DOCSLIB.ORG

Antigen Receptor Signaling: Integration of Protein Tyrosine Kinase Functions

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Antigen Receptor Signaling: Integration of Protein Tyrosine Kinase Functions Oncogene (1998) 17, 1353 ± 1364 1998 Stockton Press All rights reserved 0950 ± 9232/98 $12.00 http://www.stockton-press.co.uk/onc Antigen receptor signaling: integration of protein tyrosine kinase functions Idan Tamir1 and John C Cambier1 1Division of Basic Sciences, Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, Colorado 80206, USA Antigen receptors on T and B cells function to processing and presentation to T cells, and to transduce signals leading to a variety of biologic transduce signals that lead to multiple, often alter- responses minimally including antigen receptor editing, native responses. This receptor, termed the B cell apoptotic death, developmental progression, cell activa- antigen receptor (BCR), belongs to the family of tion, proliferation and survival. The response to antigen Multichain Immune Recognition Receptors (MIRR), depends upon antigen anity and valence, involvement which includes the T cell receptor (TCR) and receptors of coreceptors in signaling and dierentiative stage of for the Fc portions of IgG (FcgRI, FcgRIIA, FcgRIIC, the responding cell. The requirement that these FcgRIIIA) and IgE (FceRI). Common to this family of receptors integrate signals that drive an array of receptors is an oligomeric structure which uses dierent responses may explain their evolved structural complex- membrane-spanning subunits for the purpose of ity. Antigen receptors are composed of multiple subunits antigen/Ig recognition vs signal transduction. The compartmentalized to provide antigen recognition and BCR is comprised of a membrane-associated form of signal transduction function. In lieu of on-board immunoglobulin (mIg), noncovalently associated with enzymatic activity these receptors rely on associated a disul®de linked CD79a/CD79b heterodimer (Figure Protein Tyrosine Kinases (PTKs) for their signaling 1) (for review see Cambier, 1995a; Gold and function. By aggregating the receptors, and hence their DeFranco, 1994). Immunoglobulins of any isotype appended PTKs, antigens induce PTK transphosphor- can function as the mIg component of the BCR. ylation, activating them to phosphorylate the receptor While immature B cells express only mIgM-containing within conserved motifs termed Immunoreceptor Tyr- receptors, mature B cells co-express mIgM and mIgD, osine-based Activation Motifs (ITAMs) found in and memory B cells express the isotype, i.e., IgG, IgA transducer subunits. The tyrosyl phosphorylated ITAMs or IgE, that their daughter cells will secrete. then interact with Src Homology 2 (SH2) domains Membrane-associated immunoglobulins dier from within the PTKs leading to their further activation. As their secreted counterparts in containing a short receptor phosphorylation is ampli®ed, other eectors, spacer sequence at the normal heavy chain C- such as Shc, dock by virtue of SH2 binding, and serve, terminus, a single transmembrane spanning region in-turn, as substrates for these PTKs. This sequence of and a short [3 (mIgM and mIgD) to 28 (mIgM) events not only provides a signal ampli®cation mechan- residues] cytoplasmic tail. Although the mIg tail ism by combining multiple consecutive steps with contributes to signaling (Pleiman et al., 1994b; Weiser positive feedback, but also allows for signal diversi®ca- et al., 1997), CD79a and CD79b function as the tion by dierential recruitment of eectors that provide receptor's primary signal transducers (Cambier, 1995a; access to distinct parallel downstream signaling path- Gold and DeFranco, 1994; Pao et al., 1997). They are ways. The subject of antigen receptor signaling has been members of the immunoglobulin superfamily, contain- recently reviewed in depth (DeFranco, 1997; Kurosaki, ing a single extracellular immunoglobulin-like domain, 1997). Here we discuss the biochemical basis of antigen a single transmembrane spanning region and cytoplas- receptor signal transduction, using the B cell receptor mic tails of 48 (CD79b) and 61 (CD79a) amino acid (BCR) as a paradigm, with speci®c emphasis on the residues. The cytoplasmic domains of both CD79a and involved PTKs. We review several speci®c mechanisms CD79b contain the sequence motif YX2LX7YX2L, by which responses through these receptors are termed the Immunoreceptor Tyrosine-Based Activa- propagated and modi®ed by accessory molecules, and tion Motif or ITAM (Cambier, 1995b), that functions discuss how signal ampli®cation and diversi®cation are as the receptor's interface with cytoplasmic eectors. achieved. This motif is highly conserved among the cytoplasmic tails of MIRR and has been shown to be both Keywords: signal transduction; antigen receptors; sucient and necessary for signal transduction. Both protein tyrosine kinases the residue spacing (9 ± 11) between the two tyrosines in this motif and the presence of hydrophobic residues (leucine or isoleucine) at position +3 to both tyrosyl residues are required for proper ITAM function. As Antigen receptors-the MIRR family will be discussed below, these structural constraints are important for both ITAM phosphorylation and signal As pre-B cells transit into the immature stage they propagation by eector binding. begin to express speci®c receptors that function to recognize and internalize antigen for subsequent Antigen receptor activation of Src family PTKs The resting BCR associates with protein tyrosine Correspondence: JC Cambier kinases (PTKs) of the Src-family by virtue of an Signal transduction in lymphocytes I Tamir and JC Cambier 1354 interaction involving the receptor's ITAM and a these domains in Src-family PTK activation is domain found in the kinases' N-terminus (Clark et discussed below. al., 1992; Pleiman et al., 1994a; Yamanashi et al., 1991) The resting BCR-associated Src-family PTKs exist (Figure 1). The kinases bind preferentially to the in a dynamic equilibrium between inactive and CD79a ITAM via a site which involves the DCSM partially active states. The transition between these sequence found in CD79a, but not in CD79b (Clark et states has been shown to correlate with the phosphor- al., 1994). This low anity interaction of non- ylation of a single tyrosyl residue found at the kinase's phosphorylated ITAM with the kinase N-terminal C-terminal tail (Cooper and Howell, 1993; Pao and region is stabilized in vivo by concurrent kinase Cambier, 1998). The phosphorylation of this residue, association with the adjacent plasma membrane via which is conserved among Src-family members, is its covalent N-terminal myristylation/palmitylation mediated by the cytosolic PTK Csk (for C-terminal (Resh, 1993, 1994). In the absence of these mem- Src-family kinase) and results in an enzymatically- brane-docking modi®cations, the association of these inactive state (Hata et al., 1994). Dephosphorylation kinases with the plasma membrane and thus their of this residue, which is mediated by the transmem- ability to respond to receptor aggregation are inhibited branal protein tyrosine phosphatase (PTP) CD45, (Kabouridis et al., 1997; Timson-Gauen et al., 1996). leads to partial activation of the kinase (Mayer, The N-terminal sequence of Src-family PTKs, which is 1997; Thomas, 1989). The steady-state equilibrium of responsible for their association with the resting Src-family kinases in resting lymphocytes between the receptor, diers extensively among Src-family mem- C-terminally phosphorylated and non-phosphorylated bers and is thus termed `unique'. In addition to this forms favors the latter, probably due to the higher domain, Src-family members share four structurally- intrinsic activity of and dierent localization of CD45 homologous domains, namely the catalytic domain (membrane) compared to Csk (cytosolic). Hence, most (termed SH1 ± for src-homology 1), the SH2, SH3 (for of the resting receptor-associated Src-family PTK Src-Homology 2 and 3, respectively) and a C-terminal molecules are in the partially active state that allows tail containing a conserved tyrosyl residue (Brown and them to rapidly respond to receptor aggregation. Cooper, 1996). SH2 and SH3 domains are found in Several studies have suggested that kinase inactivity many proteins and are involved in mediating protein- results from an intramolecular interaction of the C- protein interactions. SH2 domains bind inter- or intra- terminal phosphotyrosyl residue with the kinase's SH2 molecularly to phosphotyrosyl residues with speci®city domain (Brown and Cooper, 1996). The recent three- which is governed by the phosphotyrosyl ¯anking dimensional structures of two Src-family kinases, residues. SH3 domains interact with proline-rich namely c-Src and Hck, solved by X-ray crystal- domains found within many adaptor proteins (Cohen lography (Sicheri et al., 1997; Xu et al., 1997), have and Baltimore, 1995; Pawson, 1995). The role(s) of actually demonstrated such interaction. Figure 1 Schematic representation of early signaling events activated upon BCR aggregation Signal transduction in lymphocytes I Tamir and JC Cambier 1355 These crystallographic studies have also shed light studies using B cells from Lyn knock-out mice (Chan on another facet of Src regulation involving its SH3 et al., 1997) have shown delayed, yet normal tyrosyl domain. It has been known for some time that the phosphorylation of CD79a, Syk and Shc upon BCR kinase's SH3 domain plays some role in regulating it's aggregation. Taken together, these data suggest that activity (Pleiman et al., 1994c; Superti-Fuga et al., Src-family members are the most proximal element 1993), however the mechanism was obscure
Load more

Recommended publications
  • Itk Tyrosine Kinase Substrate Docking Is Mediated by a Nonclassical SH2 Domain Surface of PLC␥1
    Itk tyrosine kinase substrate docking is mediated by a nonclassical SH2 domain surface of PLC␥1 Lie Min, Raji E. Joseph, D. Bruce Fulton, and Amy H. Andreotti1 Department of Biochemistry, Biophysics, and Molecular Biology, Iowa State University, Ames, IA 50011 Edited by Susan S. Taylor, University of California at San Diego, La Jolla, CA, and approved October 20, 2009 (received for review October 1, 2009) Interleukin-2 tyrosine kinase (Itk) is a Tec family tyrosine kinase that We have previously shown that the PLC␥1 SH2C domain mediates signaling processes after T cell receptor engagement. Acti- (spanning residues 659–756 within full-length PLC␥1) binds di- vation of Itk requires recruitment to the membrane via its pleckstrin rectly to the Itk kinase domain and is required for efficient homology domain, phosphorylation of Itk by the Src kinase, Lck, and phosphorylation of Y783 by Itk (26). Fragments of PLC␥1 that binding of Itk to the SLP-76/LAT adapter complex. After activation, Itk contain Y783 but not the SH2C domain are not efficiently phos- phosphorylates and activates phospholipase C-␥1 (PLC-␥1), leading to phorylated by Itk. Moreover, phosphorylation of PLC␥1 substrate production of two second messengers, DAG and IP3. We have previ- fragments that contain both SH2C and Y783 (spanning 659–789, ously shown that phosphorylation of PLC-␥1 by Itk requires a direct, hereafter referred to as PLC␥1 SH2C-linker) can be inhibited by phosphotyrosine-independent interaction between the Src homol- titration with isolated PLC␥1 SH2C domain (26). The excess, free ogy 2 (SH2) domain of PLC-␥1 and the kinase domain of Itk.
    [Show full text]
  • Novel Protein-Tyrosine Kinase Gene (Hck) Preferentially Expressed in Cells of Hematopoietic Origin STEVEN F
    MOLECULAR AND CELLULAR BIOLOGY, June 1987, p. 2276-2285 Vol. 7, No. 6 0270-7306/87/062276-10$02.00/0 Copyright © 1987, American Society for Microbiology Novel Protein-Tyrosine Kinase Gene (hck) Preferentially Expressed in Cells of Hematopoietic Origin STEVEN F. ZIEGLER,"12 JAMEY D. MARTH,"', DAVID B. LEWIS,4 AND ROGER M. PERLMUTTER' 2,5* Howard Hughes Medical Institute' and the Departments ofBiochemistry,2 Medicine,s Pediatrics,4 and Pharmacology,3 University of Washington School of Medicine, Seattle, Washington 98195 Received 16 December 1986/Accepted 18 March 1987 Protein-tyrosine kinases are implicated in the control of cell growth by virtue of their frequent appearance as products of retroviral oncogenes and as components of growth factor receptors. Here we report the characterization of a novel human protein-tyrosine kinase gene (hck) that is primarily expressed in hematopoietic cells, particularly granulocytes. The hck gene encodes a 505-residue polypeptide that is closely related to pp56kk, a lymphocyte-specific protein-tyrosine kinase. The exon breakpoints of the hck gene, partially defined by using murine genomic clones, demonstrate that hck is a member of the src gene family and has been subjected to strong selection pressure during mammalian evolution. High-level expression of hck transcripts in granulocytes is especially provocative since these cells are terminally differentiated and typically survive in vivo for only a few hours. Thus the hck gene, like other members of the src gene family, appears to function primarily in cells with little growth potential. Specific phosphorylation of proteins on tyrosine residues line Ml induces monocytoid differentiation (18), presumably was first detected in lysates of cells infected with acutely as a result of activation of endogenous pp60csrc (7).
    [Show full text]
  • Src-Family Kinases Impact Prognosis and Targeted Therapy in Flt3-ITD+ Acute Myeloid Leukemia
    Src-Family Kinases Impact Prognosis and Targeted Therapy in Flt3-ITD+ Acute Myeloid Leukemia Title Page by Ravi K. Patel Bachelor of Science, University of Minnesota, 2013 Submitted to the Graduate Faculty of School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2019 Commi ttee Membership Pa UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE Commi ttee Membership Page This dissertation was presented by Ravi K. Patel It was defended on May 31, 2019 and approved by Qiming (Jane) Wang, Associate Professor Pharmacology and Chemical Biology Vaughn S. Cooper, Professor of Microbiology and Molecular Genetics Adrian Lee, Professor of Pharmacology and Chemical Biology Laura Stabile, Research Associate Professor of Pharmacology and Chemical Biology Thomas E. Smithgall, Dissertation Director, Professor and Chair of Microbiology and Molecular Genetics ii Copyright © by Ravi K. Patel 2019 iii Abstract Src-Family Kinases Play an Important Role in Flt3-ITD Acute Myeloid Leukemia Prognosis and Drug Efficacy Ravi K. Patel, PhD University of Pittsburgh, 2019 Abstract Acute myelogenous leukemia (AML) is a disease characterized by undifferentiated bone-marrow progenitor cells dominating the bone marrow. Currently the five-year survival rate for AML patients is 27.4 percent. Meanwhile the standard of care for most AML patients has not changed for nearly 50 years. We now know that AML is a genetically heterogeneous disease and therefore it is unlikely that all AML patients will respond to therapy the same way. Upregulation of protein-tyrosine kinase signaling pathways is one common feature of some AML tumors, offering opportunities for targeted therapy.
    [Show full text]
  • Inhibition of Src Family Kinases and Receptor Tyrosine Kinases by Dasatinib: Possible Combinations in Solid Tumors
    Published OnlineFirst June 13, 2011; DOI: 10.1158/1078-0432.CCR-10-2616 Clinical Cancer Molecular Pathways Research Inhibition of Src Family Kinases and Receptor Tyrosine Kinases by Dasatinib: Possible Combinations in Solid Tumors Juan Carlos Montero1, Samuel Seoane1, Alberto Ocaña2,3, and Atanasio Pandiella1 Abstract Dasatinib is a small molecule tyrosine kinase inhibitor that targets a wide variety of tyrosine kinases implicated in the pathophysiology of several neoplasias. Among the most sensitive dasatinib targets are ABL, the SRC family kinases (SRC, LCK, HCK, FYN, YES, FGR, BLK, LYN, and FRK), and the receptor tyrosine kinases c-KIT, platelet-derived growth factor receptor (PDGFR) a and b, discoidin domain receptor 1 (DDR1), c-FMS, and ephrin receptors. Dasatinib inhibits cell duplication, migration, and invasion, and it triggers apoptosis of tumoral cells. As a consequence, dasatinib reduces tumoral mass and decreases the metastatic dissemination of tumoral cells. Dasatinib also acts on the tumoral microenvironment, which is particularly important in the bone, where dasatinib inhibits osteoclastic activity and favors osteogenesis, exerting a bone-protecting effect. Several preclinical studies have shown that dasatinib potentiates the antitumoral action of various drugs used in the oncology clinic, paving the way for the initiation of clinical trials of dasatinib in combination with standard-of-care treatments for the therapy of various neoplasias. Trials using combinations of dasatinib with ErbB/HER receptor antagonists are being explored in breast, head and neck, and colorectal cancers. In hormone receptor–positive breast cancer, trials using combina- tions of dasatinib with antihormonal therapies are ongoing. Dasatinib combinations with chemother- apeutic agents are also under development in prostate cancer (dasatinib plus docetaxel), melanoma (dasatinib plus dacarbazine), and colorectal cancer (dasatinib plus oxaliplatin plus capecitabine).
    [Show full text]
  • Second Generation Inhibitors of BCR- ABL for the Treatment of Imatinib- Resistant Chronic Myeloid Leukaemia
    REVIEWS Second generation inhibitors of BCR- ABL for the treatment of imatinib- resistant chronic myeloid leukaemia Ellen Weisberg*, Paul W. Manley‡, Sandra W. Cowan-Jacob§, Andreas Hochhaus|| and James D. Griffin¶ Abstract | Imatinib, a small-molecule ABL kinase inhibitor, is a highly effective therapy for early-phase chronic myeloid leukaemia (CML), which has constitutively active ABL kinase activity owing to the expression of the BCR-ABL fusion protein. However, there is a high relapse rate among advanced- and blast-crisis-phase patients owing to the development of mutations in the ABL kinase domain that cause drug resistance. Several second-generation ABL kinase inhibitors have been or are being developed for the treatment of imatinib- resistant CML. Here, we describe the mechanism of action of imatinib in CML, the structural basis of imatinib resistance, and the potential of second-generation BCR-ABL inhibitors to circumvent resistance. The BCR-ABL oncogene, which is the product of the design of new drugs to circumvent resistance, and Philadelphia chromosome (Ph) 22q, encodes a chimeric several new agents have been developed specifically BCR-ABL protein that has constitutively activated ABL for this purpose. These compounds have been well tyrosine kinase activity; it is the underlying cause of characterized for efficacy against the mutant enzymes chronic myeloid leukaemia (CML)1–3. Whereas the 210 in preclinical studies, and impressive therapeutic activ- kDa BCR-ABL protein is expressed in patients with ity has now been reported for two second generation CML, a 190 kDa BCR-ABL protein, resulting from an drugs in phase I and II clinical trials in patients with *Dana Farber Cancer alternative breakpoint in the BCR gene, is expressed in imatinib-resistant CML.
    [Show full text]
  • Supplementary Table 1. in Vitro Side Effect Profiling Study for LDN/OSU-0212320. Neurotransmitter Related Steroids
    Supplementary Table 1. In vitro side effect profiling study for LDN/OSU-0212320. Percent Inhibition Receptor 10 µM Neurotransmitter Related Adenosine, Non-selective 7.29% Adrenergic, Alpha 1, Non-selective 24.98% Adrenergic, Alpha 2, Non-selective 27.18% Adrenergic, Beta, Non-selective -20.94% Dopamine Transporter 8.69% Dopamine, D1 (h) 8.48% Dopamine, D2s (h) 4.06% GABA A, Agonist Site -16.15% GABA A, BDZ, alpha 1 site 12.73% GABA-B 13.60% Glutamate, AMPA Site (Ionotropic) 12.06% Glutamate, Kainate Site (Ionotropic) -1.03% Glutamate, NMDA Agonist Site (Ionotropic) 0.12% Glutamate, NMDA, Glycine (Stry-insens Site) 9.84% (Ionotropic) Glycine, Strychnine-sensitive 0.99% Histamine, H1 -5.54% Histamine, H2 16.54% Histamine, H3 4.80% Melatonin, Non-selective -5.54% Muscarinic, M1 (hr) -1.88% Muscarinic, M2 (h) 0.82% Muscarinic, Non-selective, Central 29.04% Muscarinic, Non-selective, Peripheral 0.29% Nicotinic, Neuronal (-BnTx insensitive) 7.85% Norepinephrine Transporter 2.87% Opioid, Non-selective -0.09% Opioid, Orphanin, ORL1 (h) 11.55% Serotonin Transporter -3.02% Serotonin, Non-selective 26.33% Sigma, Non-Selective 10.19% Steroids Estrogen 11.16% 1 Percent Inhibition Receptor 10 µM Testosterone (cytosolic) (h) 12.50% Ion Channels Calcium Channel, Type L (Dihydropyridine Site) 43.18% Calcium Channel, Type N 4.15% Potassium Channel, ATP-Sensitive -4.05% Potassium Channel, Ca2+ Act., VI 17.80% Potassium Channel, I(Kr) (hERG) (h) -6.44% Sodium, Site 2 -0.39% Second Messengers Nitric Oxide, NOS (Neuronal-Binding) -17.09% Prostaglandins Leukotriene,
    [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]
  • Src Protein-Tyrosine Kinase Structure, Mechanism, and Small Molecule Inhibitors
    Pharmacological Research 94 (2015) 9–25 Contents lists available at ScienceDirect Pharmacological Research j ournal homepage: www.elsevier.com/locate/yphrs Invited Review Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors ∗ Robert Roskoski Jr. Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116, Box 19, Horse Shoe, NC 28742-8814, United States a r t i c l e i n f o a b s t r a c t Article history: The physiological Src proto-oncogene is a protein-tyrosine kinase that plays key roles in cell growth, Received 26 January 2015 division, migration, and survival signaling pathways. From the N- to C-terminus, Src contains a unique Accepted 26 January 2015 domain, an SH3 domain, an SH2 domain, a protein-tyrosine kinase domain, and a regulatory tail. The Available online 3 February 2015 chief phosphorylation sites of human Src include an activating pTyr419 that results from phosphory- lation in the kinase domain by an adjacent Src molecule and an inhibitory pTyr530 in the regulatory This paper is dedicated to the memory of tail that results from phosphorylation by C-terminal Src kinase (Csk) or Chk (Csk homologous kinase). Prof. Donald F. Steiner (1930–2014) – advisor, mentor, and discoverer of The oncogenic Rous sarcoma viral protein lacks the equivalent of Tyr530 and is constitutively activated. proinsulin. Inactive Src is stabilized by SH2 and SH3 domains on the rear of the kinase domain where they form an immobilizing and inhibitory clamp. Protein kinases including Src contain hydrophobic regulatory and Chemical compounds studied in this article: catalytic spines and collateral shell residues that are required to assemble the active enzyme.
    [Show full text]
  • Structure, Regulation, Signaling, and Targeting of Abl Kinases in Cancer
    436 M MONOGRAPHS Genes & Cancer 3(5-6) 436 –446 © The Author(s) 2012 Reprints and permission: Structure, Regulation, Signaling, and sagepub.com/journalsPermissions.nav DOI: 10.1177/1947601912458584 Targeting of Abl Kinases in Cancer http://ganc.sagepub.com Oliver Hantschel Abstract Abl kinases are prototypic cytoplasmic tyrosine kinases and are involved in a variety of chromosomal aberrations in different cancers. This causes the expression of Abl fusion proteins, such as Bcr-Abl, that are constitutively activated and drivers of tumorigenesis. Over the past decades, biochemical and functional studies on the molecular mechanisms of Abl regulation have gone hand in hand with progression of our structural understanding of autoinhibited and active Abl conformations. In parallel, Abl oncoproteins have become prime molecular targets for cancer therapy, using adenosine triphosphate (ATP)–competitive kinase inhibitors, such as imatinib. Abl-targeting drugs serve as a paradigm for our understanding of kinase inhibitor action, specificity, and resistance development. In this review article, I will review the molecular mechanisms that are responsible for the regulation of Abl kinase activity and how oncogenic Abl fusions signal. Furthermore, past and ongoing efforts to target Abl oncoproteins using ATP-competitive and allosteric inhibitors, as well as future possibilities using combination therapy, will be discussed. Keywords: tyrosine kinase, Bcr-Abl, kinase inhibitor, kinase structure Structure and Regulation of Abl of Abl play key roles in mediating
    [Show full text]
  • Anti-FGR Antibody (ARG55365)
    Product datasheet [email protected] ARG55365 Package: 100 μl anti-FGR antibody Store at: -20°C Summary Product Description Rabbit Polyclonal antibody recognizes FGR Tested Reactivity Hu Tested Application ICC/IF, IHC-P, WB Host Rabbit Clonality Polyclonal Isotype IgG Target Name FGR Antigen Species Human Immunogen KLH-conjugated synthetic peptide corresponding to aa. 3-33 (N-terminus) of Human FGR. Conjugation Un-conjugated Alternate Names p58-Fgr; v-fgr; Tyrosine-protein kinase Fgr; p55-Fgr; p58c-Fgr; SRC2; Proto-oncogene c-Fgr; p55c-fgr; p58c-fgr; Gardner-Rasheed feline sarcoma viral; c-fgr; c-src2; EC 2.7.10.2 Application Instructions Application table Application Dilution ICC/IF 1:10 - 1:50 IHC-P 1:50 - 1:100 WB 1:1000 Application Note * The dilutions indicate recommended starting dilutions and the optimal dilutions or concentrations should be determined by the scientist. Positive Control Ramos Calculated Mw 59 kDa Properties Form Liquid Purification Purification with Protein G. Buffer PBS and 0.09% (W/V) Sodium azide Preservative 0.09% (W/V) Sodium azide Storage instruction For continuous use, store undiluted antibody at 2-8°C for up to a week. For long-term storage, aliquot and store at -20°C or below. Storage in frost free freezers is not recommended. Avoid repeated freeze/thaw cycles. Suggest spin the vial prior to opening. The antibody solution should be gently mixed before use. www.arigobio.com 1/3 Note For laboratory research only, not for drug, diagnostic or other use. Bioinformation Database links GeneID: 2268 Human Swiss-port # P09769 Human Gene Symbol FGR Gene Full Name FGR proto-oncogene, Src family tyrosine kinase Background This gene is a member of the Src family of protein tyrosine kinases (PTKs).
    [Show full text]
  • Inhibition of ERK 1/2 Kinases Prevents Tendon Matrix Breakdown Ulrich Blache1,2,3, Stefania L
    www.nature.com/scientificreports OPEN Inhibition of ERK 1/2 kinases prevents tendon matrix breakdown Ulrich Blache1,2,3, Stefania L. Wunderli1,2,3, Amro A. Hussien1,2, Tino Stauber1,2, Gabriel Flückiger1,2, Maja Bollhalder1,2, Barbara Niederöst1,2, Sandro F. Fucentese1 & Jess G. Snedeker1,2* Tendon extracellular matrix (ECM) mechanical unloading results in tissue degradation and breakdown, with niche-dependent cellular stress directing proteolytic degradation of tendon. Here, we show that the extracellular-signal regulated kinase (ERK) pathway is central in tendon degradation of load-deprived tissue explants. We show that ERK 1/2 are highly phosphorylated in mechanically unloaded tendon fascicles in a vascular niche-dependent manner. Pharmacological inhibition of ERK 1/2 abolishes the induction of ECM catabolic gene expression (MMPs) and fully prevents loss of mechanical properties. Moreover, ERK 1/2 inhibition in unloaded tendon fascicles suppresses features of pathological tissue remodeling such as collagen type 3 matrix switch and the induction of the pro-fbrotic cytokine interleukin 11. This work demonstrates ERK signaling as a central checkpoint to trigger tendon matrix degradation and remodeling using load-deprived tissue explants. Tendon is a musculoskeletal tissue that transmits muscle force to bone. To accomplish its biomechanical function, tendon tissues adopt a specialized extracellular matrix (ECM) structure1. Te load-bearing tendon compart- ment consists of highly aligned collagen-rich fascicles that are interspersed with tendon stromal cells. Tendon is a mechanosensitive tissue whereby physiological mechanical loading is vital for maintaining tendon archi- tecture and homeostasis2. Mechanical unloading of the tissue, for instance following tendon rupture or more localized micro trauma, leads to proteolytic breakdown of the tissue with severe deterioration of both structural and mechanical properties3–5.
    [Show full text]
  • Amplification of the Human Epidermal Growth Factor Receptor 2 (HER2) Gene Is Associated with a Microsatellite Stable Status in Chinese Gastric Cancer Patients
    387 Original Article Amplification of the human epidermal growth factor receptor 2 (HER2) gene is associated with a microsatellite stable status in Chinese gastric cancer patients He Huang1#, Zhengkun Wang2#, Yi Li2, Qun Zhao3, Zhaojian Niu2 1Department of Gastrointestinal Surgery, The First Hospital of Shanxi Medical University, Shanxi, China; 2Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China; 3Department of Gastrosurgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China Contributions: I) Conception and design: Z Niu, Q Zhao, H Huang; (II) Administrative support: Z Niu, H Huang, Z Wang; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: Z Wang, Q Zhao; (V) Data analysis and interpretation: Z Niu, H Huang; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. #These authors contributed equally to this work. Correspondence to: Zhaojian Niu. Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Shinan District, Qingdao 260003, China. Email: [email protected]; Qun Zhao. Department of Gastrosurgery, The Fourth Hospital of Hebei Medical University, No. 12 Jiankang Road, Shijiazhuang 050011, China. Email: [email protected]. Background: Gastric cancer (GC) is one of the most common cancers worldwide. However, little is known about the combination of HER2 amplification and microsatellite instability (MSI) status in GC. This study aimed to analyze the correlation of HER2 amplification with microsatellite instability (MSI) status, clinical characteristics, and the tumor mutational burden (TMB) of patients. Methods: A total of 192 gastric cancer (GC) patients were enrolled in this cohort. To analyze genomic alterations (GAs), deep sequencing was performed on 450 target cancer genes.
    [Show full text]