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Science Signaling

Akiyuki Nishimura, Tsukasa Shimauchi, Tomohiro Tanaka, Kakeru Shimoda, Takashi Toyama, Naoyuki Kitajima, Tatsuya Ishikawa, Naoya Shindo, Takuro Numaga-Tomita, Satoshi Yasuda, Yoji Sato, Koichiro Kuwahara, Yoshito Kumagai, Takaaki Akaike, Tomomi Ide, Akio Ojida, Yasuo Mori, Motohiro Nishida
Defective mitochondrial dynamics through aberrant interactions between mitochondria and actin cytoskeleton is increasingly recognized as a key determinant of cardiac fragility after myocardial infarction (MI). Dynamin-related protein 1 (Drp1), a mitochondrial fission-accelerating factor, is activated locally at the fission site through interactions with actin. Here, we report that the actin-binding protein filamin A acted as a guanine nucleotide exchange factor for Drp1 and mediated mitochondrial fission-associated myocardial senescence in mice after MI...
November 13, 2018: Science Signaling
Ivana Halova, Monika Bambouskova, Lubica Draberova, Viktor Bugajev, Petr Draber
Chemotaxis of mast cells is one of the crucial steps in their development and function. Non-T cell activation linker (NTAL) is a transmembrane adaptor protein that inhibits the activation of mast cells and B cells in a phosphorylation-dependent manner. Here, we studied the role of NTAL in the migration of mouse mast cells stimulated by prostaglandin E2 (PGE2 ). Although PGE2 does not induce the tyrosine phosphorylation of NTAL, unlike IgE immune complex antigens, we found that loss of NTAL increased the chemotaxis of mast cells toward PGE2 Stimulation of mast cells that lacked NTAL with PGE2 enhanced the phosphorylation of AKT and the production of phosphatidylinositol 3,4,5-trisphosphate...
November 13, 2018: Science Signaling
Michael J Boyer, Satoru Eguchi
The interplay between the actin cytoskeleton and mitochondria has been implicated in cell and tissue homeostasis and physiological function. In this issue of Science Signaling , Nishimura et al. demonstrate that inhibiting the interaction of filamin A, an actin cytoskeleton regulator, with Drp1, a modulator of mitochondrial dynamics, attenuates mitochondrial hyperfission and cardiomyocyte senescence after myocardial infarction.
November 13, 2018: Science Signaling
JingJing Liu, Xianlin Zou, Tetsuya Gotoh, Anne M Brown, Liang Jiang, Esther L Wisdom, Jae Kyoung Kim, Carla V Finkielstein
The circadian clock relies on posttranslational modifications to set the timing for degradation of core regulatory components, which drives clock progression. Ubiquitin-modifying enzymes that target clock components for degradation mainly recognize phosphorylated substrates. Degradation of the circadian clock component PERIOD 2 (PER2) is mediated by its phospho-specific recognition by β-transducin repeat-containing proteins (β-TrCPs), which are F-box-containing proteins that function as substrate recognition subunits of the SCFβ-TRCP ubiquitin ligase complex...
November 13, 2018: Science Signaling
Dalee Zhou, Koji Ota, Charlee Nardin, Michelle Feldman, Adam Widman, Olivia Wind, Amanda Simon, Michael Reilly, Lonny R Levin, Jochen Buck, Kazumasa Wakamatsu, Shosuke Ito, Jonathan H Zippin
The production of melanin increases skin pigmentation and reduces the risk of skin cancer. Melanin production depends on the pH of melanosomes, which are more acidic in lighter-skinned than in darker-skinned people. We showed that inhibition of soluble adenylyl cyclase (sAC) controlled pigmentation by increasing the pH of melanosomes both in cells and in vivo. Distinct from the canonical melanocortin 1 receptor (MC1R)-dependent cAMP pathway that controls pigmentation by altering gene expression, we found that inhibition of sAC increased pigmentation by increasing the activity of tyrosinase, the rate-limiting enzyme in melanin synthesis, which is more active at basic pH...
November 6, 2018: Science Signaling
David Pincus, Jai P Pandey, Zoë A Feder, Pau Creixell, Orna Resnekov, Kimberly A Reynolds
Phosphoregulation, in which the addition of a negatively charged phosphate group modulates protein activity, enables dynamic cellular responses. To understand how new phosphoregulation might be acquired, we mutationally scanned the surface of a prototypical yeast kinase (Kss1) to identify potential regulatory sites. The data revealed a set of spatially distributed "hotspots" that might have coevolved with the active site and preferentially modulated kinase activity. By engineering simple consensus phosphorylation sites at these hotspots, we rewired cell signaling in yeast...
November 6, 2018: Science Signaling
Jeffrey S Smith, Lowell T Nicholson, Jutamas Suwanpradid, Rachel A Glenn, Nicole M Knape, Priya Alagesan, Jaimee N Gundry, Thomas S Wehrman, Amber Reck Atwater, Michael D Gunn, Amanda S MacLeod, Sudarshan Rajagopal
The chemokine receptor CXCR3 plays a central role in inflammation by mediating effector/memory T cell migration in various diseases; however, drugs targeting CXCR3 and other chemokine receptors are largely ineffective in treating inflammation. Chemokines, the endogenous peptide ligands of chemokine receptors, can exhibit so-called biased agonism by selectively activating either G protein- or β-arrestin-mediated signaling after receptor binding. Biased agonists might be used as more targeted therapeutics to differentially regulate physiological responses, such as immune cell migration...
November 6, 2018: Science Signaling
Jimin Yuan, Wan Hwa Ng, Zizi Tian, Jiajun Yap, Manuela Baccarini, Zhongzhou Chen, Jiancheng Hu
RAS-RAF-MEK-ERK signaling has a well-defined role in cancer biology. Although aberrant pathway activation occurs mostly upstream of the kinase MEK, mutations in MEK are prevalent in some cancer subsets. Here, we found that cancer-related, activating mutations in MEK can be classified into two groups: those that relieve inhibitory interactions with the helix A region and those that are in-frame deletions of the β3-αC loop, which enhance MEK1 homodimerization. The former, helix A-associated mutants, are inhibited by traditional MEK inhibitors...
October 30, 2018: Science Signaling
Laura Vachel, Nikolay Shcheynikov, Osamu Yamazaki, Moran Fremder, Ehud Ohana, Aran Son, Dong Min Shin, Ai Yamazaki-Nakazawa, Chin-Rang Yang, Mark A Knepper, Shmuel Muallem
IRBIT is a multifunctional protein that controls the activity of various epithelial ion transporters including NBCe1-B. Interaction with IRBIT increases NBCe1-B activity and exposes two cryptic Cl- -sensing GXXXP sites that enable regulation of NBCe1-B by intracellular Cl- (Cl- in ). Here, phosphoproteomic analysis revealed that IRBIT controlled five phosphorylation sites in NBCe1-B that determined both the active conformation of the transporter and its regulation by Cl- in Mutational analysis suggested that the phosphorylation status of Ser232 , Ser233 , and Ser235 was regulated by IRBIT and determined whether NBCe1 transporters are in active or inactive conformations...
October 30, 2018: Science Signaling
Mykhaylo V Artamonov, Swapnil K Sonkusare, Miranda E Good, Ko Momotani, Masumi Eto, Brant E Isakson, Thu H Le, Eric L Cope, Zygmunt S Derewenda, Urszula Derewenda, Avril V Somlyo
Smooth muscle contraction is triggered when Ca2+ /calmodulin-dependent myosin light chain kinase (MLCK) phosphorylates the regulatory light chain of myosin (RLC20 ). However, blood vessels from Mlck -deficient mouse embryos retain the ability to contract, suggesting the existence of additional regulatory mechanisms. We showed that the p90 ribosomal S6 kinase 2 (RSK2) also phosphorylated RLC20 to promote smooth muscle contractility. Active, phosphorylated RSK2 was present in mouse resistance arteries under normal basal tone, and phosphorylation of RSK2 increased with myogenic vasoconstriction or agonist stimulation...
October 30, 2018: Science Signaling
Eugenio Santos, Piero Crespo
Data accumulated over more than three decades demonstrate that the assembly of macrocomplexes, mainly of dimers, is widespread among the members of the different tiers that constitute the RAS-ERK pathway. In this issue of Science Signaling , Yuan et al. report that MEK1 homodimerization is necessary for signal transduction through the RAF-ERK pathway and that cancer-related MEK1 mutations confer enhanced dimerization and resistance to MEK inhibitors. These findings endorse interference with RAS-ERK pathway-component dimerization as a potential therapeutic strategy in cancer patients...
October 30, 2018: Science Signaling
Kexin Shen, Jamie A Moroco, Ravi K Patel, Haibin Shi, John R Engen, Heather R Dorman, Thomas E Smithgall
Fgr is a member of the Src family of nonreceptor tyrosine kinases, which are overexpressed and constitutively active in many human cancers. Fgr expression is restricted to myeloid hematopoietic cells and is markedly increased in a subset of bone marrow samples from patients with acute myeloid leukemia (AML). Here, we investigated the oncogenic potential of Fgr using Rat-2 fibroblasts that do not express the kinase. Expression of either wild-type or regulatory tail-mutant constructs of Fgr promoted cellular transformation (inferred from colony formation in soft agar), which was accompanied by phosphorylation of the Fgr activation loop, suggesting that the kinase domain of Fgr functions independently of regulation by its noncatalytic SH3-SH2 region...
October 23, 2018: Science Signaling
Ganlan Bian, Caiyong Yu, Ling Liu, Chao Fang, Kun Chen, Pan Ren, Qian Zhang, Fangfang Liu, Kun Zhang, Qian Xue, Jie Xiang, Hongmin Guo, Jun Song, Yu Zhao, Wutian Wu, Sookja K Chung, Ruixia Sun, Gong Ju, Jian Wang
In many mammals, the eyelids migrate over the eye and fuse during embryogenesis to protect the cornea from damage during birth and early life. Loss-of-function mutations affecting the epidermal growth factor receptor (EGFR) signaling pathway cause an eyes-open-at-birth (EOB) phenotype in rodents. We identified an insertional mutation in Spinster homolog 2 ( Spns2 ) in a strain of transgenic rats exhibiting the EOB phenotype. Spns2, a sphingosine 1-phosphate (S1P) transporter that releases S1P from cells, was enriched at the tip of developing eyelids in wild-type rat embryos...
October 23, 2018: Science Signaling
Claire Angebault, Jérémy Fauconnier, Simone Patergnani, Jennifer Rieusset, Alberto Danese, Corentin A Affortit, Jolanta Jagodzinska, Camille Mégy, Mélanie Quiles, Chantal Cazevieille, Julia Korchagina, Delphine Bonnet-Wersinger, Dan Milea, Christian Hamel, Paolo Pinton, Marc Thiry, Alain Lacampagne, Benjamin Delprat, Cécile Delettre
Communication between the endoplasmic reticulum (ER) and mitochondria plays a pivotal role in Ca2+ signaling, energy metabolism, and cell survival. Dysfunction in this cross-talk leads to metabolic and neurodegenerative diseases. Wolfram syndrome is a fatal neurodegenerative disease caused by mutations in the ER-resident protein WFS1. Here, we showed that WFS1 formed a complex with neuronal calcium sensor 1 (NCS1) and inositol 1,4,5-trisphosphate receptor (IP3 R) to promote Ca2+ transfer between the ER and mitochondria...
October 23, 2018: Science Signaling
Alexis Kaushansky, Lizbeth Hedstrom, Aaron Goldman, Juswinder Singh, Priscilla L Yang, Pradipsinh K Rathod, Michael Cynamon, Dominik Wodarz, Daruka Mahadevan, Andrew Tomaras, Manuel A Navia, Celia A Schiffer
This Editorial discusses the state of research on drug resistance in the fields of cancer, infectious disease, and agriculture. Reaching across the aisle for a more cross-collaborative approach may lead to exciting breakthroughs toward tackling the challenges of drug resistance in each field.
October 23, 2018: Science Signaling
Emily Lorenzen, Emilie Ceraudo, Yamina A Berchiche, Carlos A Rico, Alexandre Fürstenberg, Thomas P Sakmar, Thomas Huber
Chemokines and some chemical analogs of chemokines prevent cellular HIV-1 entry when bound to the HIV-1 coreceptors C-C chemokine receptor 5 (CCR5) or C-X-C chemokine receptor 4 (CXCR4), which are G protein-coupled receptors (GPCRs). The ideal HIV-1 entry blocker targeting the coreceptors would display ligand bias and avoid activating G protein-mediated pathways that lead to inflammation. We compared CCR5-dependent activation of second messenger pathways in a single cell line. We studied two endogenous chemokines [RANTES (also known as CCL5) and MIP-1α (also known as CCL3)] and four chemokine analogs of RANTES (5P12-, 5P14-, 6P4-, and PSC-RANTES)...
October 16, 2018: Science Signaling
Yue Yang, Song Li, Zi-Run Jin, Hong-Bo Jing, Hong-Yan Zhao, Bo-Heng Liu, Ya-Jing Liang, Ling-Yu Liu, Jie Cai, You Wan, Guo-Gang Xing
Cancer-associated pain is debilitating. Understanding the mechanisms that cause it can inform drug development that may improve quality of life in patients. Here, we found that the reduced abundance of potassium channels called TRESK in dorsal root ganglion (DRG) neurons sensitized nociceptive sensory neurons and cancer-associated pain. Overexpressing TRESK in DRG neurons suppressed tumor-induced neuronal hyperexcitability and pain hypersensitivity in bone metastasis model rats, whereas knocking down TRESK increased neuronal hyperexcitability and pain hypersensitivity in normal rats...
October 16, 2018: Science Signaling
Ben Hitchinson, Jonathan M Eby, Xianlong Gao, Francois Guite-Vinet, Joshua J Ziarek, Hazem Abdelkarim, Youngshim Lee, Yukari Okamoto, Sojin Shikano, Matthias Majetschak, Nikolaus Heveker, Brian F Volkman, Nadya I Tarasova, Vadim Gaponenko
Repeated dosing of drugs targeting G protein-coupled receptors can stimulate antagonist tolerance, which reduces their efficacy; thus, strategies to avoid tolerance are needed. The efficacy of AMD3100, a competitive antagonist of the chemokine receptor CXCR4 that mobilizes leukemic blasts from the bone marrow into the blood to sensitize them to chemotherapy, is reduced after prolonged treatment. Tolerance to AMD3100 increases the abundance of CXCR4 on the surface of leukemic blasts, which promotes their rehoming to the bone marrow...
October 16, 2018: Science Signaling
Ameer L Elaimy, Arthur M Mercurio
Vascular endothelial growth factor (VEGF) stimulates endothelial cells to promote both developmental and pathological angiogenesis. VEGF also directly affects tumor cells and is associated with the initiation, progression, and recurrence of tumors, as well as the emergence and maintenance of cancer stem cells (CSCs). Studies have uncovered the importance of the transcriptional regulators YAP and TAZ in mediating VEGF signaling. For example, VEGF stimulates the GTPase activity of Rho family members and thereby alters cytoskeletal dynamics, which contributes to the activation of YAP and TAZ...
October 16, 2018: Science Signaling
Emiliano Cocco, F Javier Carmona, Pedram Razavi, Helen H Won, Yanyan Cai, Valentina Rossi, Carmen Chan, James Cownie, Joanne Soong, Eneda Toska, Sophie G Shifman, Ivana Sarotto, Peter Savas, Michael J Wick, Kyriakos P Papadopoulos, Alyssa Moriarty, Richard E Cutler, Francesca Avogadri-Connors, Alshad S Lalani, Richard P Bryce, Sarat Chandarlapaty, David M Hyman, David B Solit, Valentina Boni, Sherene Loi, José Baselga, Michael F Berger, Filippo Montemurro, Maurizio Scaltriti
Mutations in ERBB2 , the gene encoding epidermal growth factor receptor (EGFR) family member HER2, are common in and drive the growth of "HER2-negative" (not ERBB2 amplified) tumors but are rare in "HER2-positive" ( ERBB2 amplified) breast cancer. We analyzed DNA-sequencing data from HER2-positive patients and used cell lines and a patient-derived xenograft model to test the consequence of HER2 mutations on the efficacy of anti-HER2 agents such as trastuzumab, lapatinib, and neratinib, an irreversible pan-EGFR inhibitor...
October 9, 2018: Science Signaling
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