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Science Signaling

Zack Zurawski, Analisa D Thompson Gray, Lillian J Brady, Brian Page, Emily Church, Nicholas A Harris, Michael R Dohn, Yun Young Yim, Karren Hyde, Douglas P Mortlock, Carrie K Jones, Danny G Winder, Simon Alford, Heidi E Hamm
G protein-coupled receptors (GPCRs) that couple to Gi/o proteins modulate neurotransmission presynaptically by inhibiting exocytosis. Release of Gβγ subunits from activated G proteins decreases the activity of voltage-gated Ca2+ channels (VGCCs), decreasing excitability. A less understood Gβγ-mediated mechanism downstream of Ca2+ entry is the binding of Gβγ to SNARE complexes, which facilitate the fusion of vesicles with the cell plasma membrane in exocytosis. Here, we generated mice expressing a form of the SNARE protein SNAP25 with premature truncation of the C terminus and that were therefore partially deficient in this interaction...
February 19, 2019: Science Signaling
Sumit J Bandekar, Nadia Arang, Ena S Tully, Brittany A Tang, Brenna L Barton, Sheng Li, J Silvio Gutkind, John J G Tesmer
The C-terminal guanine nucleotide exchange factor (GEF) module of Trio (TrioC) transfers signals from the Gαq/11 subfamily of heterotrimeric G proteins to the small guanosine triphosphatase (GTPase) RhoA, enabling Gαq/11 -coupled G protein-coupled receptors (GPCRs) to control downstream events, such as cell motility and gene transcription. This conserved signal transduction axis is crucial for tumor growth in uveal melanoma. Previous studies indicate that the GEF activity of the TrioC module is autoinhibited, with release of autoinhibition upon Gαq/11 binding...
February 19, 2019: Science Signaling
Shin-Ichi Kano, Eric Y Choi, Eisuke Dohi, Swati Agarwal, Daniel J Chang, Ashley M Wilson, Brian D Lo, Indigo V L Rose, Santiago Gonzalez, Takashi Imai, Akira Sawa
Astrocytes and microglia play critical roles in brain inflammation. Here, we report that glutathione S -transferases (GSTs), particularly GSTM1, promote proinflammatory signaling in astrocytes and contribute to astrocyte-mediated microglia activation during brain inflammation. In vivo, astrocyte-specific knockdown of GSTM1 in the prefrontal cortex attenuated microglia activation in brain inflammation induced by systemic injection of lipopolysaccharides (LPS). Knocking down GSTM1 in astrocytes also attenuated LPS-induced production of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) by microglia when the two cell types were cocultured...
February 19, 2019: Science Signaling
Maria C Ramello, Ismahène Benzaïd, Brent M Kuenzi, Maritza Lienlaf-Moreno, Wendy M Kandell, Daniel N Santiago, Mibel Pabón-Saldaña, Lancia Darville, Bin Fang, Uwe Rix, Sean Yoder, Anders Berglund, John M Koomen, Eric B Haura, Daniel Abate-Daga
Adoptive transfer of T cells that express a chimeric antigen receptor (CAR) is an approved immunotherapy that may be curative for some hematological cancers. To better understand the therapeutic mechanism of action, we systematically analyzed CAR signaling in human primary T cells by mass spectrometry. When we compared the interactomes and the signaling pathways activated by distinct CAR-T cells that shared the same antigen-binding domain but differed in their intracellular domains and their in vivo antitumor efficacy, we found that only second-generation CARs induced the expression of a constitutively phosphorylated form of CD3ζ that resembled the endogenous species...
February 12, 2019: Science Signaling
Mariacarmela Allocca, Joshua J Corrigan, Aprotim Mazumder, Kimberly R Fake, Leona D Samson
DNA-alkylating agents are commonly used to kill cancer cells, but the base excision repair (BER) pathway they trigger can also produce toxic intermediates that cause tissue damage, such as retinal degeneration (RD). Apoptosis, a process of programmed cell death, is assumed to be the main mechanism of this alkylation-induced photoreceptor (PR) cell death in RD. Here, we studied the involvement of necroptosis (another programmed cell death process) and inflammation in alkylation-induced RD. Male mice exposed to a methylating agent exhibited a reduced number of PR cell rows, active gliosis, and cytokine induction and macrophage infiltration in the retina...
February 12, 2019: Science Signaling
Marc Herb, Alexander Gluschko, Katja Wiegmann, Alina Farid, Anne Wolf, Olaf Utermöhlen, Oleg Krut, Martin Krönke, Michael Schramm
A major function of macrophages during infection is initiation of the proinflammatory response, leading to the secretion of cytokines that help to orchestrate the immune response. Here, we identify reactive oxygen species (ROS) as crucial mediators of proinflammatory signaling leading to cytokine secretion in Listeria monocytogenes- infected macrophages. ROS produced by NADPH oxidases (Noxes), such as Nox2, are key components of the macrophage response to invading pathogens; however, our data show that the ROS that mediated proinflammatory signaling were produced by mitochondria (mtROS)...
February 12, 2019: Science Signaling
Fernanda G Kugeratski, Samuel J Atkinson, Lisa J Neilson, Sergio Lilla, John R P Knight, Jens Serneels, Amelie Juin, Shehab Ismail, David M Bryant, Elke K Markert, Laura M Machesky, Massimiliano Mazzone, Owen J Sansom, Sara Zanivan
Intratumoral hypoxia causes the formation of dysfunctional blood vessels, which contribute to tumor metastasis and reduce the efficacy of therapeutic treatments. Blood vessels are embedded in the tumor stroma of which cancer-associated fibroblasts (CAFs) constitute a prominent cellular component. We found that hypoxic human mammary CAFs promoted angiogenesis in CAF-endothelial cell cocultures in vitro. Mass spectrometry-based proteomic analysis of the CAF secretome unraveled that hypoxic CAFs contributed to blood vessel abnormalities by altering their secretion of various pro- and anti-angiogenic factors...
February 5, 2019: Science Signaling
Mei Suen Kong, Akiko Hashimoto-Tane, Yusuke Kawashima, Machie Sakuma, Tadashi Yokosuka, Kohei Kometani, Reiko Onishi, Nick Carpino, Osamu Ohara, Tomohiro Kurosaki, Kia Kien Phua, Takashi Saito
T cell activation is initiated by signaling molecules downstream of the T cell receptor (TCR) that are organized by adaptor proteins. CIN85 (Cbl-interacting protein of 85 kDa) is one such adaptor protein. Here, we showed that CIN85 limited T cell responses to TCR stimulation. Compared to activated wild-type (WT) T cells, those that lacked CIN85 produced more IL-2 and exhibited greater proliferation. After stimulation of WT T cells with their cognate antigen, CIN85 was recruited to the TCR signaling complex...
February 5, 2019: Science Signaling
Makhdum Ahmed, Elizabeth Lorence, Jeffrey Wang, Dayoung Jung, Liang Zhang, Krystle Nomie, Michael Wang
Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma that is largely chemoresistant. Ibrutinib, a drug that inhibits Bruton's tyrosine kinase (BTK), has improved the overall survival of patients with MCL; however, resistance to ibrutinib has emerged as a decisive, negative factor in the prognosis of MCL. Adopting a more patient-centric therapeutic approach that incorporates applied genomics and interrogation of B cell signaling pathways may offer an alternative route to reach durable remission in patients with MCL...
February 5, 2019: Science Signaling
Arnaud Augert, Emily Eastwood, Ali H Ibrahim, Nan Wu, Eli Grunblatt, Ryan Basom, Denny Liggitt, Keith D Eaton, Renato Martins, John T Poirier, Charles M Rudin, Francesca Milletti, Wei-Yi Cheng, Fiona Mack, David MacPherson
Small cell lung cancer (SCLC) is a recalcitrant, aggressive neuroendocrine-type cancer for which little change to first-line standard-of-care treatment has occurred within the last few decades. Unlike nonsmall cell lung cancer (NSCLC), SCLC harbors few actionable mutations for therapeutic intervention. Lysine-specific histone demethylase 1A (LSD1 also known as KDM1A) inhibitors were previously shown to have selective activity in SCLC models, but the underlying mechanism was elusive. Here, we found that exposure to the selective LSD1 inhibitor ORY-1001 activated the NOTCH pathway, resulting in the suppression of the transcription factor ASCL1 and the repression of SCLC tumorigenesis...
February 5, 2019: Science Signaling
Shawn T Beug, Herman H Cheung, Tarun Sanda, Martine St-Jean, Caroline E Beauregard, Hapsatou Mamady, Stephen D Baird, Eric C LaCasse, Robert G Korneluk
The controlled production and downstream signaling of the inflammatory cytokine tumor necrosis factor-α (TNF-α) are important for immunity and its anticancer effects. Although chronic stimulation with TNF-α is detrimental to the health of the host in several autoimmune and inflammatory disorders, TNF-α-contrary to what its name implies-leads to cancer formation by promoting cell proliferation and survival. Smac mimetic compounds (SMCs), small-molecule antagonists of inhibitor of apoptosis proteins (IAPs), switch the TNF-α signal from promoting survival to promoting death in cancer cells...
January 29, 2019: Science Signaling
Aaron B Edmund, Timothy F Walseth, Nicholas M Levinson, Lincoln R Potter
Natriuretic peptides regulate multiple physiologic systems by activating transmembrane receptors containing intracellular guanylyl cyclase domains, such as GC-A and GC-B, also known as Npr1 and Npr2, respectively. Both enzymes contain an intracellular, phosphorylated pseudokinase domain (PKD) critical for activation of the C-terminal cGMP-synthesizing guanylyl cyclase domain. Because ATP allosterically activates GC-A and GC-B, we investigated how ATP binding to the PKD influenced guanylyl cyclase activity. Molecular modeling indicated that all the residues of the ATP-binding site of the prototypical kinase PKA, except the catalytic aspartate, are conserved in the PKDs of GC-A and GC-B...
January 29, 2019: Science Signaling
Tara H W Dobson, Rong-Hua Tao, Jyothishmathi Swaminathan, Shinji Maegawa, Shavali Shaik, Javiera Bravo-Alegria, Ajay Sharma, Bridget Kennis, Yanwen Yang, Keri Callegari, Amanda R Haltom, Pete Taylor, Mari Kogiso, Lin Qi, Soumen Khatua, Stewart Goldman, Rishi R Lulla, Jason Fangusaro, Tobey J MacDonald, Xiao-Nan Li, Cynthia Hawkins, Veena Rajaram, Vidya Gopalakrishnan
In medulloblastomas (MBs), the expression and activity of RE1-silencing transcription factor (REST) is increased in tumors driven by the sonic hedgehog (SHH) pathway, specifically the SHH-α (children 3 to 16 years) and SHH-β (infants) subgroups. Neuronal maturation is greater in SHH-β than SHH-α tumors, but both correlate with poor overall patient survival. We studied the contribution of REST to MB using a transgenic mouse model ( RESTTG ) wherein conditional NeuroD2 -controlled REST transgene expression in lineage-committed Ptch1 +/- cerebellar granule neuron progenitors (CGNPs) accelerated tumorigenesis and increased penetrance and infiltrative disease...
January 22, 2019: Science Signaling
Elise J Needham, Benjamin L Parker, Timur Burykin, David E James, Sean J Humphrey
Protein phosphorylation is a major regulator of protein function and biological outcomes. This was first recognized through functional biochemical experiments, and in the past decade, major technological advances in mass spectrometry have enabled the study of protein phosphorylation on a global scale. This rapidly growing field of phosphoproteomics has revealed that more than 100,000 distinct phosphorylation events occur in human cells, which likely affect the function of every protein. Phosphoproteomics has improved the understanding of the function of even the most well-characterized protein kinases by revealing new downstream substrates and biology...
January 22, 2019: Science Signaling
Michael B Yaffe
Genetic approaches to cancer research have dramatically advanced our understanding of the pathophysiology of this disease, leading to similar genetics-based approaches for precision therapy, which have been less successful. Reconfiguring and adapting the types of technologies that underlie genetic research to dissect tumor cell signaling in clinical samples may offer an alternative road forward.
January 22, 2019: Science Signaling
Martin Schwill, Rastislav Tamaskovic, Aaron S Gajadhar, Florian Kast, Forest M White, Andreas Plückthun
Drug-induced compensatory signaling and subsequent rewiring of the signaling pathways that support cell proliferation and survival promote the development of acquired drug resistance in tumors. Here, we sought to analyze the adaptive kinase response in cancer cells after distinct treatment with agents targeting human epidermal growth factor receptor 2 (HER2), specifically those that induce either only temporary cell cycle arrest or, alternatively, apoptosis in HER2-overexpressing cancers. We compared trastuzumab, ARRY380, the combination thereof, and a biparatopic, HER2-targeted designed ankyrin repeat protein (DARPin; specifically, 6L1G) and quantified the phosphoproteome by isobaric tagging using tandem mass tag liquid chromatography/tandem mass spectrometry (TMT LC-MS/MS)...
January 22, 2019: Science Signaling
Jenny J Y Lin, Shalini T Low-Nam, Katherine N Alfieri, Darren B McAffee, Nicole C Fay, Jay T Groves
T cell receptor (TCR) binding to agonist peptide major histocompatibility complex (pMHC) triggers signaling events that initiate T cell responses. This system is remarkably sensitive, requiring only a few binding events to successfully activate a cellular response. On average, activating pMHC ligands exhibit mean dwell times of at least a few seconds when bound to the TCR. However, a T cell accumulates pMHC-TCR interactions as a stochastic series of discrete, single-molecule binding events whose individual dwell times are broadly distributed...
January 15, 2019: Science Signaling
Mariko Takahashi, Kumi Izawa, Makoto Urai, Yoshinori Yamanishi, Akie Maehara, Masamichi Isobe, Toshihiro Matsukawa, Ayako Kaitani, Ayako Takamori, Shino Uchida, Hiromichi Yamada, Masakazu Nagamine, Tomoaki Ando, Toshiaki Shimizu, Hideoki Ogawa, Ko Okumura, Yuki Kinjo, Toshio Kitamura, Jiro Kitaura
Zymosan is a glucan that is a component of the yeast cell wall. Here, we determined the mechanisms underlying the zymosan-induced accumulation of neutrophils in mice. Loss of the receptor CD300b reduced the number of neutrophils recruited to dorsal air pouches in response to zymosan, but not in response to lipopolysaccharide (LPS), a bacterial membrane component recognized by Toll-like receptor 4 (TLR4). An inhibitor of nitric oxide (NO) synthesis reduced the number of neutrophils in the zymosan-treated air pouches of wild-type mice to an amount comparable to that in CD300b-/- mice...
January 15, 2019: Science Signaling
Monika Lodyga, Elizabeth Cambridge, Henna M Karvonen, Pardis Pakshir, Brian Wu, Stellar Boo, Melanie Kiebalo, Riitta Kaarteenaho, Michael Glogauer, Mohit Kapoor, Kjetil Ask, Boris Hinz
Macrophages contribute to the activation of fibroblastic cells into myofibroblasts, which secrete collagen and contract the collagen matrix to acutely repair injured tissue. Persistent myofibroblast activation leads to the accumulation of fibrotic scar tissue that impairs organ function. We investigated the key processes that turn acute beneficial repair into destructive progressive fibrosis. We showed that homotypic cadherin-11 interactions promoted the specific binding of macrophages to and persistent activation of profibrotic myofibroblasts...
January 15, 2019: Science Signaling
Souvarish Sarkar, Dharmin Rokad, Emir Malovic, Jie Luo, Dilshan S Harischandra, Huajun Jin, Vellareddy Anantharam, Xuemei Huang, Mechelle Lewis, Arthi Kanthasamy, Anumantha G Kanthasamy
Chronic, sustained inflammation underlies many pathological conditions, including neurodegenerative diseases. Divalent manganese (Mn2+ ) exposure can stimulate neurotoxicity by increasing inflammation. In this study, we examined whether Mn2+ activates the multiprotein NLRP3 inflammasome complex to promote neuroinflammation. Exposing activated mouse microglial cells to Mn2+ substantially augmented NLRP3 abundance, caspase-1 cleavage, and maturation of the inflammatory cytokine interleukin-1β (IL-1β). Exposure of mice to Mn2+ had similar effects in brain microglial cells...
January 8, 2019: Science Signaling
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