DOCSLIB.ORG

Src-Family and Syk Kinases in Activating and Inhibitory Pathways in Innate Immune Cells: Signaling Cross Talk

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Src-Family and Syk Kinases in Activating and Inhibitory Pathways in Innate Immune Cells: Signaling Cross Talk Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Src-family and Syk Kinases in Activating and Inhibitory Pathways in Innate Immune Cells: Signaling Cross Talk Clifford A. Lowell Department of Laboratory Medicine, University of California, San Francisco, California 94143 Correspondence: [email protected] The response of innate immune cells to growth factors, immune complexes, extracellular matrix proteins, cytokines, pathogens, cellular damage, and many other stimuli is regulated by a complex net of intracellular signal transduction pathways. The majority of these path- ways are either initiated or modulated by Src-family or Syk tyrosine kinases present in innate cells. The Src-family kinases modulate the broadest range of signaling responses, including regulating immunoreceptors, C-type lectins, integrins, G-protein-coupled recep- tors, and many others. Src-family kinases also modulate the activity of other kinases, includ- ing the Tec-family members as well as FAK and Pyk2. Syk kinase is required for initiation of signaling involving receptors that utilize immunoreceptor tyrosine activation (ITAM) domains. This article reviews the major activating and inhibitory signaling pathways regu- lated by these cytoplasmic tyrosine kinases, illuminating the many examples of signaling cross talk between pathways. nnate immune cells, including macrophages, important roles in innate cells. They are not dis- Idendritic cells, granulocytes, and mast cells, cussed in detail in this article, but are reviewed function as the first line of defense against elsewhere in articles on the subject. pathogens. These cells use a dizzying array of There are eight members of the Src family; cell-surface receptors, which are connected to innate immune cells primarily express Hck, an equally complicated intracellular signal trans- Fgr, Lyn, and to a lesser extent, Src (Lowell duction network, to sense pathogen molecules 2004). The Syk-ZAP70 family has only two and then orchestrate the appropriate immune members and only Syk is found in innate cells. response. Among the intracellular signaling mol- Most innate cell types express the same spec- ecules that are most crucial for innate immune trum of kinases with some specific cellular dif- cells are the cytoplasmic tyrosine kinases. Two ferences. For example, mast cells express a majorkinasefamiliesthat operateintheproximal broader range of Src-family kinases than macro- intracellular signaling pathways in innate cells are phages or dendritic cells (Colgan and Hankel the Src-family kinases and the Syk-ZAP70 family. 2010). In general, Src-family and Syk kinases A third familyof kinases, the Tek family, also have tend to operate together in signaling pathways, Editors: Lawrence E. Samelson and Andrey S. Shaw Additional Perspectives on Immunoreceptor Signaling available at www.cshperspectives.org Copyright # 2010 Cold Spring Harbor Laboratory Press; all rights reserved. Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a002352 1 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press C.A. Lowell with the Src-family being “upstream” or acti- of interaction and cross regulation. Together, vated first in response to pathogen detection. these pathways impinge on downstream factors, These enzymes then communicate downstream such as MAPK kinases, which have broad effects to Tec-family members. The Tec-family kinases on gene transcription; the Rac/Rho pathway to expressed in innate cells include Btk, Bmx, and modulate cytoskeletal function; the inositol Tec (Koprulu and Ellmeier 2009; Tohyama and trisphosphate (IP3), and diacylglycerol pathway Yamamura 2009). Additionally, Src-family kin- (DAG), which regulates Ca2þ entry into cells ases activate yet another family of PTKs, the and activation of various isoforms of protein FAK/Pyk2 tyrosine kinases, which play a major kinase C (PKC). Overall, the outline of the pro- role in integrin signaling (Hauck et al. 2000). totypical immunoreceptor pathway as described Though primarily studied in activating path- here is similar in both innate and adaptive im- ways, Src-family and Syk kinases also activate mune cells (Smith-Garvin et al. 2009; Kurosaki inhibitory signaling pathways (Nimmerjahn and et al. 2010). Ravetch 2008). In many situations, inhibitory signaling often overrides the activating signal. New Concepts in Immunoreceptor Signaling: Pathways can also be initiated at different times CARD9 and Receptor Diversity or rates. Finally, to add even more complexity, activating and inhibitory pathways often inter- Recent and exciting developments in the immu- act indirectly, for example, through the produc- noreceptor paradigm include recent progress in tion of cytokines and growth factors and not delineating how this pathway is connected to through direct intracellular biochemical inter- NF-kB and the demonstration that many innate actions; Hence the term signaling “cross talk,” immune receptors utilize the “immunoreceptor which now appears commonly in the literature pathway” even though they lack ITAMs and (O’Neill 2008; Ivashkiv 2009; Page et al. 2009). therefore are not technically immunoreceptors. The adapter protein CARD9, which con- tains a caspase-recruitment domain (CARD), OVERVIEW OF ACTIVATING PATHWAYS has now been shown to be the link between a variety of ITAM-containing receptors involved Classical Immunoreceptor Pathways in recognition of fungal and probably other In the prototypical immunoreceptor pathway, pathogen structures and NF-kB (Fig. 2) (Gross engagement of the receptor leads to activation et al. 2006; Gross et al. 2009). CARD9 is closely of Src-family kinases, which in turn phosphor- related to the lymphocyte protein CARMA-1, ylate immunoreceptor tyrosine-based activa- which forms a complex with the adapter pro- tion motifs (ITAMs) present on either the teins Bcl-10 and MALT1, and thus links the T- receptor or associated subunits (Fig. 1). This and B-cell receptors to the NF-kBpathway leads to recruitment of Syk, by binding of the (Rawlings et al. 2006). CARD9 forms the same Syk SH2 protein domain to the phospho-ITAM complex in innate cells. In lymphoid cells, residues, and activation of Syk allowing it CARMA-1 is activated by PKC isoforms (PKCu to phosphorylate downstream substrates. One in T-cells and PKCb in B-cells), which phos- of the enzymes activated downstream is phos- phorylate CARMA-1, resulting in a conforma- phoinositide3-kinase(PI3-kinase), which gener- tional change that allows it to interact with ates membrane-associated phosphatidylinositol IKK, leading to IkB turnover and NF-kB activa- (3,4,5)-triphosphate (PIP3). The FAK/Pyk2 tion. In myeloid cells, it remains unclear if kinases are activated directly via the Src-family CARD9 activation is directly downstream of kinases, where they contribute to downstream PKC activation (Hara and Saito 2009). Never- responses involving cell adhesion and migra- theless, it is clear that in the absence of tion. Though usually depicted as a linear signal- CARD9, receptors involved in fungal pathogen ing pathway with Src-kinases at the top and recognition (Dectin-1, Dectin-2) are unable to FAK/Pyk2 at the bottom, there are many points activate NF-kB, and more importantly, the 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a002352 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Cytoplasmic Tyrosine Kinases in Innate Immune Cells Classical immunoreceptors Receptors co-opting ITAM signaling FcRγ Receptors DAP12 Receptors FcεR, FcγRs TREMs Dual Receptors Dectin-2 MDL-1 Hemi-ITAM Receptors Integrins Mincle CD200R3 Dectin-1 IL-3R DCAR Siglec-H CLEC2 PSGL-1 γ PIR-A MAIR-II CLEC9A IFN R SIRP-β RANK FcRγ DAP12 DAP12 FcRγ +– + – PIP3 PIP2 SLP-76SSLLLP-7P-P P Y Y P P Y Y P Y P SOS PI3-KPPI3-K P Y Y P Y Y Syk Syk Syk Syk P P LAT/NTAL Y Y P P Y Y P Y γ P Y Y Y Y SFK SFK PLCPLC Vav Tec Ks Fak/Pyk2 CARD9 Ras DAG IP3 RasGRP RhoRho GTPase WASPW NF-kB pathway PKC 2+ MAPKs Ca Actin polymerization Cytokine secretion Cytokine secretion NFAT proliferation gene transcription Migration degranulation Figure 1. Cytoplasmic tyrosine kinases in the activating signaling pathways utilizing ITAM-containing adapters. Examples of immunoreceptors, hemi-ITAM C-type lectin receptors, and nonimmunoreceptors that utilize ITAM-signaling adapters and the cytoplasmic tyrosine kinases (indicated as shaded molecules) discussed in this article are shown. “Classical immunoreceptors” refers to those signaling molecules that are directly coupled to ITAMadapters FcRg (group shown on the left) or DAP12 (group shown on the right) through transmembrane charged residues, shown as “þ” and “2” in the figure. These immunoreceptors consist of immunoglobulin superfamily-containing proteins (such as the Fc receptors, PIR-A, or the TREMs) or the C-type lectin receptors (Dectin-2, Mincle, or MDL-1). In some cases, receptors may utilize either signaling adapter (see Hamerman et al. 2009). Examples of the C-type lectin receptors that have ITAM-like sequences as imbedded domains within their cytoplasmic tails are Dectin-1, CLEC2, and CLEC9A. The sequences with the ITAM domain of these receptors differs in that the membrane distal tyrosine resides in a YxxxL sequence (or YxxxI for mouse), as opposed to the traditional YxxL ITAM sequence found around the proximal tyrosine. As a result, the membrane distal tyro- sine is dispensable for signaling, leading to the designation of these receptors as “hemi-ITAM” molecules (Ker- rigan and Brown 2010). For a more complete list of FcRg- and DAP12-associated receptors, see Lanier (2009), Graham and Brown (2009), and Kanazawa (2007). Not shown is the human FcgRIIA receptor, which is unique among the Fc receptors for having an ITAMsequence directly imbedded in its cytoplasmic tail (see Nimmerjahn and Ravetch 2008). Tothe right are shown examples of receptorsthat link to orco-opt the ITAMpathway, with the best example being the leukocyte integrins (see Abram and Lowell 2009).
Load more

Recommended publications
  • Review Tec Kinases: a Family with Multiple Roles in Immunity
    Immunity, Vol. 12, 373±382, April, 2000, Copyright 2000 by Cell Press Tec Kinases: A Family Review with Multiple Roles in Immunity Wen-Chin Yang,*³§ Yves Collette,*³ inositol phosphates, but they are thought to be relevant Jacques A. NuneÁ s,*³ and Daniel Olive*² for binding of PtdIns lipids to the same sites. In most *INSERM U119 cases, PH domains bind preferentially to PtdIns (4,5)P2 Universite de la Me diterrane e and inositol (1,4,5) P3 (Ins (1,4,5) P3). However, the Btk 13009 Marseille PH domain binds PtdIns (3,4,5)P3 and Ins (1, 3, 4, 5)P4 France the tightest. PtdIns (3, 4, 5)P3, one of the products of the action of PI3K, is thought to act as a second messen- ger to recruit regulatory proteins to the plasma mem- brane via their PH domains (see below). Many of the Antigen receptors on T, B, and mast cells are multimo- mutations in Btk that lead to XLA are point mutations lecular complexes that are activated by interactions with that cluster at one end of the PH domain and could be external signals. These signals are then transmitted to predicted to impair binding to Ins (3,4,5)P (for review regulate gene expression and posttranscriptional modi- 3 see Satterthwaite et al., 1998a) (Figure 1b). Similarly, fications. Nonreceptor tyrosine kinases (NRTK) are key CBA/N xid mice carry an R28C mutation in the Btk PH players that relay and integrate these signals. NRTK are domain. The recent structure of the PH domain from divided into distinct families defined by a prototypic Btk complexed with Ins (1,3,4,5)P4 provides an explana- member: Src, Tec, Syk, Csk, Fes, Abl, Jak, Fak, Ack, tion for several mutations associated with XLA: mis- Brk, and Srm (Bolen and Brugge, 1997).
    [Show full text]
  • Evidence for an Interaction Between the Insulin Receptor and Grb7. a Role for Two of Its Binding Domains, PIR and SH2
    Oncogene (2000) 19, 2052 ± 2059 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Evidence for an interaction between the insulin receptor and Grb7. A role for two of its binding domains, PIR and SH2 Anne Kasus-Jacobi1,2,3,Ve ronique Be re ziat1,3, Dominique Perdereau1, Jean Girard1 and Anne-FrancËoise Burnol*,1 1Endocrinologie MeÂtabolisme et DeÂveloppement, CNRS, UPR 1524, 9 rue Jules Hetzel, 92190 Meudon, France The molecular adapter Grb7 is likely to be implicated in new family of adapters has recently emerged, the Grb7 the development of certain cancer types. In this study we family of proteins, comprising Grb7, Grb10 and show that Grb7 binds the insulin receptors, when they Grb14. The members of this family were originally are activated and tyrosine phosphorylated. This interac- cloned by interaction with EGF receptor, using the tion is documented by two-hybrid experiments, GST CORT (cloning of receptor target) system (Daly et al., pull-down assays and in vivo coimmunoprecipitations. In 1996; Margolis, 1994; Ooi et al., 1995), and the use of addition, our results argue in favor of a preferential the yeast two-hybrid technology has emphasized their association between Grb7 and the insulin receptors when implication in signal transduction (Daly, 1998). These compared to other tyrosine kinase receptors like the adapters bind also other tyrosine kinase receptors, like EGF receptor, the FGF receptor and Ret. Interestingly, erbB2, Ret, Elk, PDGF receptors, insulin receptors and Grb7 is not a substrate of the insulin receptor tyrosine IGF-1 receptors (Daly et al., 1996; Dey et al., 1996; kinase activity.
    [Show full text]
  • Lipid-Targeting Pleckstrin Homology Domain Turns Its Autoinhibitory Face Toward the TEC Kinases
    Lipid-targeting pleckstrin homology domain turns its autoinhibitory face toward the TEC kinases Neha Amatyaa, Thomas E. Walesb, Annie Kwonc, Wayland Yeungc, Raji E. Josepha, D. Bruce Fultona, Natarajan Kannanc, John R. Engenb, and Amy H. Andreottia,1 aRoy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011; bDepartment of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115; and cInstitute of Bioinformatics and Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602 Edited by Natalie G. Ahn, University of Colorado Boulder, Boulder, CO, and approved September 17, 2019 (received for review May 3, 2019) The pleckstrin homology (PH) domain is well known for its phos- activation loop phosphorylation site are also controlled by noncatalytic pholipid targeting function. The PH-TEC homology (PHTH) domain domains (17). In addition to the N-terminal PHTH domain, the within the TEC family of tyrosine kinases is also a crucial component TEC kinases contain a proline-rich region (PRR) and Src ho- of the autoinhibitory apparatus. The autoinhibitory surface on the mology 3 (SH3) and Src homology 2 (SH2) domains that impinge PHTH domain has been previously defined, and biochemical investi- on the kinase domain to alter the conformational ensemble and gations have shown that PHTH-mediated inhibition is mutually thus the activation status of the enzyme. A crystal structure of the exclusive with phosphatidylinositol binding. Here we use hydrogen/ BTK SH3-SH2-kinase fragment has been solved (10) showing that deuterium exchange mass spectrometry, nuclear magnetic resonance the SH3 and SH2 domains of BTK assemble onto the distal side of (NMR), and evolutionary sequence comparisons to map where and the kinase domain (the surface opposite the activation loop), how the PHTH domain affects the Bruton’s tyrosine kinase (BTK) stabilizing the autoinhibited form of the kinase in a manner similar domain.
    [Show full text]
  • Signal Adaptor DAP10 Associates with MDL-1 and Triggers Osteoclastogenesis in Cooperation with DAP12
    Signal adaptor DAP10 associates with MDL-1 and triggers osteoclastogenesis in cooperation with DAP12 Masanori Inuia,1, Yuki Kikuchia,1, Naoko Aokib, Shota Endoa, Tsutomu Maedaa, Akiko Sugahara-Tobinaia, Shion Fujimuraa, Akira Nakamuraa, Atsushi Kumanogohc, Marco Colonnad, and Toshiyuki Takaia,2 aDepartment of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo 4-1, Sendai 980-8575, Japan; bDepartment of Pathology, Asahikawa Medical College, Higashi 2-1-1, Midorigaoka, Asahikawa 078-8510, Japan; cDepartment of Immunopathology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan; and dDepartment of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid, St. Louis, MO 63110 Communicated by Jeffrey V. Ravetch, The Rockfeller University, New York, NY, January 22, 2009 (received for review May 14, 2008) Osteoclasts, cells of myeloid lineage, play a unique role in bone the Ig superfamily or C-type lectin family. They primarily mediate resorption, maintaining skeletal homeostasis in concert with bone- a Src-family kinase-initiated activation signal, leading to a series of producing osteoblasts. Osteoclast development and maturation (os- events including Syk kinase recruitment, triggering of calcium teoclastogenesis) is driven by receptor activator of NF-␬B ligand and signaling mediated by phospholipase C␥ (PLC␥), and activation of macrophage-colony stimulating factor and invariably requires a sig- the MAPK cascade, culminating in cell proliferation and cytokine nal initiated by immunoreceptor tyrosine-based activation motif production as the output of cellular responses. In osteoclast pre- (ITAM)-harboring Fc receptor common ␥ chain or DNAX-activating cursor cells, FcR␥ and DAP12 associate with several cognate protein (DAP)12 (also referred to as KARAP or TYROBP) that associates cell-surface immunoreceptors (9) such as osteoclast-associated with the cognate immunoreceptors.
    [Show full text]
  • Insulin Receptor Membrane Retention by a Traceable Chimeric Mutant Jimena Giudice1,2,4, Elizabeth a Jares-Erijman2ˆ and Federico Coluccio Leskow1,3*
    Giudice et al. Cell Communication and Signaling 2013, 11:45 http://www.biosignaling.com/content/11/1/45 RESEARCH Open Access Insulin receptor membrane retention by a traceable chimeric mutant Jimena Giudice1,2,4, Elizabeth A Jares-Erijman2ˆ and Federico Coluccio Leskow1,3* Abstract Background: The insulin receptor (IR) regulates glucose homeostasis, cell growth and differentiation. It has been hypothesized that the specific signaling characteristics of IR are in part determined by ligand-receptor complexes localization. Downstream signaling could be triggered from the plasma membrane or from endosomes. Regulation of activated receptor's internalization has been proposed as the mechanism responsible for the differential isoform and ligand-specific signaling. Results: We generated a traceable IR chimera that allows the labeling of the receptor at the cell surface. This mutant binds insulin but fails to get activated and internalized. However, the mutant heterodimerizes with wild type IR inhibiting its auto-phosphorylation and blocking its internalization. IR membrane retention attenuates AP-1 transcriptional activation favoring Akt activation. Conclusions: These results suggest that the mutant acts as a selective dominant negative blocking IR internalization-mediated signaling. Keywords: Insulin receptor, Membrane retention, Dominant negative, Endocytosis Background events between the two isoforms, indicating specific Insulin receptor (IR) is a tetrameric tyrosine kinase re- functions [13-15]. Using an elegant harmonic oscillator ceptor involved on glucose homeostasis, cell growth and mathematical model, Knudson et al. reported that insu- differentiation. Two IR variants are produced in mam- lin has 1.5-fold higher affinity and a 2-fold higher dis- mals by alternative splicing: IR-A lacking exon 11 and sociation rate for IR-A, than for IR-B [16].
    [Show full text]
  • Hepatocyte Growth Factor: a Regulator of Inflammation and Autoimmunity
    Autoimmunity Reviews 14 (2015) 293–303 Contents lists available at ScienceDirect Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev Review Hepatocyte growth factor: A regulator of inflammation and autoimmunity Nicolas Molnarfi a,b,1, Mahdia Benkhoucha a,b,1, Hiroshi Funakoshi d, Toshikazu Nakamura e, Patrice H. Lalive a,b,c,⁎ a Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland b Department of Clinical Neurosciences, Division of Neurology, Unit of Neuroimmunology and Multiple Sclerosis, University Hospital of Geneva, Geneva, Switzerland c Department of Genetics and Laboratory Medicine, Laboratory Medicine Service, University Hospital of Geneva, Geneva, Switzerland d Center for Advanced Research and Education, Asahikawa Medical University, Asahikawa, Japan e Neurogen Inc., Nakahozumi, Ibaraki, Osaka, Japan article info abstract Article history: Hepatocyte growth factor (HGF) is a pleiotropic cytokine that has been extensively studied over several decades, Received 20 November 2014 but was only recently recognized as a key player in mediating protection of many types of inflammatory and au- Accepted 25 November 2014 toimmune diseases. HGF was reported to prevent and attenuate disease progression by influencing multiple Available online 1 December 2014 pathophysiological processes involved in inflammatory and immune response, including cell migration, matura- tion, cytokine production, antigen presentation, and T cell effector function. In this review, we discuss the actions Keywords: fl HGF and mechanisms of HGF in in ammation and immunity and the therapeutic potential of this factor for the treat- fl c-Met ment of in ammatory and autoimmune diseases. Inflammation © 2014 Elsevier B.V. All rights reserved. Autoimmunity Autoimmune regulator Therapy Contents 1.
    [Show full text]
  • Regulation of Hematopoietic Stem Cells by the Steel Factor/KIT
    Molecular Pathways Regulation of Hematopoietic Stem Cells by the Steel Factor/KIT Signaling Pathway David Kent, Michael Copley, Claudia Benz, Brad Dykstra, Michelle Bowie, and Connie Eaves Abstract Understanding the intrinsic pathways that regulate hematopoietic stem cell (HSC) proliferation and self-renewal responses to external signals offers a rational approach to developing improved strategies for HSC expansion for therapeutic applications. Such studies are also likely to reveal new targets for the treatment of human myeloid malignancies because perturbations of the biological processes that control normal HSC self-renewal divisions are believed to drive the propagation of many of these diseases. Here, we review recent findings that point to the impor- tance of using stringent functional criteria to define HSCs as cells with longterm repopulating activity and evidence that activation of the KITreceptor and many downstream effectors serve as major regulators of changing HSC proliferative and self-renewal behavior during development. Background the discovery of a rare subset of cells in mice that generate multilineage clones in the spleen of myeloablated recipients Hematopoietic stem cells (HSC) constitute a rare, self- and that are sustained throughout life (10). The finding that sustaining population that appears early in the development these ‘‘colony-forming units spleen’’ are present in all hemato- of the embryo and is then responsible for mature blood cell poietic tissues and exhibit some self-renewal activity when production throughout life. HSC numbers can be regulated serially transplanted led to their use as a tool for establishing extrinsically by three mechanisms: (a) altered exposure to many basic principles expected of an HSC population.
    [Show full text]
  • Distinct Gene Expression Pathways in Islets from Individuals with Short- and Long
    Mastracci Teresa (Orcid ID: 0000-0003-1956-1951) Distinct Gene Expression Pathways in Islets from Individuals with Short- and Long- Duration Type 1 Diabetes Teresa L. Mastracci1,2*, Jean-Valery Turatsinze3, Benita K. Book4, Ivan A. Restrepo5, Michael J. Pugia1, Eric A. Wiebke4, Mark D. Pescovitz4, Decio L. Eizirik3 and Raghavendra G. Mirmira2,5,6,7 1 Indiana Biosciences Research Institute, Indianapolis, IN, USA. 2 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA. 3 ULB Center for Diabetes Research, Universite Libre de Bruxelles, Brussels, Belgium. 4 Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA. 5 Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA. 6 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA. 7 Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. * Corresponding Author: Teresa L. Mastracci, 1345 W. 16th St., Suite 300, Indianapolis, IN 46202 USA. E-mail: [email protected] Running Title: Functional Genomics Analysis of T1D Islets Abstract word count: 272 This is the author's manuscript of the article published in final edited form as: Mastracci, T. L., Turatsinze, J.-V., Book, B. K., Restrepo, I. A., Pugia, M. J., Wiebke, E. A., … Mirmira, R. G. (n.d.). Distinct Gene Expression Pathways in Islets from Individuals with Short‐ and Long‐Duration Type 1 Diabetes. Diabetes, Obesity and Metabolism. https://doi.org/10.1111/dom.13298 Main text word count: 2730 References: 27; Tables: 2; Figures: 3 Abstract Aims: Our current understanding of the pathogenesis of type 1 diabetes (T1D) arose in large part from studies using the non-obese diabetic (NOD) mouse model.
    [Show full text]
  • Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia
    cancers Review Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia Kalpana K. Bhanumathy 1,*, Amrutha Balagopal 1, Frederick S. Vizeacoumar 2 , Franco J. Vizeacoumar 1,3, Andrew Freywald 2 and Vincenzo Giambra 4,* 1 Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; [email protected] (A.B.); [email protected] (F.J.V.) 2 Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; [email protected] (F.S.V.); [email protected] (A.F.) 3 Cancer Research Department, Saskatchewan Cancer Agency, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada 4 Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy * Correspondence: [email protected] (K.K.B.); [email protected] (V.G.); Tel.: +1-(306)-716-7456 (K.K.B.); +39-0882-416574 (V.G.) Simple Summary: Protein phosphorylation is a key regulatory mechanism that controls a wide variety of cellular responses. This process is catalysed by the members of the protein kinase su- perfamily that are classified into two main families based on their ability to phosphorylate either tyrosine or serine and threonine residues in their substrates. Massive research efforts have been invested in dissecting the functions of tyrosine kinases, revealing their importance in the initiation and progression of human malignancies. Based on these investigations, numerous tyrosine kinase inhibitors have been included in clinical protocols and proved to be effective in targeted therapies for various haematological malignancies.
    [Show full text]
  • Assembly of High-Affinity Insulin Receptor Agonists and Antagonists from Peptide Building Blocks
    Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks Lauge Scha¨ ffer*†, Renee E. Brissette‡, Jane C. Spetzler*, Renuka C. Pillutla‡, Søren Østergaard*, Michael Lennick‡, Jakob Brandt*, Paul W. Fletcher‡, Gillian M. Danielsen*, Ku-Chuan Hsiao‡, Asser S. Andersen*, Olga Dedova‡, Ulla Ribel*, Thomas Hoeg-Jensen*, Per Hertz Hansen*, Arthur J. Blume‡, Jan Markussen*, and Neil I. Goldstein‡ *Novo Nordisk A͞S, DK-2800 Bagsvaerd, Denmark; and ‡DGI BioTechnologies, Edison, NJ 08818 Edited by Donald F. Steiner, University of Chicago, Chicago, IL, and approved February 26, 2003 (received for review January 3, 2003) Insulin is thought to elicit its effects by crosslinking the two Materials and Methods extracellular ␣-subunits of its receptor, thereby inducing a confor- Solid-Phase Peptide Synthesis. Peptides were synthesized manually mational change in the receptor, which activates the intracellular or on an Advanced ChemTech 396 synthesizer. Synthesis was tyrosine kinase signaling cascade. Previously we identified a series performed on TentaGel S RAM resin (Rapp Polymere, Tu¨- of peptides binding to two discrete hotspots on the insulin recep- bingen, Germany). Fluorenylmethoxycarbonyl amino acids pur- tor. Here we show that covalent linkage of such peptides into chased from Novabiochem were coupled by using a diisopropyl- homodimers or heterodimers results in insulin agonists or antag- carbodiimide͞1-hydroxy-7-azabenzotriazole coupling strategy. onists, depending on how the peptides are linked. An optimized Peptides were cleaved as amides from the resin by using 90% agonist has been shown, both in vitro and in vivo, to have a trifluoroacetic acid, 5% triisopropylsilane, 3% thioanisol, and potency close to that of insulin itself.
    [Show full text]
  • Supplementary Materials
    Supplementary Materials Supplemental Figure S1. Distinct difference in expression of 576 sensome genes comparing cortex versus microglia. (A) This heatmap shows all 576 sensome candidate genes ordered by DE and with the left column shows if the gene is present in the “Hickman et al. sensome” Supplemental Figure S2. Mouse sensome and human sensome genes categorized by group. (A) Bar graph showing the number of mouse and human sensome genes per group (Cell-Cell Interactions, Chemokine and related receptors, Cytokine receptors, ECM receptors, Endogenous ligands receptors, sensors and transporters, Fc receptors, Pattern recognition and related receptors, Potential sensors but no known ligands and Purinergic and related receptors). Supplementary Figure S3. Overlap of ligands recognized by microglia sensome (A) Overlap between the ligands of the receptors from respectively human and mouse core sensome was shown using Venn Diagrams. (B) Ligands of human and mouse receptors categorized in groups (Glycoproteins, Cytokines, Immunoglobulin, Amino acids, Carbohydrates, Electrolytes, Lipopeptides, Chemokines, Neuraminic acids, Nucleic acids, Receptors, Lipids, Fatty acids, Leukotrienes, Hormones, Steroids and Phospholipids) and spread of different groups shown as parts of whole again highlighting that the distribution of ligands what the human and mouse sensome genes can sense (Categorization of ligands in Supplementary Table S1). Supplementary Figure S4. Microglia core sensome expression during aging. (A) Two-log fold change of microglia core sensome genes in aging mice derived from Holtman et al. [12]. (B) Accelerated aging model (ERCC1), with impaired DNA repair mechanism, shows changes of microglia core sensome expression [12]. (C) Microglia core sensome expression during aging in human derived from Olah et al.
    [Show full text]
  • A Transcriptomic Atlas of Aged Human Microglia
    ARTICLE DOI: 10.1038/s41467-018-02926-5 OPEN A transcriptomic atlas of aged human microglia Marta Olah1,2, Ellis Patrick 3, Alexandra-Chloe Villani2,4, Jishu Xu 2, Charles C. White2, Katie J. Ryan5, Paul Piehowski 6, Alifiya Kapasi6, Parham Nejad2, Maria Cimpean 5, Sarah Connor1,2, Christina J. Yung1, Michael Frangieh5, Allison McHenry5, Wassim Elyaman1,2, Vlad Petyuk 6, Julie A. Schneider7, David A. Bennett7, Philip L. De Jager 1,2 & Elizabeth M. Bradshaw1,2 With a rapidly aging global human population, finding a cure for late onset neurodegenerative diseases has become an urgent enterprise. However, these efforts are hindered by the lack of 1234567890():,; understanding of what constitutes the phenotype of aged human microglia—the cell type that has been strongly implicated by genetic studies in the pathogenesis of age-related neuro- degenerative disease. Here, we establish the set of genes that is preferentially expressed by microglia in the aged human brain. This HuMi_Aged gene set captures a unique phenotype, which we confirm at the protein level. Furthermore, we find this gene set to be enriched in susceptibility genes for Alzheimer’s disease and multiple sclerosis, to be increased with advancing age, and to be reduced by the protective APOEε2 haplotype. APOEε4 has no effect. These findings confirm the existence of an aging-related microglial phenotype in the aged human brain and its involvement in the pathological processes associated with brain aging. 1 Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York City, NY 10032, USA. 2 Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
    [Show full text]