding, selectivity, and signaling are still poorly understood. Here, building on our latest structural model, we used a systematic mutagenesis strategy to dissect the functional anatomy of the CXCR4-CXCL12 complex. Key charge swap mutagenesis experiments provided evidence for pairwise interactions between oppositely charged residues in the receptor and chemokine, confirming the accuracy of ...
Source: Science Signaling - July 14, 2020 Category: Biomedical Science Authors: Stephens BS, Ngo T, Kufareva I, Handel TM Tags: Sci Signal Source Type: research

Untangling the ties that bind different systemic signals in plants.
Abstract Systemic signaling in plants is orchestrated by a complex network of interconnected systemic signals and cell types. In this issue of Science Signaling, Shao et al unveil how different wound-induced signals integrate into a well-regulated systemic response. PMID: 32665414 [PubMed - in process] (Source: Science Signaling)
Source: Science Signaling - July 14, 2020 Category: Biomedical Science Authors: Fichman Y, Zandalinas SI, Mittler R Tags: Sci Signal Source Type: research

Aurora A regulation by reversible cysteine oxidation reveals evolutionarily conserved redox control of Ser/Thr protein kinase activity.
In this study, we found that the catalytic activity of the Ser/Thr kinase Aurora A was inhibited by the oxidation of a conserved cysteine residue (Cys290) that lies adjacent to Thr288, a critical phosphorylation site in the activation segment. Cys is present at the equivalent position in ~100 human Ser/Thr kinases, a residue that we found was important not only for the activity of human Aurora A but also for that of fission yeast MAPK-activated kinase (Srk1) and PKA (Pka1). Moreover, the presence of this conserved Cys predicted biochemical redox sensitivity among a cohort of human CAMK, AGC, and AGC-like kinases. Thus, we ...
Source: Science Signaling - July 7, 2020 Category: Biomedical Science Authors: Byrne DP, Shrestha S, Galler M, Cao M, Daly LA, Campbell AE, Eyers CE, Veal EA, Kannan N, Eyers PA Tags: Sci Signal Source Type: research

BMP-1 disrupts cell adhesion and enhances TGF- β activation through cleavage of the matricellular protein thrombospondin-1.
BMP-1 disrupts cell adhesion and enhances TGF-β activation through cleavage of the matricellular protein thrombospondin-1. Sci Signal. 2020 Jul 07;13(639): Authors: Anastasi C, Rousselle P, Talantikite M, Tessier A, Cluzel C, Bachmann A, Mariano N, Dussoyer M, Alcaraz LB, Fortin L, Aubert A, Delolme F, El Kholti N, Armengaud J, Fournié P, Auxenfans C, Valcourt U, Goff SV, Moali C Abstract Bone morphogenetic protein 1 (BMP-1) is an important metalloproteinase that synchronizes growth factor activation with extracellular matrix assembly during morphogenesis and tissue repair. The mechanisms ...
Source: Science Signaling - July 7, 2020 Category: Biomedical Science Authors: Anastasi C, Rousselle P, Talantikite M, Tessier A, Cluzel C, Bachmann A, Mariano N, Dussoyer M, Alcaraz LB, Fortin L, Aubert A, Delolme F, El Kholti N, Armengaud J, Fournié P, Auxenfans C, Valcourt U, Goff SV, Moali C Tags: Sci Signal Source Type: research

A redox-active switch in fructosamine-3-kinases expands the regulatory repertoire of the protein kinase superfamily.
Abstract Aberrant regulation of metabolic kinases by altered redox homeostasis substantially contributes to aging and various diseases, such as diabetes. We found that the catalytic activity of a conserved family of fructosamine-3-kinases (FN3Ks), which are evolutionarily related to eukaryotic protein kinases, is regulated by redox-sensitive cysteine residues in the kinase domain. The crystal structure of the FN3K homolog from Arabidopsis thaliana revealed that it forms an unexpected strand-exchange dimer in which the ATP-binding P-loop and adjoining β strands are swapped between two chains in the dimer. This...
Source: Science Signaling - July 7, 2020 Category: Biomedical Science Authors: Shrestha S, Katiyar S, Sanz-Rodriguez CE, Kemppinen NR, Kim HW, Kadirvelraj R, Panagos C, Keyhaninejad N, Colonna M, Chopra P, Byrne DP, Boons GJ, van der Knaap E, Eyers PA, Edison AS, Wood ZA, Kannan N Tags: Sci Signal Source Type: research

Ubiquitination and functional modification of GluN2B subunit-containing NMDA receptors by Cbl-b in the spinal cord dorsal horn.
Abstract N-methyl-d-aspartate (NMDA) glutamate receptors (NMDARs) containing GluN2B subunits are prevalent early after birth in most brain regions in rodents. Upon synapse maturation, GluN2B is progressively removed from synapses, which affects NMDAR function and synaptic plasticity. Aberrant recruitment of GluN2B into mature synapses has been implicated in several neuropathologies that afflict adults. We found that the E3 ubiquitin ligase Cbl-b was enriched in the spinal cord dorsal horn neurons of mice and rats and suppressed GluN2B abundance during development and inflammatory pain. Cbl-b abundance increased fr...
Source: Science Signaling - June 30, 2020 Category: Biomedical Science Authors: Zhang ZY, Bai HH, Guo Z, Li HL, Diao XT, Zhang TY, Yao L, Ma JJ, Cao Z, Li YX, Bai X, Chen HK, Suo ZW, Yang X, Hu XD Tags: Sci Signal Source Type: research

The ER chaperone calnexin controls mitochondrial positioning and respiration.
men T Abstract Chaperones in the endoplasmic reticulum (ER) control the flux of Ca2+ ions into mitochondria, thereby increasing or decreasing the energetic output of the oxidative phosphorylation pathway. An example is the abundant ER lectin calnexin, which interacts with sarco/endoplasmic reticulum Ca2+ ATPase (SERCA). We found that calnexin stimulated the ATPase activity of SERCA by maintaining its redox state. This function enabled calnexin to control how much ER Ca2+ was available for mitochondria, a key determinant for mitochondrial bioenergetics. Calnexin-deficient cells compensated for the loss of this func...
Source: Science Signaling - June 30, 2020 Category: Biomedical Science Authors: Gutiérrez T, Qi H, Yap MC, Tahbaz N, Milburn LA, Lucchinetti E, Lou PH, Zaugg M, LaPointe PG, Mercier P, Overduin M, Bischof H, Burgstaller S, Malli R, Ballanyi K, Shuai J, Simmen T Tags: Sci Signal Source Type: research

TRPML1ng on sparks.
Abstract In this issue of Science Signaling, Thakore et al. report that the Ca2+-permeable channel TRPML1 closely associates with ryanodine receptors to induce Ca2+ sparks in native arterial myocytes. Functional studies revealed a key role for TRPML1 channels in regulation of arterial myocyte contractility and blood pressure. PMID: 32576679 [PubMed - in process] (Source: Science Signaling)
Source: Science Signaling - June 23, 2020 Category: Biomedical Science Authors: Nieves-Cintron M, Santana LF, Navedo MF Tags: Sci Signal Source Type: research

TRPML1 channels initiate Ca2+ sparks in vascular smooth muscle cells.
Abstract TRPML1 (transient receptor potential mucolipin 1) is a Ca2+-permeable, nonselective cation channel localized to the membranes of endosomes and lysosomes and is not present or functional on the plasma membrane. Ca2+ released from endosomes and lysosomes into the cytosol through TRPML1 channels is vital for trafficking, acidification, and other basic functions of these organelles. Here, we investigated the function of TRPML1 channels in fully differentiated contractile vascular smooth muscle cells (SMCs). In live-cell confocal imaging studies, we found that most endosomes and lysosomes in freshly isolated S...
Source: Science Signaling - June 23, 2020 Category: Biomedical Science Authors: Thakore P, Pritchard HAT, Griffin CS, Yamasaki E, Drumm BT, Lane C, Sanders KM, Feng Earley Y, Earley S Tags: Sci Signal Source Type: research

A PI3K- and GTPase-independent Rac1-mTOR mechanism mediates MET-driven anchorage-independent cell growth but not migration.
ant S Abstract 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,...
Source: Science Signaling - June 23, 2020 Category: Biomedical Science Authors: Hervieu A, Heuss SF, Zhang C, Barrow-McGee R, Joffre C, Ménard L, Clarke PA, Kermorgant S Tags: Sci Signal Source Type: research

High-throughput dynamic BH3 profiling may quickly and accurately predict effective therapies in solid tumors.
Abstract Despite decades of effort, the sensitivity of patient tumors to individual drugs is often not predictable on the basis of molecular markers alone. Therefore, unbiased, high-throughput approaches to match patient tumors to effective drugs, without requiring a priori molecular hypotheses, are critically needed. Here, we improved upon a method that we previously reported and developed called high-throughput dynamic BH3 profiling (HT-DBP). HT-DBP is a microscopy-based, single-cell resolution assay that enables chemical screens of hundreds to thousands of candidate drugs on freshly isolated tumor cells. The me...
Source: Science Signaling - June 16, 2020 Category: Biomedical Science Authors: Bhola PD, Ahmed E, Guerriero JL, Sicinska E, Su E, Lavrova E, Ni J, Chipashvili O, Hagan T, Pioso MS, McQueeney K, Ng K, Aguirre AJ, Cleary JM, Cocozziello D, Sotayo A, Ryan J, Zhao JJ, Letai A Tags: Sci Signal Source Type: research

Crystal structure of the hinge domain of Smchd1 reveals its dimerization mode and nucleic acid-binding residues.
Abstract Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) is an epigenetic regulator in which polymorphisms cause the human developmental disorder, Bosma arhinia micropthalmia syndrome, and the degenerative disease, facioscapulohumeral muscular dystrophy. SMCHD1 is considered a noncanonical SMC family member because its hinge domain is C-terminal, because it homodimerizes rather than heterodimerizes, and because SMCHD1 contains a GHKL-type, rather than an ABC-type ATPase domain at its N terminus. The hinge domain has been previously implicated in chromatin association; however, the...
Source: Science Signaling - June 16, 2020 Category: Biomedical Science Authors: Chen K, Birkinshaw RW, Gurzau AD, Wanigasuriya I, Wang R, Iminitoff M, Sandow JJ, Young SN, Hennessy PJ, Willson TA, Heckmann DA, Webb AI, Blewitt ME, Czabotar PE, Murphy JM Tags: Sci Signal Source Type: research

Endothelial-to-mesenchymal transition compromises vascular integrity to induce Myc-mediated metabolic reprogramming in kidney fibrosis.
Abstract Endothelial-to-mesenchymal transition (EndMT) is a cellular transdifferentiation program in which endothelial cells partially lose their endothelial identity and acquire mesenchymal-like features. Renal capillary endothelial cells can undergo EndMT in association with persistent damage of the renal parenchyma. The functional consequence(s) of EndMT in kidney fibrosis remains unexplored. Here, we studied the effect of Twist or Snail deficiency in endothelial cells on EndMT in kidney fibrosis. Conditional deletion of Twist1 (which encodes Twist) or Snai1 (which encodes Snail) in VE-cadherin+ or Tie1+ endoth...
Source: Science Signaling - June 9, 2020 Category: Biomedical Science Authors: Lovisa S, Fletcher-Sananikone E, Sugimoto H, Hensel J, Lahiri S, Hertig A, Taduri G, Lawson E, Dewar R, Revuelta I, Kato N, Wu CJ, Bassett RL, Putluri N, Zeisberg M, Zeisberg EM, LeBleu VS, Kalluri R Tags: Sci Signal Source Type: research

Molecular alterations in the extracellular matrix in the brains of newborns with congenital Zika syndrome.
eira-de-Azevedo I, Nishiyama MY, Ho PL, Schanoski AS, Schuch V, Tanuri A, Chimelli L, Vasconcelos ZFM, Domont GB, Vasconcelos ATR, Nakaya HI Abstract Zika virus (ZIKV) infection during pregnancy can cause a set of severe abnormalities in the fetus known as congenital Zika syndrome (CZS). Experiments with animal models and in vitro systems have substantially contributed to our understanding of the pathophysiology of ZIKV infection. Here, to investigate the molecular basis of CZS in humans, we used a systems biology approach to integrate transcriptomic, proteomic, and genomic data from the postmortem brains of neona...
Source: Science Signaling - June 9, 2020 Category: Biomedical Science Authors: Aguiar RS, Pohl F, Morais GL, Nogueira FCS, Carvalho JB, Guida L, Arge LWP, Melo A, Moreira MEL, Cunha DP, Gomes L, Portari EA, Velasquez E, Melani RD, Pezzuto P, de Castro FL, Geddes VEV, Gerber AL, Azevedo GS, Schamber-Reis BL, Gonçalves AL, Junqueira- Tags: Sci Signal Source Type: research

The interdependence of renal epithelial and endothelial metabolism and cell state.
Abstract In this issue of Science Signaling, Lovisa et al. demonstrate the contribution of endothelial-to-mesenchymal transition (EndMT) to kidney fibrosis development. Their studies reveal the interdependence of endothelial and epithelial metabolism in health and disease. PMID: 32518144 [PubMed - in process] (Source: Science Signaling)
Source: Science Signaling - June 9, 2020 Category: Biomedical Science Authors: Balzer MS, Susztak K Tags: Sci Signal Source Type: research

The kinase IRAK4 promotes endosomal TLR and immune complex signaling in B cells and plasmacytoid dendritic cells.
ao K, Xu D, Hunley E, Brightbill HD, Warming S, Roose-Girma M, Wong A, Tam L, Emson CL, Crawford JJ, Young WB, Pappu R, McKenzie BS, Asghari V, Vucic D, Hackney JA, Austin CD, Lee WP, Lekkerkerker A, Ghilardi N, Bryan MC, Kiefer JR, Townsend MJ, Zarrin AA Abstract The dysregulation of multiple signaling pathways, including those through endosomal Toll-like receptors (TLRs), Fc gamma receptors (FcγR), and antigen receptors in B cells (BCR), promote an autoinflammatory loop in systemic lupus erythematosus (SLE). Here, we used selective small-molecule inhibitors to assess the regulatory roles of interleukin-1 r...
Source: Science Signaling - June 2, 2020 Category: Biomedical Science Authors: Corzo CA, Varfolomeev E, Setiadi AF, Francis R, Klabunde S, Senger K, Sujatha-Bhaskar S, Drobnick J, Do S, Suto E, Huang Z, Eastham-Anderson J, Katewa A, Pang J, Domeyer M, Dela Cruz C, Paler-Martinez A, Lau VWC, Hadadianpour A, Ramirez-Carrozi V, Sun Y, Tags: Sci Signal Source Type: research

A G protein-biased S1P1 agonist, SAR247799, protects endothelial cells without affecting lymphocyte numbers.
AA Abstract Endothelial dysfunction is a hallmark of tissue injury and is believed to initiate the development of vascular diseases. Sphingosine-1 phosphate receptor-1 (S1P1) plays fundamental physiological roles in endothelial function and lymphocyte homing. Currently available clinical molecules that target this receptor are desensitizing and are essentially S1P1 functional antagonists that cause lymphopenia. They are clinically beneficial in autoimmune diseases such as multiple sclerosis. In patients, several side effects of S1P1 desensitization have been attributed to endothelial damage, suggesting that drugs...
Source: Science Signaling - June 2, 2020 Category: Biomedical Science Authors: Poirier B, Briand V, Kadereit D, Schäfer M, Wohlfart P, Philippo MC, Caillaud D, Gouraud L, Grailhe P, Bidouard JP, Trellu M, Muslin AJ, Janiak P, Parkar AA Tags: Sci Signal Source Type: research

IGF-1 receptor activity in the Golgi of migratory cancer cells depends on adhesion-dependent phosphorylation of Tyr1250 and Tyr1251.
Abstract 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...
Source: Science Signaling - May 26, 2020 Category: Biomedical Science Authors: Rieger L, O'Shea S, Godsmark G, Stanicka J, Kelly G, O'Connor R Tags: Sci Signal Source Type: research

The tale of a tail: The secret behind IGF-1R's oncogenic power.
Abstract The C-terminal tail of insulin-like growth factor 1 receptor (IGF-1R) has long been appreciated to drive much of this receptor's oncogenic power. In this issue of Science Signaling, Rieger et al. have shown that Tyr1250 and Tyr1251 of IGF-1R are autophosphorylated in a cell adhesion-dependent manner, uncovering a previously unknown plasma membrane-Golgi trafficking route for IGF-1R in migratory cells, an integral part of the malignant phenotype. PMID: 32457114 [PubMed - in process] (Source: Science Signaling)
Source: Science Signaling - May 26, 2020 Category: Biomedical Science Authors: Crudden C, Girnita L Tags: Sci Signal Source Type: research

Myeloma cells shift osteoblastogenesis to adipogenesis by inhibiting the ubiquitin ligase MURF1 in mesenchymal stem cells.
Abstract The suppression of bone formation is a hallmark of multiple myeloma. Myeloma cells inhibit osteoblastogenesis from mesenchymal stem cells (MSCs), which can also differentiate into adipocytes. We investigated myeloma-MSC interactions and the effects of such interactions on the differentiation of MSCs into adipocytes or osteoblasts using single-cell RNA sequencing, in vitro coculture, and subcutaneous injection of MSCs and myeloma cells into mice. Our results revealed that the α4 integrin subunit on myeloma cells stimulated vascular cell adhesion molecule-1 (VCAM1) on MSCs, leading to the activation o...
Source: Science Signaling - May 26, 2020 Category: Biomedical Science Authors: Liu Z, Liu H, He J, Lin P, Tong Q, Yang J Tags: Sci Signal Source Type: research

A protein kinase A-regulated network encodes short- and long-lived cellular memories.
Abstract Cells can store memories of prior experiences to modulate their responses to subsequent stresses, as seen for the protein kinase A (PKA)-mediated general stress response in yeast, which is required for resistance against future stressful conditions. Using microfluidics and time-lapse microscopy, we quantitatively analyzed how the cellular memory of stress adaptation is encoded in single yeast cells. We found that cellular memory was biphasic. Short-lived memory was mediated by trehalose synthase and trehalose metabolism. Long-lived memory was mediated by PKA-regulated stress-responsive transcription facto...
Source: Science Signaling - May 19, 2020 Category: Biomedical Science Authors: Jiang Y, AkhavanAghdam Z, Li Y, Zid BM, Hao N Tags: Sci Signal Source Type: research

The extracellular matrix protein TasA is a developmental cue that maintains a motile subpopulation within Bacillus subtilis biofilms.
odkin-Gal I Abstract In nature, bacteria form biofilms-differentiated multicellular communities attached to surfaces. Within these generally sessile biofilms, a subset of cells continues to express motility genes. We found that this subpopulation enabled Bacillus subtilis biofilms to expand on high-friction surfaces. The extracellular matrix (ECM) protein TasA was required for the expression of flagellar genes. In addition to its structural role as an adhesive fiber for cell attachment, TasA acted as a developmental signal stimulating a subset of biofilm cells to revert to a motile phenotype. Transcriptomic analys...
Source: Science Signaling - May 19, 2020 Category: Biomedical Science Authors: Steinberg N, Keren-Paz A, Hou Q, Doron S, Yanuka-Golub K, Olender T, Hadar R, Rosenberg G, Jain R, Cámara-Almirón J, Romero D, van Teeffelen S, Kolodkin-Gal I Tags: Sci Signal Source Type: research

Phosphoproteomics of CD2 signaling reveals AMPK-dependent regulation of lytic granule polarization in cytotoxic T cells.
Abstract Understanding the costimulatory signaling that enhances the activity of cytotoxic T cells (CTLs) could identify potential targets for immunotherapy. Here, we report that CD2 costimulation plays a critical role in target cell killing by freshly isolated human CD8+ T cells, which represent a challenging but valuable model to gain insight into CTL biology. We found that CD2 stimulation critically enhanced signaling by the T cell receptor in the formation of functional immune synapses by promoting the polarization of lytic granules toward the microtubule-organizing center (MTOC). To gain insight into the unde...
Source: Science Signaling - May 12, 2020 Category: Biomedical Science Authors: Zurli V, Montecchi T, Heilig R, Poschke I, Volkmar M, Wimmer G, Boncompagni G, Turacchio G, D'Elios MM, Campoccia G, Resta N, Offringa R, Fischer R, Acuto O, Baldari CT, Kabanova A Tags: Sci Signal Source Type: research

The death-inducing activity of RIPK1 is regulated by the pH environment.
Abstract Receptor-interacting protein kinase 1 (RIPK1) is a serine/threonine kinase that dictates whether cells survive or die in response to the cytokine tumor necrosis factor (TNF) and other inflammatory stimuli. The activity of RIPK1 is tightly controlled by multiple posttranslational modification mechanisms, including ubiquitination and phosphorylation. Here, we report that sensitivity to TNF-induced, RIPK1-dependent cell death was tunable by the pH environment. We found that an acidic extracellular pH, which led to a concomitant decrease in intracellular pH, impaired the kinase activation of RIPK1 and autopho...
Source: Science Signaling - May 12, 2020 Category: Biomedical Science Authors: Moriwaki K, Balaji S, Ka-Ming Chan F Tags: Sci Signal Source Type: research

Inhibition of Hsp90 in the spinal cord enhances the antinociceptive effects of morphine by activating an ERK-RSK pathway.
Abstract Morphine and other opioids are commonly used to treat pain despite their numerous adverse side effects. Modulating μ-opioid receptor (MOR) signaling is one way to potentially improve opioid therapy. In mice, the chaperone protein Hsp90 mediates MOR signaling within the brain. Here, we found that inhibiting Hsp90 specifically in the spinal cord enhanced the antinociceptive effects of morphine in mice. Intrathecal, but not systemic, administration of the Hsp90 inhibitors 17-AAG or KU-32 amplified the effects of morphine in suppressing sensitivity to both thermal and mechanical stimuli in mice. Hsp90 inhi...
Source: Science Signaling - May 5, 2020 Category: Biomedical Science Authors: Duron DI, Lei W, Barker NK, Stine C, Mishra S, Blagg BSJ, Langlais PR, Streicher JM Tags: Sci Signal Source Type: research

p53 is regulated by aerobic glycolysis in cancer cells by the CtBP family of NADH-dependent transcriptional regulators.
Abstract High rates of glycolysis in cancer cells are a well-established characteristic of many human tumors, providing rapidly proliferating cancer cells with metabolites that can be used as precursors for anabolic pathways. Maintenance of high glycolytic rates depends on the lactate dehydrogenase-catalyzed regeneration of NAD+ from GAPDH-generated NADH because an increased NADH:NAD+ ratio inhibits GAPDH. Here, using human breast cancer cell models, we identified a pathway in which changes in the extramitochondrial-free NADH:NAD+ ratio signaled through the CtBP family of NADH-sensitive transcriptional regulators ...
Source: Science Signaling - May 5, 2020 Category: Biomedical Science Authors: Birts CN, Banerjee A, Darley M, Dunlop CR, Nelson S, Nijjar SK, Parker R, West J, Tavassoli A, Rose-Zerilli MJJ, Blaydes JP Tags: Sci Signal Source Type: research

Regulation of the error-prone DNA polymerase Pol κ by oncogenic signaling and its contribution to drug resistance.
Regulation of the error-prone DNA polymerase Polκ by oncogenic signaling and its contribution to drug resistance. Sci Signal. 2020 Apr 28;13(629): Authors: Temprine K, Campbell NR, Huang R, Langdon EM, Simon-Vermot T, Mehta K, Clapp A, Chipman M, White RM Abstract The DNA polymerase Polκ plays a key role in translesion synthesis, an error-prone replication mechanism. Polκ is overexpressed in various tumor types. Here, we found that melanoma and lung and breast cancer cells experiencing stress from oncogene inhibition up-regulated the expression of Polκ and shifted its localizat...
Source: Science Signaling - April 28, 2020 Category: Biomedical Science Authors: Temprine K, Campbell NR, Huang R, Langdon EM, Simon-Vermot T, Mehta K, Clapp A, Chipman M, White RM Tags: Sci Signal Source Type: research

DNA polymerase κ: Friend or foe?
DNA polymerase κ: Friend or foe? Sci Signal. 2020 Apr 28;13(629): Authors: Sweasy JB Abstract In this issue of Science Signaling, Temprine et al report that up-regulation of the translesion DNA polymerase Polκ mediates resistance to BRAF pathway-targeted inhibitors and starvation in melanoma cells. These results exemplify the role that Polκ plays in cellular adaptation to stress. PMID: 32345726 [PubMed - in process] (Source: Science Signaling)
Source: Science Signaling - April 28, 2020 Category: Biomedical Science Authors: Sweasy JB Tags: Sci Signal Source Type: research

Local Ca2+ signals couple activation of TRPV1 and ANO1 sensory ion channels.
Abstract ANO1 (TMEM16A) is a Ca2+-activated Cl- channel (CaCC) expressed in peripheral somatosensory neurons that are activated by painful (noxious) stimuli. These neurons also express the Ca2+-permeable channel and noxious heat sensor TRPV1, which can activate ANO1. Here, we revealed an intricate mechanism of TRPV1-ANO1 channel coupling in rat dorsal root ganglion (DRG) neurons. Simultaneous optical monitoring of CaCC activity and Ca2+ dynamics revealed that the TRPV1 ligand capsaicin activated CaCCs. However, depletion of endoplasmic reticulum (ER) Ca2+ stores reduced capsaicin-induced Ca2+ increases and CaCC ac...
Source: Science Signaling - April 28, 2020 Category: Biomedical Science Authors: Shah S, Carver CM, Mullen P, Milne S, Lukacs V, Shapiro MS, Gamper N Tags: Sci Signal Source Type: research

PhoQ is an unsaturated fatty acid receptor that fine-tunes Salmonella pathogenic traits.
Véscovi EG Abstract The Salmonella enterica PhoP/PhoQ two-component signaling system coordinates the spatiotemporal expression of key virulence factors that confer pathogenic traits. Through biochemical and structural analyses, we found that the sensor histidine kinase PhoQ acted as a receptor for long-chain unsaturated fatty acids (LCUFAs), which induced a conformational change in the periplasmic domain of the PhoQ protein. This resulted in the repression of PhoQ autokinase activity, leading to inhibition of the expression of PhoP/PhoQ-dependent genes. Recognition of the LCUFA linoleic acid (LA) by PhoQ wa...
Source: Science Signaling - April 21, 2020 Category: Biomedical Science Authors: Carabajal MA, Viarengo G, Yim L, Martínez-Sanguiné A, Mariscotti JF, Chabalgoity JA, Rasia RM, Véscovi EG Tags: Sci Signal Source Type: research

Mitochondrial pyruvate and fatty acid flux modulate MICU1-dependent control of MCU activity.
n S, Soboloff J, Madesh M Abstract The tricarboxylic acid (TCA) cycle converts the end products of glycolysis and fatty acid β-oxidation into the reducing equivalents NADH and FADH2 Although mitochondrial matrix uptake of Ca2+ enhances ATP production, it remains unclear whether deprivation of mitochondrial TCA substrates alters mitochondrial Ca2+ flux. We investigated the effect of TCA cycle substrates on MCU-mediated mitochondrial matrix uptake of Ca2+, mitochondrial bioenergetics, and autophagic flux. Inhibition of glycolysis, mitochondrial pyruvate transport, or mitochondrial fatty acid transport triggered...
Source: Science Signaling - April 21, 2020 Category: Biomedical Science Authors: Nemani N, Dong Z, Daw CC, Madaris TR, Ramachandran K, Enslow BT, Rubannelsonkumar CS, Shanmughapriya S, Mallireddigari V, Maity S, SinghMalla P, Natarajanseenivasan K, Hooper R, Shannon CE, Tourtellotte WG, Singh BB, Reeves WB, Sharma K, Norton L, Srikant Tags: Sci Signal Source Type: research

Sporadic activation of an oxidative stress-dependent NRF2-p53 signaling network in breast epithelial spheroids and premalignancies.
Abstract Breast and mammary epithelial cells experience different local environments during tissue development and tumorigenesis. Microenvironmental heterogeneity gives rise to distinct cell regulatory states whose identity and importance are just beginning to be appreciated. Cellular states diversify when clonal three-dimensional (3D) spheroids are cultured in basement membrane, and one such state is associated with stress tolerance and poor response to anticancer therapeutics. Here, we found that this state was jointly coordinated by the NRF2 and p53 pathways, which were costabilized by spontaneous oxidative str...
Source: Science Signaling - April 14, 2020 Category: Biomedical Science Authors: Pereira EJ, Burns JS, Lee CY, Marohl T, Calderon D, Wang L, Atkins KA, Wang CC, Janes KA Tags: Sci Signal Source Type: research

Diacylglycerol kinase ζ promotes actin cytoskeleton remodeling and mechanical forces at the B cell immune synapse.
Diacylglycerol kinase ζ promotes actin cytoskeleton remodeling and mechanical forces at the B cell immune synapse. Sci Signal. 2020 Apr 14;13(627): Authors: Merino-Cortés SV, Gardeta SR, Roman-Garcia S, Martínez-Riaño A, Pineau J, Liebana R, Merida I, Dumenil AL, Pierobon P, Husson J, Alarcon B, Carrasco YR Abstract 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 DGKζ promotes lymphocyte function-associated antigen 1 (LFA-1)-media...
Source: Science Signaling - April 14, 2020 Category: Biomedical Science Authors: Merino-Cortés SV, Gardeta SR, Roman-Garcia S, Martínez-Riaño A, Pineau J, Liebana R, Merida I, Dumenil AL, Pierobon P, Husson J, Alarcon B, Carrasco YR Tags: Sci Signal Source Type: research

IFN- κ suppresses the replication of influenza A viruses through the IFNAR-MAPK-Fos-CHD6 axis.
IFN-κ suppresses the replication of influenza A viruses through the IFNAR-MAPK-Fos-CHD6 axis. Sci Signal. 2020 Apr 07;13(626): Authors: He Y, Fu W, Cao K, He Q, Ding X, Chen J, Zhu L, Chen T, Ding L, Yang Y, Zhu C, Yuan S, Li Z, Zhao C, Zhang X, Xu J Abstract Type I interferons (IFNs) are the first line of defense against viral infection. Using a mouse model of influenza A virus infection, we found that IFN-κ was one of the earliest responding type I IFNs after infection with H9N2, a low-pathogenic avian influenza A virus, whereas this early induction did not occur upon infection with the ...
Source: Science Signaling - April 7, 2020 Category: Biomedical Science Authors: He Y, Fu W, Cao K, He Q, Ding X, Chen J, Zhu L, Chen T, Ding L, Yang Y, Zhu C, Yuan S, Li Z, Zhao C, Zhang X, Xu J Tags: Sci Signal Source Type: research

Endothelium-targeted deletion of the miR-15a/16-1 cluster ameliorates blood-brain barrier dysfunction in ischemic stroke.
Abstract The blood-brain barrier (BBB) maintains a stable brain microenvironment. Breakdown of BBB integrity during cerebral ischemia initiates a devastating cascade of events that eventually leads to neuronal loss. MicroRNAs are small noncoding RNAs that suppress protein expression, and we previously showed that the miR-15a/16-1 cluster is involved in the pathogenesis of ischemic brain injury. Here, we demonstrated that when subjected to experimentally induced stroke, mice with an endothelial cell (EC)-selective deletion of miR-15a/16-1 had smaller brain infarcts, reduced BBB leakage, and decreased infiltration o...
Source: Science Signaling - April 7, 2020 Category: Biomedical Science Authors: Ma F, Sun P, Zhang X, Hamblin MH, Yin KJ Tags: Sci Signal Source Type: research

Calmodulin disrupts plasma membrane localization of farnesylated KRAS4b by sequestering its lipid moiety.
Abstract KRAS4b is a small guanosine triphosphatase (GTPase) protein that regulates several signal transduction pathways that underlie cell proliferation, differentiation, and survival. KRAS4b function requires prenylation of its C terminus and recruitment to the plasma membrane, where KRAS4b activates effector proteins including the RAF family of kinases. The Ca2+-sensing protein calmodulin (CaM) has been suggested to regulate the localization of KRAS4b through direct, Ca2+-dependent interaction, but how CaM and KRAS4b functionally interact is controversial. Here, we determined a crystal structure, which was supp...
Source: Science Signaling - March 31, 2020 Category: Biomedical Science Authors: Grant BMM, Enomoto M, Back SI, Lee KY, Gebregiworgis T, Ishiyama N, Ikura M, Marshall CB Tags: Sci Signal Source Type: research

Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists.
Abstract Biased agonism at G protein-coupled receptors describes the phenomenon whereby some drugs can activate some downstream signaling activities to the relative exclusion of others. Descriptions of biased agonism focusing on the differential engagement of G proteins versus β-arrestins are commonly limited by the small response windows obtained in pathways that are not amplified or are less effectively coupled to receptor engagement, such as β-arrestin recruitment. At the μ-opioid receptor (MOR), G protein-biased ligands have been proposed to induce less constipation and respiratory depressant side e...
Source: Science Signaling - March 31, 2020 Category: Biomedical Science Authors: Gillis A, Gondin AB, Kliewer A, Sanchez J, Lim HD, Alamein C, Manandhar P, Santiago M, Fritzwanker S, Schmidel F, Katte TA, Reekie T, Grimsey NL, Kassiou M, Kellam B, Krasel C, Halls ML, Connor M, Lane JR, Schulz S, Christie MJ, Canals M Tags: Sci Signal Source Type: research

4-1BB costimulation promotes CAR T cell survival through noncanonical NF- κB signaling.
4-1BB costimulation promotes CAR T cell survival through noncanonical NF-κB signaling. Sci Signal. 2020 Mar 31;13(625): Authors: Philipson BI, O'Connor RS, May MJ, June CH, Albelda SM, Milone MC Abstract Clinical response to chimeric antigen receptor (CAR) T cell therapy is correlated with CAR T cell persistence, especially for CAR T cells that target CD19+ hematologic malignancies. 4-1BB-costimulated CAR (BBζ) T cells exhibit longer persistence after adoptive transfer than do CD28-costimulated CAR (28ζ) T cells. 4-1BB signaling improves T cell persistence even in the context of 28&zet...
Source: Science Signaling - March 31, 2020 Category: Biomedical Science Authors: Philipson BI, O'Connor RS, May MJ, June CH, Albelda SM, Milone MC Tags: Sci Signal Source Type: research

Noncanonical STAT1 phosphorylation expands its transcriptional activity into promoting LPS-induced IL-6 and IL-12p40 production.
Abstract 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-κB. In human macrophages, TLR4 endocytosis activated a noncanonical phosphorylation of STAT1 at Thr749, which subsequently promoted the production of interleukin-6 (IL-6) an...
Source: Science Signaling - March 24, 2020 Category: Biomedical Science Authors: Metwally H, Tanaka T, Li S, Parajuli G, Kang S, Hanieh H, Hashimoto S, Chalise JP, Gemechu Y, Standley DM, Kishimoto T Tags: Sci Signal Source Type: research

An atlas of human metabolism.
sen J Abstract Genome-scale metabolic models (GEMs) are valuable tools to study metabolism and provide a scaffold for the integrative analysis of omics data. Researchers have developed increasingly comprehensive human GEMs, but the disconnect among different model sources and versions impedes further progress. We therefore integrated and extensively curated the most recent human metabolic models to construct a consensus GEM, Human1. We demonstrated the versatility of Human1 through the generation and analysis of cell- and tissue-specific models using transcriptomic, proteomic, and kinetic data. We also present an ...
Source: Science Signaling - March 24, 2020 Category: Biomedical Science Authors: Robinson JL, Kocabaş P, Wang H, Cholley PE, Cook D, Nilsson A, Anton M, Ferreira R, Domenzain I, Billa V, Limeta A, Hedin A, Gustafsson J, Kerkhoven EJ, Svensson LT, Palsson BO, Mardinoglu A, Hansson L, Uhlén M, Nielsen J Tags: Sci Signal Source Type: research

RAS, wanted dead or alive: Advances in targeting RAS mutant cancers.
Abstract Oncogenic RAS proteins, which are mutated in approximately 24% of all human cancers, have earned a well-deserved reputation as being "undruggable." However, several studies have challenged that reputation. With the first small molecules that directly target one oncogenic RAS mutant (G12C) undergoing clinical evaluation, there have been substantial advances in finding anti-RAS therapeutic strategies. Furthermore, new insights have come from the growing appreciation that neither all RAS proteins (HRAS, NRAS, and KRAS4A/KRAS4B) nor all oncogenic RAS mutations (such as at residues Gly12, Gly13, and ...
Source: Science Signaling - March 24, 2020 Category: Biomedical Science Authors: Stalnecker CA, Der CJ Tags: Sci Signal Source Type: research

Stress granules sense metabolic stress at the plasma membrane and potentiate recovery by storing active Pkc1.
Abstract As the physical barrier between the cell and the outside environment, the plasma membrane is well-positioned to be the first responder to stress. The membrane is also highly vulnerable to many types of perturbation, including heat, force, osmotic pressure, lipid shortage, and starvation. To determine whether the structural changes in the plasma membrane of Saccharomyces cerevisiae brought about by nutrient stress can be communicated to regulatory networks within the cell, we identified proteins that interact with stress granules (SGs), subcellular structures composed of proteins, and nontranslated RNAs th...
Source: Science Signaling - March 17, 2020 Category: Biomedical Science Authors: Amen T, Kaganovich D Tags: Sci Signal Source Type: research

PTPN22 phosphorylation acts as a molecular rheostat for the inhibition of TCR signaling.
Abstract 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 ...
Source: Science Signaling - March 17, 2020 Category: Biomedical Science Authors: Yang S, Svensson MND, Harder NHO, Hsieh WC, Santelli E, Kiosses WB, Moresco JJ, Yates JR, King CC, Liu L, Stanford SM, Bottini N Tags: Sci Signal Source Type: research

SERP1 is an assembly regulator of γ-secretase in metabolic stress conditions.
SERP1 is an assembly regulator of γ-secretase in metabolic stress conditions. Sci Signal. 2020 Mar 17;13(623): Authors: Jung S, Hyun J, Nah J, Han J, Kim SH, Park J, Oh Y, Gwon Y, Moon S, Jo DG, Jung YK Abstract The enzyme γ-secretase generates β-amyloid (Aβ) peptides by cleaving amyloid protein precursor (APP); the aggregation of these peptides is associated with Alzheimer's disease (AD). Despite the development of various γ-secretase regulators, their clinical use is limited by coincident disruption of other γ-secretase-regulated substrates, such as Notch. Using a g...
Source: Science Signaling - March 17, 2020 Category: Biomedical Science Authors: Jung S, Hyun J, Nah J, Han J, Kim SH, Park J, Oh Y, Gwon Y, Moon S, Jo DG, Jung YK Tags: Sci Signal Source Type: research

Mortalin (HSPA9) facilitates BRAF-mutant tumor cell survival by suppressing ANT3-mediated mitochondrial membrane permeability.
Abstract Mortalin [also known as heat shock protein family A (HSP70) member 9 (HSPA9) or glucose-regulated protein 75 (GRP75)] is a mitochondrial molecular chaperone that is often up-regulated and mislocalized in tumors with abnormal activation of the kinases MEK and ERK. Here, we found that mortalin depletion was selectively lethal to tumor and immortalized normal cells expressing the mutant kinase B-RafV600E or the chimeric protein ΔRaf-1:ER and that MEK-ERK-sensitive regulation of the peptide-binding domain in mortalin was critical to cell survival or death. Proteomics screening identified adenine nucleot...
Source: Science Signaling - March 10, 2020 Category: Biomedical Science Authors: Wu PK, Hong SK, Chen W, Becker AE, Gundry RL, Lin CW, Shao H, Gestwicki JE, Park JI Tags: Sci Signal Source Type: research