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From the research laboratory to the database: the Caenorhabditis elegans kinome in UniProtKB

Rossana Zaru, Michele Magrane, Claire O'Donovan
2017 Biochemical Journal  
Protein kinases form one of the largest protein families and are found in all species, from viruses to humans. They catalyze the reversible phosphorylation of proteins, often modifying their activity and localization. They are implicated in virtually all cellular processes and are one of the most intensively studied protein families. In recent years, they have become key therapeutic targets in drug development as natural mutations affecting kinase genes are the cause of many diseases. The vast
more » ... mount of data contained in the primary literature and across a variety of biological data collections highlights the need for a repository where this information is stored in a concise and easily accessible manner. The UniProt Knowledgebase meets this need by providing the scientific community with a comprehensive, high-quality and freely accessible resource of protein sequence and functional information. Here, we describe the expert curation process for kinases, focusing on the Caenorhabditis elegans kinome. The C. elegans kinome is composed of 438 kinases and almost half of them have been functionally characterized, highlighting that C. elegans is a valuable and versatile model organism to understand the role of kinases in biological processes.
doi:10.1042/bcj20160991 pmid:28159896 pmcid:PMC5290486 fatcat:5ttpxbuc5narlgfn73jzyoxrou

Immunological Synapses Are Versatile Structures Enabling Selective T Cell Polarization

David Depoil, Rossana Zaru, Martine Guiraud, Anne Chauveau, Julie Harriague, Georges Bismuth, Clemens Utzny, Sabina Müller, Salvatore Valitutti
2005 Immunity  
(W6/32, ATCC) as described (Zaru et al., 2002) .  ...  Here, we show that accessory molecules also scribed (Zaru et al., 2002) and stained with anti-phosphotyrosine contribute to T cell polarization (Figure 3).  ... 
doi:10.1016/j.immuni.2004.12.010 pmid:15723807 fatcat:voxgjdyjo5bpflup5w46degvce

Exclusion of CD45 from the T-cell receptor signaling area in antigen-stimulated T lymphocytes

Olivier Leupin, Rossana Zaru, Thierry Laroche, Sabina Müller, Salvatore Valitutti
2000 Current Biology  
T lymphocytes are activated by the engagement of their antigen receptors (TCRs) with complexes of peptide and major histocompatibility complex (MHC) molecules displayed on the cell surface of antigen-presenting cells (APCs) [1]. An unresolved question of antigen recognition by T cells is how TCR triggering actually occurs at the cell-cell contact area. We visualized T-cell-APC contact sites using confocal microscopy and three-dimensional reconstruction of z-sections. We show the rapid formation
more » ... of a specialized signaling domain at the T-cell-APC contact site that is characterized by a broad and sustained area of tyrosine phosphorylation. The T-lymphocyte cell-surface molecule CD2 is rapidly recruited into this signaling domain, whereas TCRs progressively percolate from the entire T-cell surface into the phosphorylation area. Remarkably, the highly expressed phosphatase CD45 is excluded from the signaling domain. Our results indicate that physiological TCR triggering at the T-cell-APC contact site is the result of a localized alteration in the balance between cellular kinases and phosphatases. We therefore provide experimental evidence to support current models of T-cell activation based on CD45 exclusion from the TCR signaling area [2-4].
doi:10.1016/s0960-9822(00)00362-6 pmid:10712909 fatcat:yjvmxphuwfe7dclvldqpxe623u

The PDK1–Rsk Signaling Pathway Controls Langerhans Cell Proliferation and Patterning

Rossana Zaru, Stephen P. Matthews, Alexander J. Edgar, Alan R. Prescott, Diego Gomez-Nicola, André Hanauer, Colin Watts
2015 Journal of Immunology  
Langerhans cells (LC), the dendritic cells of the epidermis, are distributed in a distinctive regularly spaced array. In the mouse, the LC array is established in the first few days of life from proliferating local precursors, but the regulating signaling pathways are not fully understood. We found that mice lacking the kinase phosphoinositide-dependent kinase 1 selectively lack LC. Deletion of the phosphoinositide-dependent kinase 1 target kinases, ribosomal S6 kinase 1 (Rsk1) and Rsk2,
more » ... d a striking perturbation in the LC network: LC density was reduced 2-fold, but LC size was increased by the same magnitude. Reduced LC numbers in Rsk1/2 2/2 mice was not due to accelerated emigration from the skin but rather to reduced proliferation at least in adults. Rsk1/2 were required for normal LC patterning in neonates, but not when LC were ablated in adults and replaced by bone marrowderived cells. Increased LC size was an intrinsic response to reduced LC numbers, reversible on LC emigration, and could be observed in wild type epidermis where LC size also correlated inversely with LC density. Our results identify a key signaling pathway needed to establish a normal LC network and suggest that LC might maintain epidermal surveillance by increasing their "footprint" when their numbers are limited.
doi:10.4049/jimmunol.1501520 pmid:26401001 pmcid:PMC4640173 fatcat:dyw3iggxgnerpi2cw6srw3o34q

A combination of SILAC and nucleotide acyl phosphate labelling reveals unexpected targets of the Rsk inhibitor BI-D1870

Alexander J. Edgar, Matthias Trost, Colin Watts, Rossana Zaru
2014 Bioscience Reports  
., Watts, C. and Zaru, R. (2014) A combination of SILAC and nucleotide acyl phosphate labelling reveals unexpected targets of the Rsk inhibitor BI-D1870. Biosci. Rep. 34(1), art:e00091.  ...  AUTHOR CONTRIBUTION Alexander Edgar and Rossana Zaru did the experiments; Matthias Trost performed the proteomics analysis and interpreted the data; Rossana Zaru and Colin Watts designed the study, interpreted  ...  Zaru, unpublished work). This result indicates that Rsk negatively regulates PKB activation. The kinetics of Rsk and PKB activation by LPS in DC appear to be different.  ... 
doi:10.1042/bsr20130094 pmid:27919044 pmcid:PMC3908613 fatcat:b6r5na4iivd6hbn3de527wx2cy

3-Phosphoinositide-dependent Kinase 1 Deficiency Perturbs Toll-like Receptor Signaling Events and Actin Cytoskeleton Dynamics in Dendritic Cells

Rossana Zaru, Pamela Mollahan, Colin Watts
2007 Journal of Biological Chemistry  
The adaptive immune response depends on dendritic cell (DC) activation by microbial products that signal via pattern recognition receptors and activate mitogen-activated protein kinases, NFB and PI3K. The contribution of the AGC kinase family, including protein kinase B, protein kinase C, p90kDa ribosomal S6 kinase, and S6 kinase, has been little investigated because the probable redundancy among their isoforms makes their study difficult. We took advantage of the fact that all these kinases
more » ... regulated by the upstream master kinase 3-phosphoinositide-dependent kinase 1 (PDK1). Here we analyze various properties of DC from mice expressing ϳ10% of normal PDK1 (PDK1 fl/؊ ). DC populations in lymphoid and nonlymphoid tissues appeared normal in PDK1 fl/؊ mice, and some in vitro responses to lipopolysaccharide (LPS) such as cytokine production were normal in cultured bone marrow DC. However, LPS-induced expression of class II major histocompatibility complex and CD86 were elevated in PDK1 fl/؊ BMDC and PDK1 fl/؊ spleen DC produced more interleukin-10 and -12, implying an attenuating role for PDK1. Unexpectedly, PDK1 fl/؊ DC had a significantly reduced capacity for LPS-stimulated macropinocytosis and phagocytosis that correlated with a lowered F-actin/Gactin ratio, apparently because of increased actin depolymerization. Several PDK1-regulated kinases, some of which feed into actin regulators, showed reduced activation in PDK1 fl/؊ DC. Reintroduction of PDK1 restored S6 kinase activity, increased levels of F-actin, and boosted macropinocytosis thus linking PDK1 and its downstream effectors to the unusual phenotype of PDK1 fl/؊ DC.
doi:10.1074/jbc.m708069200 pmid:17991746 fatcat:as2c2dtrnnbxfh6prca2l3nav4

Structural and Functional Basis for p38-MK2-Activated Rsk Signaling in Toll-Like Receptor-Stimulated Dendritic Cells

Rossana Zaru, Alexander J. Edgar, André Hanauer, Colin Watts
2014 Molecular and Cellular Biology  
Rsk kinases play important roles in several cellular processes such as proliferation, metabolism, and migration. Until recently, Rsk activation was thought to be exclusively initiated by Erk1/2, but in dendritic cells (DC) Rsk is also activated by p38 mitogen-activated protein (MAP) kinase via its downstream substrates, MK2/3. How and why this noncanonical configuration of the MAP kinase pathway is adopted by these key immune cells are not known. We demonstrate that the Erk1/2-activated
more » ... al kinase domain of Rsk is dispensable for p38-MK2/3 activation and show that compared with fibroblasts, a greater fraction of p38 and MK2/3 is located in the cytosol of DC prior to stimulation, suggesting a partial explanation for the operation of the noncanonical pathway of Rsk activation in these cells. p38/MK2/3-activated Rsk phosphorylated downstream targets and is physiologically important because in plasmacytoid DC (pDC) stimulated with Toll-like receptor 7 (TLR7) agonists, Erk1/2 activation is very weak relative to p38. As a result, Rsk activation is entirely p38 dependent. We show that this unusual configuration of MAP kinase signaling contributes substantially to production of type I interferons, a hallmark of pDC activation.
doi:10.1128/mcb.00773-14 pmid:25332232 pmcid:PMC4295372 fatcat:rygnalkeiverhge32gjvzb26di

Fas triggers an alternative, caspase-8–independent cell death pathway using the kinase RIP as effector molecule

Nils Holler, Rossana Zaru, Olivier Micheau, Margot Thome, Antoine Attinger, Salvatore Valitutti, Jean-Luc Bodmer, Pascal Schneider, Brian Seed, Jürg Tschopp
2000 Nature Immunology  
Cell death is achieved by two fundamentally different mechanisms: apoptosis and necrosis. Apoptosis is dependent on caspase activation, whereas the caspase-independent necrotic signaling pathway remains largely uncharacterized. We show here that Fas kills activated primary T cells efficiently in the absence of active caspases, which results in necrotic morphological changes and late mitochondrial damage but no cytochrome c release. This Fas ligand-induced caspase-independent death is absent in
more » ... cells that are deficient in either Fas-associated death domain (FADD) or receptor-interacting protein (RIP). RIP is also required for necrotic death induced by tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand (TRAIL). In contrast to its role in nuclear factor κB activation, RIP requires its own kinase activity for death signaling. Thus, Fas, TRAIL and TNF receptors can initiate cell death by two alternative pathways, one relying on caspase-8 and the other dependent on the kinase RIP.
doi:10.1038/82732 pmid:11101870 fatcat:prbcwc2nufbtld3ggywmh47tvq

The MAPK-activated kinase Rsk controls an acute Toll-like receptor signaling response in dendritic cells and is activated through two distinct pathways

Rossana Zaru, Natalia Ronkina, Matthias Gaestel, J Simon C Arthur, Colin Watts
2007 Nature Immunology  
Most dendritic cell (DC) responses to Toll-like receptor (TLR) ligands depend on the activation of mitogen-activated protein kinases (MAPKs), but the contributions of the many MAPK-activated kinases (MKs) that act 'downstream' of the MAPKs Erk and p38 are not known. Here we sought to determine which MKs are required for acute TLR-driven, MAPK-dependent DC endocytic responses. Two specific and structurally different inhibitors of the MK Rsk suppressed TLR-induced endocytosis, thus defining in
more » ... a specific requirement for MKs in TLR responses. In addition, we identify in DCs a previously unknown configuration of the MAPK system whereby Rsk is activated not only by Erk but also by p38 through the intermediates MK2 and MK3. Thus, in DCs, p38 contributes to the activation of all known MK families. Microbial stimuli induce a set of responses in dendritic cells (DCs) that enhance their performance as antigen-presenting cells, stimulate their migration to lymphoid tissues and boost their ability to induce T cell activation 1-3 . Some responses, such as cytokine secretion, influence events in the external environment, whereas others influence the capacity of the DC itself to capture, process and present antigen. For example, Toll-like receptor (TLR) signaling induces enhanced acidification of antigen-processing compartments, transport of major histocompatibility complex class I molecules 4 and class II molecules 5,6 to the cell surface, and deubiquitination of the latter to ensure they remain stably displayed on the cell surface 7,8 . TLR signaling also boosts antigen capture by both macropinocytosis and phagocytosis 9,10 and influences protein turnover and the storage of ubiquitinated proteins 11 . Whereas the production of cytokines influencing T helper cell polarization requires activation of NF-kB and IRF transcription factors and one or more of the main mitogen-activated protein kinase (MAPK) pathways 12 , the TLR signaling pathways that drive the DC maturation program described above have not been defined. The Erk1/2 and p38 MAPKs are probably involved in most of these responses 9,10 , but information on which 'downstream' signaling pathways are involved is lacking. In addition to activating transcription factors and some other substrates, Erk1/2 and p38 phosphorylate and activate a group of kinases called 'MAPK-activated protein kinases' (MKs), which include MK2 and MK3 (also called MAPKAP-K2 and MAPKAP-K3), the mitogen-and stress-activated kinases MSK1 and MSK2, the MAPKinteracting kinases MNK1 and MNK2, and the p90 ribosomal S6 kinases Rsk1, Rsk2, Rsk3 and Rsk4 (refs. 13, 14, 15 ). Detailed studies of various cell types have shown that whereas MSK1, MSK2 (ref. 16) and MNK1 (ref. 17) can be activated by both p38 and Erk1/2, MK2 and MK3 are exclusively activated by p38 and MNK2 (ref. 17), and 19) are exclusively activated by Erk1/2. Rsk4 seems to be constitutively active 20 . The related MSK and Rsk kinases have two distinct kinase domains; activation of the carboxy (C)-terminal domain, induced by 'upstream' MAPKs, is required for activation of the amino (N)-terminal domain. For MSK, the C-terminal domain directly activates the N-terminal domain 16,21 , whereas for Rsk, the C-terminal domain phosphorylates a hydrophobic motif between the two domains, creating a docking site for PDK1, a member of the AGC kinase family, which then phosphorylates the activation loop of the Rsk N-terminal kinase domain (NTKD) 18, 22 . Full activation is then achieved after the dissociation of PDK1 and the binding of the phosphorylated hydrophobic motif to a binding pocket in the NTKD 23 . Thus, phosphorylation of the hydrophobic motif is pivotal for Rsk activation. The MKs control a broad range of cellular functions. MK2 controls the stability and translation of tumor necrosis factor mRNA 24-26 and rearrangement of the actin cytoskeleton through the chaperone Hsp27 (ref. 27). MSK1 and MSK2 influence activation of the transcription factors CREB and ATF1 (ref. 16) and induce chromatin remodeling by phosphorylating histone H3 (refs. 28,29). MNK1 and MNK2 regulate mRNA translation by phosphorylating the initiation factor eIF4E 30 . Rsk has been proposed to activate a wide variety of substrates linked to the control of transcription, cell proliferation, cytoskeleton rearrangement, glycogen metabolism and cell survival 13 . MKs are probably key agents in the propagation of p38-and Erk1/2-dependent responses
doi:10.1038/ni1517 pmid:17906627 fatcat:iujteqcfovdq3izgzuzycfvdwe

UniProt: the universal protein knowledgebase in 2021

The UniProt Consortium, Alex Bateman, Maria-Jesus Martin, Sandra Orchard, Michele Magrane, Rahat Agivetova, Shadab Ahmad, Emanuele Alpi, Emily H Bowler-Barnett, Ramona Britto, Borisas Bursteinas, Hema Bye-A-Jee (+122 others)
2020 Nucleic Acids Research  
The aim of the UniProt Knowledgebase is to provide users with a comprehensive, high-quality and freely accessible set of protein sequences annotated with functional information. In this article, we describe significant updates that we have made over the last two years to the resource. The number of sequences in UniProtKB has risen to approximately 190 million, despite continued work to reduce sequence redundancy at the proteome level. We have adopted new methods of assessing proteome
more » ... s and quality. We continue to extract detailed annotations from the literature to add to reviewed entries and supplement these in unreviewed entries with annotations provided by automated systems such as the newly implemented Association-Rule-Based Annotator (ARBA). We have developed a credit-based publication submission interface to allow the community to contribute publications and annotations to UniProt entries. We describe how UniProtKB responded to the COVID-19 pandemic through expert curation of relevant entries that were rapidly made available to the research community through a dedicated portal. UniProt resources are available under a CC-BY (4.0) license via the web at https://www.uniprot.org/.
doi:10.1093/nar/gkaa1100 pmid:33237286 pmcid:PMC7778908 fatcat:6rwvp6l5uzb3li4lygf2gny6qq

A crowdsourcing open platform for literature curation in UniProt

Yuqi Wang, Qinghua Wang, Hongzhan Huang, Wei Huang, Yongxing Chen, Peter B. McGarvey, Cathy H. Wu, Cecilia N. Arighi, on behalf of the UniProt Consortium
2021 PLoS Biology  
Zaru, and Hermann Zellner at the EMBL-European Bioinformatics Institute; Alan Bridge, Sylvain Poux, Nicole Redaschi, Lucila Aimo, Ghislaine Argoud-Puy, Andrea Auchincloss, Kristian Axelsen, Parit Bansal  ...  Shriya Raj, Daniel Rice, Milagros Rodriguez Lopez, Rabie Saidi, Joseph Sampson, Tony Sawford, Elena Speretta, Edward Turner, Nidhi Tyagi, Preethi Vasudev, Vladimir Volynkin, Kate Warner, Xavier Watkins, Rossana  ... 
doi:10.1371/journal.pbio.3001464 pmid:34871295 pmcid:PMC8675915 fatcat:6tsqu5evlre45ocilvfp4ad2ca

Cutting Edge: T Lymphocyte Activation by Repeated Immunological Synapse Formation and Intermittent Signaling

M. Faroudi, R. Zaru, P. Paulet, S. Muller, S. Valitutti
2003 Journal of Immunology  
Edge: T Lymphocyte Activation by Repeated Immunological Synapse Formation and Intermittent Signaling Mustapha Faroudi, Rossana Zaru, Pierre Paulet, Sabina Müller, and Salvatore Valitutti FIGURE 2 . 2  ... 
doi:10.4049/jimmunol.171.3.1128 pmid:12874197 fatcat:fushefzo5jfkbbyokbnseobmiq

STORIA, POLITICA, FILOSOFIA. INTERVISTA AD ANTONIO NEGRI

V Tto, Ri Mo, Rfi No
2018 Etica & Politica / Ethics & Politics, XX   unpublished
Morfino, Zaru: In questa intervista vorremmo fissare l'attenzione sugli aspetti più strettamente filosofici del tuo pensiero, consci del fatto che il tuo è uno di quei casi in cui è difficile, se non impossibile  ...  Quando dieci anni più tardi (nella seconda metà dei '70) vedevo Althusser, mi chiedeva come stava Rossana [Rossanda] o Ingrao, che erano per lui il modello del politico.  ...  Morfino, Zaru: Su questo torniamo a breve.  ... 
fatcat:fqdkyk62w5a7fi7u2oxlrxhhlm

Effect of sequence padding on the performance of deep learning models in archaeal protein functional prediction

Angela Lopez-del Rio, Maria Martin, Alexandre Perera-Lluna, Rabie Saidi
2020 Scientific Reports  
The authors thank Sergio Picart-Armada for helpful discussions and statistical advice; Rossana Zaru and Antonio Ribeiro for helping with the biological/enzymatic interpretation of the results and Mahdi  ... 
doi:10.1038/s41598-020-71450-8 pmid:32884053 fatcat:gkqazsmi4fbevb4bwdn6eaib2y

TLR ligand–induced podosome disassembly in dendritic cells is ADAM17 dependent

Michele A. West, Alan R. Prescott, Kui Ming Chan, Zhongjun Zhou, Stefan Rose-John, Jürgen Scheller, Colin Watts
2008 Journal of Cell Biology  
Zaru and Christian Gawden-Bone for discussions, and Pamela Mollahan for GFP-actin retrovirus production.  ...  Murphy and colleagues for generous provision of reagents and advice, Dylan Edwards for quantitative MMP expression analysis, Claude Libert and Zena Werb for cells from MMP2-and MMP9-defi cient mice, Rossana  ... 
doi:10.1083/jcb.200801022 pmid:18762577 pmcid:PMC2528573 fatcat:4xm2fk2emzajfelcyghw6y6nni
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