Genomes and Genes
Gene Symbol: Lck
Description: lymphocyte-specific protein tyrosine kinase
Alias: LSK, YT16, p56lck, pp58lck, T-lymphocyte specific protein tyrosine kinase p56lck, leukocyte C-terminal Src kinase, lymphocyte cell-specific protein-tyrosine kinase, p56(LSTRA) protein-tyrosine kinase, proto-oncogene tyrosine-protein kinase LCK, t cell-specific protein-tyrosine kinase, tyrosine-protein kinase Lck
Publications226 found, 100 shown here
- Constitutively active Lck kinase in T cells drives antigen receptor signal transductionKonstantina Nika
T Cell Signaling Laboratory, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
Immunity 32:766-77. 2010..TCR) and coreceptor ligation is thought to initiate signal transduction by inducing activation of the kinase Lck. Here we showed that catalytically active Lck was present in unstimulated naive T cells and thymocytes and was ..
- Function of the Src-family kinases, Lck and Fyn, in T-cell development and activationEmil H Palacios
Rosalind Russell Medical Research Center for Arthritis, Department of Medicine and The Howard Hughes Medical Institute, University of California, San Francisco 94143 0795, USA
Oncogene 23:7990-8000. 2004The function of the Src-family kinases (SFKs) Lck and Fyn in T cells has been intensively studied over the past 15 years...
- Phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), a novel ubiquitously expressed transmembrane adaptor protein, binds the protein tyrosine kinase csk and is involved in regulation of T cell activationT Brdicka
Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, 14220 Prague, Czech Republic
J Exp Med 191:1591-604. 2000..These findings collectively suggest that in the absence of external stimuli, the PAG-Csk complex transmits negative regulatory signals and thus may help to keep resting T cells in a quiescent state...
- HIV-1 Nef compensates for disorganization of the immunological synapse by inducing trans-Golgi network-associated Lck signalingXiaoyu Pan
Department of Infectious Diseases, Virology, University Hospital Heidelberg, Germany
Blood 119:786-97. 2012..Nef reroutes kinase-active pools of the TCR signaling master switch Lck away from the plasma membrane (PM) to the trans-Golgi network (TGN), thereby preventing the recruitment of active ..
- Modulation of Lck function through multisite docking to T cell-specific adapter proteinStine Granum
Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Box 1105, Blindern, N 0317 Oslo, Norway
J Biol Chem 283:21909-19. 2008T cell-specific adapter protein (TSAd), encoded by the SH2D2A gene, interacts with Lck through its C terminus and thus modulates Lck activity...
- Lck phosphorylates the activation loop tyrosine of the Itk kinase domain and activates Itk kinase activityS D Heyeck
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA
J Biol Chem 272:25401-8. 1997..tyrosine-phosphorylated after TCR cross-linking and that this phosphorylation depends on the presence of functional Lck. To determine if this Lck dependence results from direct phosphorylation of Itk by Lck, we generated recombinant ..
- HIV-1 Nef employs two distinct mechanisms to modulate Lck subcellular localization and TCR induced actin remodelingClaudia Haller
Abteilung Virologie, Universitatsklinikum Heidelberg, Heidelberg, Germany
PLoS ONE 2:e1212. 2007..spreading and actin polymerization upon TCR engagement, a pronounced intracellular accumulation of the Src kinase Lck and its reduced IS recruitment...
- Specific dephosphorylation of the Lck tyrosine protein kinase at Tyr-394 by the SHP-1 protein-tyrosine phosphataseG G Chiang
Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA
J Biol Chem 276:23173-8. 2001..In this study, we demonstrate that SHP-1 dephosphorylates the lymphoid-specific Src family kinase Lck at Tyr-394 when both are transiently co-expressed in nonlymphoid cells...
- A weak Lck tail bite is necessary for Lck function in T cell antigen receptor signalingKonstantina Nika
Program on Inflammatory Disease Research, Infectious and Inflammatory Disease Center, The Burnham Institute for Medical Research, La Jolla, California 92037, USA
J Biol Chem 282:36000-9. 2007..understand the relative importance of these two opposite functions of the SH2 domain of the Src family kinase Lck in TCR signaling, we created three mutants of Lck in which the intramolecular binding of the C terminus to the SH2 ..
- Intracellular signaling mechanisms leading to synergistic effects of endothelin-1 and stem cell factor on proliferation of cultured human melanocytes. Cross-talk via trans-activation of the tyrosine kinase c-kit receptorG Imokawa
Kao Biological Science Laboratories, Haga, Tochigi 321 3497, Japan
J Biol Chem 275:33321-8. 2000....
- The tyrosine kinase Hck is an inhibitor of HIV-1 replication counteracted by the viral vif proteinG Hassaine
INSERM Unit 372, Universite de la Mediterranee, 163 Avenue de Luminy, 13276 Marseilles Cedex 09, France
J Biol Chem 276:16885-93. 2001..Hck, which is present in monocyte-macrophage cells, represents the first identified cellular inhibitor of HIV-1 replication overcome by Vif...
- The N-terminus of Nef from HIV-1/SIV associates with a protein complex containing Lck and a serine kinaseA S Baur
Institut fur Klinische und Molekulare Virologie, Universitat Erlangen Nurnberg, Erlangen, Federal Republic of Germany
Immunity 6:283-91. 1997..One of the kinases was identified as Lck, whereas the second protein was found to be a serine kinase that phosphorylated Nef and Lck in vitro and could be ..
- HIV-1 Nef limits communication between linker of activated T cells and SLP-76 to reduce formation of SLP-76-signaling microclusters following TCR stimulationLibin Abraham
Department of Infectious Diseases, Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany
J Immunol 189:1898-910. 2012..Nef thus employs a dual mechanism to disturb early TCR signaling by limiting the communication between LAT and SLP-76 and preventing the dynamic formation of SLP-76-signaling MCs...
- In vitro tyrosine phosphorylation of PLC-gamma 1 and PLC-gamma 2 by src-family protein tyrosine kinasesF Liao
Department of Molecular Biology and Genetics, Johns Hopkins University, School of Medicine, Baltimore, MD 21205
Biochem Biophys Res Commun 191:1028-33. 1993..of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro...
- Repression of human immunodeficiency virus type 1 long terminal repeat-driven gene expression by binding of the virus to its primary cellular receptor, the CD4 moleculeP Berube
Centre de Recherche en Infectiologie, Centre hospitalier de l Universite Laval, Quebec, Canada
J Virol 70:4009-16. 1996..The virus-mediated signal transduction was shown to be mediated via p56lck-dependent and -independent pathways...
- The human immunodeficiency virus type 1 Nef protein binds the Src-related tyrosine kinase Lck SH2 domain through a novel phosphotyrosine independent mechanismH Dutartre
Unité 119 Instituto National de la Santé et de la Recherche Médicale, Marseille, France
Virology 247:200-11. 1998..infected monocytes, we and others have reported previously that Nef also interacts with the T-lymphocyte Src-kinase Lck, leading to specific cell signaling impairment...
- The role of C-terminal tyrosine phosphorylation in the regulation of SHP-1 explored via expressed protein ligationZhongsen Zhang
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
J Biol Chem 278:4668-74. 2003....
- Identification of a highly conserved valine-glycine-phenylalanine amino acid triplet required for HIV-1 Nef functionPieter J Meuwissen
Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, Ghent, B 9000, Belgium
Retrovirology 9:34. 2012..In this study, we aimed to study the functional importance of this VGF region...
- Tyrosine phosphorylation sites at amino acids 239 and 240 of Shc are involved in epidermal growth factor-induced mitogenic signaling that is distinct from Ras/mitogen-activated protein kinase activationN Gotoh
Department of Genetics, Institute of Medical Science, University of Tokyo, Japan
Mol Cell Biol 17:1824-31. 1997..These results suggest that Shc activates two distinct signaling pathways, Y317 to Ras/MAPK and Y239 and Y240 to another pathway including Myc, and that both are involved in EGF-induced mitogenic signaling...
- Human homologue of the Drosophila discs large tumor suppressor binds to p56lck tyrosine kinase and Shaker type Kv1.3 potassium channel in T lymphocytesT Hanada
Laboratory of Tumor Cell Biology, St Elizabeth s Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135, USA
J Biol Chem 272:26899-904. 1997..Immunoblotting experiments revealed that the immunoprecipitates of hDlg contain p56lck, a member of the Src family of tyrosine kinases...
- Phosphatidylinositol (PI) 3-kinase and PI 4-kinase binding to the CD4-p56lck complex: the p56lck SH3 domain binds to PI 3-kinase but not PI 4-kinaseK V Prasad
Division of Tumor Immunology, Dana Farber Cancer Institute, Boston, Massachusetts 02115
Mol Cell Biol 13:7708-17. 1993..It is coupled to the protein-tyrosine kinase p56lck, an interaction necessary for an optimal response of certain T cells to antigen...
- RT loop flexibility enhances the specificity of Src family SH3 domains for HIV-1 NefS Arold
Centre de Biochimie Structurale, UMR C9955 CNRS, U414 INSERM, Universite Montpellier 1, France
Biochemistry 37:14683-91. 1998..is approximately an order of magnitude tighter than those of other Src family kinases that were investigated (Fyn, Lck, and Src)...
- Cutting edge: the CD45 tyrosine phosphatase is an inhibitor of Lck activity in thymocytesU D'Oro
Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
J Immunol 162:1879-83. 1999A widely accepted model for regulation of the Lck tyrosine kinase is that it is activated by CD45-mediated dephosphorylation of its COOH-terminal negative regulatory tyrosine (Tyr505)...
- Structural basis for activation of human lymphocyte kinase Lck upon tyrosine phosphorylationH Yamaguchi
Department of Biochemistry and Molecular Biophysics, Columbia University, New York 10032, USA
Nature 384:484-9. 1996Regulation through phosphorylation is a characteristic of signalling pathways and the lymphocyte kinase Lck (p56lck) both performs phosphorylation and is affected by it...
- A requirement for caveolin-1 and associated kinase Fyn in integrin signaling and anchorage-dependent cell growthK K Wary
Cellular Biochemistry and Biophysics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
Cell 94:625-34. 1998..These findings reveal an unexpected function of caveolin-1 and Fyn in integrin signaling and anchorage-dependent cell growth...
- HIV type 1 glycoprotein 120 amplifies tumor necrosis factor-induced NF-kappa B activation in Jurkat cellsV A Shatrov
Division of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Germany
AIDS Res Hum Retroviruses 12:1209-16. 1996..In contrast, in the p56lck-deficient J.CaM1...
- Binding of human immunodeficiency virus type 1 to CD4 induces association of Lck and Raf-1 and activates Raf-1 by a Ras-independent pathwayW Popik
Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
Mol Cell Biol 16:6532-41. 1996..gp120 to CD4 receptors resulted in association and tyrosine phosphorylation and activation of tyrosine kinase Lck and serine/threonine kinase Raf-1...
- Molecular cloning of SKAP55, a novel protein that associates with the protein tyrosine kinase p59fyn in human T-lymphocytesA Marie-Cardine
Ruprecht Karls University Heidelberg, Institute of Immunology, 69120 Heidelberg, Germany
J Biol Chem 272:16077-80. 1997..Consistent with this observation, pp55 selectively binds to isolated SH2 domains of Lck, Lyn, Src, and Fyn but not to the SH2 domains of ZAP70, Syk, Shc, SLP-76, Grb2, phosphatidylinositol 3-kinase, and ..
- Proline-rich (PxxP) motifs in HIV-1 Nef bind to SH3 domains of a subset of Src kinases and are required for the enhanced growth of Nef+ viruses but not for down-regulation of CD4K Saksela
Rockefeller University, New York, NY 10021
EMBO J 14:484-91. 1995..Thus, CD4 down-regulation and promotion of viral growth are two distinct functions of Nef, and the latter is mediated via SH3 binding...
- Differential requirement for p56lck in HIV-tat versus TNF-induced cellular responses: effects on NF-kappa B, activator protein-1, c-Jun N-terminal kinase, and apoptosisS K Manna
Cytokine Research Section, Department of Bioimmunotherapy, University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA
J Immunol 164:5156-66. 2000..In the present study we investigated the role of the T cell-specific tyrosine kinase p56lck in HIV-tat and TNF-mediated cellular responses by comparing the responses of Jurkat T cells with JCaM1 cells, an ..
- HIV-1 Nef plays an essential role in two independent processes in CD4 down-regulation: dissociation of the CD4-p56(lck) complex and targeting of CD4 to lysosomesY H Kim
Laboratory of Molecular Virology, Samsung Biomedical Research Institute, Seoul, Korea
Virology 257:208-19. 1999..in cells lacking p56(lck) expression, but not in cells with p56(lck);these mutants fail to dissociate CD4 from p56lck. These results show that Nef-mediated CD4 dissociation from p56(lck) is important for CD4 down-regulation...
- Simian immunodeficiency virus and human immunodeficiency virus type 1 nef proteins show distinct patterns and mechanisms of Src kinase activationA L Greenway
AIDS Cellular Biology Unit, Macfarlane Burnet Center for Medical Research, Fairfield, Victoria 3078, Australia
J Virol 73:6152-8. 1999..We show here that the Nef protein encoded by SIVmac239 interacts with and also activates the human Src kinases Lck and Hck. This is in direct contrast to the inhibitory effect of HIV type 1 (HIV-1) Nef on Lck catalytic activity...
- The protein tyrosine kinase p56lck is required for triggering NF-kappaB activation upon interaction of human immunodeficiency virus type 1 envelope glycoprotein gp120 with cell surface CD4L Briant
Laboratoire Infections Retrovirales et Signalisation Cellulaire, CRBM CNRS UPR 1086, Institut de Biologie, Montpellier, France
J Virol 72:6207-14. 1998..Here we investigate the putative role of p56(lck) as a possible cellular intermediate in this signal transduction pathway...
- Inhibition of tyrosine kinase activation blocks the down-regulation of CXC chemokine receptor 4 by HIV-1 gp120 in CD4+ T cellsS B Su
Laboratory of Molecular Immunoregulation, Division of Basic Sciences, SAIC Frederick National Cancer Institute, MD 21702, USA
J Immunol 162:7128-32. 1999..gp120, but not SDF-1alpha, induced rapid tyrosine phosphorylation of src-like kinase p56lck in CD4+ T cells, whereas both gp120 and SDF-1alpha caused phosphorylation of the CXCR4...
- SHP2-interacting transmembrane adaptor protein (SIT), a novel disulfide-linked dimer regulating human T cell activationA Marie-Cardine
Immunomodulation Laboratory of the Institute for Immunology, University of Heidelberg, 69120 Heidelberg, Germany
J Exp Med 189:1181-94. 1999..However, binding of SHP2 to SIT is not required for inhibition of NF-AT induction, suggesting that SIT not only regulates NF-AT activity but also controls NF-AT unrelated pathways of T cell activation involving SHP2...
- T cell receptor (TCR) interacting molecule (TRIM), a novel disulfide-linked dimer associated with the TCR-CD3-zeta complex, recruits intracellular signaling proteins to the plasma membraneE Bruyns
Institute for Immunology, University of Heidelberg, 69120 Heidelberg, Germany
J Exp Med 188:561-75. 1998..Thus, TRIM represents a TCR-associated transmembrane adaptor protein which is likely involved in targeting of intracellular signaling proteins to the plasma membrane after triggering of the TCR...
- HIV-1 glycoprotein gp120 disrupts CD4-p56lck/CD3-T cell receptor interactions and inhibits CD3 signalingP Hubert
Laboratoire d Immunologie Cellulaire et Tissulaire, CNRS URA 625, Paris, France
Eur J Immunol 25:1417-25. 1995..Additionally, gp120 was shown to dissociate the tyrosine kinase p56lck from CD4 in CEM cells, with a concommittant inhibition of CD4-linked kinase activity...
- Residues Y429 and Y463 of the human CD5 are targeted by protein tyrosine kinasesJ M Vila
Servei d Immunologia, Institut d Investigacions Biomediques August Pi i Sunyer IDIBAPS, Hospital Clinic, Barcelona, Spain
Eur J Immunol 31:1191-8. 2001..This is in agreement with data from direct in vitro kinase assays using purified recombinant Lck and Fyn protein tyrosine kinases...
- gp120 ligation of CD4 induces p56lck activation and TCR desensitization independent of TCR tyrosine phosphorylationF Goldman
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206
J Immunol 153:2905-17. 1994..Studies reported here reveal that CD4 ligation initiates p56lck activation and renders human peripheral T cells and HPB-ALL cells hyporesponsive to Ag receptor stimulation, as ..
- The T-cell antigen CD5 acts as a receptor and substrate for the protein-tyrosine kinase p56lckM Raab
Division of Tumor Immunology, Dana Farber Cancer Institute, Boston, Massachusetts 02115
Mol Cell Biol 14:2862-70. 1994..In this study, we demonstrate that CD5 is coupled to the protein-tyrosine kinase p56lck and can act as a substrate for p56lck...
- Thiol/disulfide exchange is a prerequisite for CXCR4-tropic HIV-1 envelope-mediated T-cell fusion during viral entryIngrid Markovic
Center for Drug Evaluation and Research, Food and Drug Adminiatration, Bethesda, MD, USA
Blood 103:1586-94. 2004....
- Association analysis of the lymphocyte-specific protein tyrosine kinase (LCK) gene in type 1 diabetesJohn S Hulme
JDRF WT Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Addenbrooke s Hospital, Hills Road, Cambridge, CB2 2XY, UK
Diabetes 53:2479-82. 2004Prior data associating the expression of lymphocyte-specific protein tyrosine kinase (LCK) with type 1 diabetes, its critical function in lymphocytes, and the linkage of the region to diabetes in the nonobese diabetic (NOD) mouse model ..
- CIN85 associates with TNF receptor 1 via Src and modulates TNF-alpha-induced apoptosisTadashi Narita
Laboratory of Bacterial Infection and Immunity, Department of Immunology, National Institute of Infectious Diseases, 1 23 1, Toyama, Tokyo 162 8640, Japan
Exp Cell Res 304:256-64. 2005..TNF-alpha treatment recruited CIN85 to the TNFR1 signaling complex. Taken together, these results indicate that CIN85 associates with TNFR1 via Src and modulates TNF-alpha-induced apoptosis...
- The LIM protein Ajuba influences interleukin-1-induced NF-kappaB activation by affecting the assembly and activity of the protein kinase Czeta/p62/TRAF6 signaling complexYungfeng Feng
Department of Medicine, Washington University, St Louis, Missouri 63110, USA
Mol Cell Biol 25:4010-22. 2005..We propose that Ajuba is a new cytosolic component of the IL-1 signaling pathway modulating IL-1-induced NF-kappaB activation by influencing the assembly and activity of the aPKC/p62/TRAF6 multiprotein signaling complex...
- Mapping the binding site of full length HIV-1 Nef on human Lck SH3 by NMR spectroscopyLars Briese
Institut fur Molekulare Biotechnologie, 07745, Jena, Germany
J Biomed Sci 12:451-6. 2005..virus type 1 (HIV-1) is known to directly bind to the SH3 domain of human lymphocyte specific kinase (Lck) via a proline-rich region located in the amino terminal part of Nef...
- Human immunodeficiency virus type 1 glycoprotein precursor retains a CD4-p56lck complex in the endoplasmic reticulumB Crise
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510
J Virol 66:2296-301. 1992..At the plasma membrane of T cells, CD4 is tightly associated with a cytoplasmic tyrosine kinase (p56lck) that is involved in T-cell activation...
- The Src kinase Lck facilitates assembly of HIV-1 at the plasma membraneAmy B Strasner
Intergrated Bioscience Program in Immunobiology, Huck Institute of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA
J Immunol 181:3706-13. 2008..However, the pathways and cellular mediators of Gag targeting to the plasma membrane are not well characterized. Lck, a lymphoid specific Src kinase critical for T cell activation, is found in the plasma membrane as well as various ..
- The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cellsHadassah Sade
National Centre for Biological Sciences, University of Agricultural Sciences Gandhi Krishi Vignan Kendra Campus, New Bellary Road, Bangalore 560065, Karnataka, India
J Biol Chem 279:2937-44. 2004..Using a cell line deficient for the T cell-specific, Src family protein, the tyrosine kinase p56(lck) and by reconstitution approaches we demonstrate that p56(lck) is required for the Notch-1-mediated activation of ..
- Regulation of Fyn through translocation of activated Lck into lipid raftsDominik Filipp
Sunnybrook and Women s College Health Sciences Centre, and Departmentof Immunology, University of Toronto, Ontario M4N 3M5, Canada
J Exp Med 197:1221-7. 2003Whether or how the activation of Lck and Fyn during T cell receptor (TCR) signaling is coordinated, and their delivery of function integrated, is unknown...
- A natural variability in the proline-rich motif of Nef modulates HIV-1 replication in primary T cellsO T Fackler
Institute for Hygiene, Department of Virology, University of Heidelberg, D 69120, Heidelberg, Germany
Curr Biol 11:1294-9. 2001..Our report suggests that functionally and conformationally distinct Nef isoforms modulate HIV replication on the interaction level with the TCR-signaling environment once the virus enters the T cell compartment...
- No association between lck gene polymorphisms and protein level in type 1 diabetesSolange Nervi
Universite de la Mediterranee, CHU Sainte Marguerite, Marseille, France
Diabetes 51:3326-30. 2002We previously described a reduced expression of the protein tyrosine kinase Lck in T-cells from type 1 diabetic patients, the origin of which is still unknown. The human lck gene, located on chromosome 1p35-34...
- Signal transduction through decay-accelerating factor. Interaction of glycosyl-phosphatidylinositol anchor and protein tyrosine kinases p56lck and p59fyn 1A M Shenoy-Scaria
Department of Pathology, Washington University School of Medicine, St Louis, MO 63110
J Immunol 149:3535-41. 1992..Both p56lck and p59fyn were associated with DAF in DAF-transfected EL-4 cells...
- Guanidine alkaloid analogs as inhibitors of HIV-1 Nef interactions with p53, actin, and p56lckAllison Olszewski
Department of Chemistry, University of California, Irvine, CA 92697 2025, USA
Proc Natl Acad Sci U S A 101:14079-84. 2004..were used to identify a series of guanidine alkaloid-based inhibitors of Nef interactions with p53, actin, and p56(lck)...
- Identification of preferred protein interactions by phage-display of the human Src homology-3 proteomeSatu Kärkkäinen
Institute of Medical Technology, University of Tampere and Tampere University Hospital, Biokatu 8, Tampere 33014, Finland
EMBO Rep 7:186-91. 2006....
- Genetically encoded Förster resonance energy transfer sensors for the conformation of the Src family kinase LckWolfgang Paster
Department of Molecular Immunology, Center for Physiology, Pathophysiology and Immunology, Medical University of Vienna, Vienna, Austria
J Immunol 182:2160-7. 2009The current model for regulation of the Src family kinase member Lck postulates a strict correlation between structural condensation of the kinase backbone and catalytic activity...
- Selective interaction of LAT (linker of activated T cells) with the open-active form of Lck in lipid rafts reveals a new mechanism for the regulation of Lck in T cellsPanagiotis S Kabouridis
Bone and Joint Research Unit, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, Charterhouse Square, London EC1M 6BQ, UK
Biochem J 371:907-15. 2003In T cells, the lipid raft-associated Lck is strongly tyrosine phosphorylated and has reduced enzymic activity in contrast with the detergent-soluble pool, which has substantial activity...
- Lck is required for stromal cell-derived factor 1 alpha (CXCL12)-induced lymphoid cell chemotaxisMarit Inngjerdingen
Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Norway
Blood 99:4318-25. 2002..Damnacanthal, a specific Lck inhibitor, but not the Syk inhibitor piceatannol, inhibited CXCL12-induced chemotaxis of both lymphocyte subsets...
- Evidence of LAT as a dual substrate for Lck and Syk in T lymphocytesYixing Jiang
Department of Medicine and Pennstate Cancer Institute, Penn State University College of Medicine, Hershey, PA 17033, United States
Leuk Res 31:541-5. 2007..In this study, we demonstrate that LAT serves as a dual substrate for both Lck and Syk kinases. LAT phosphorylation is absent in Lck-deficient J.CaM1...
- Binding of HIV-1 to its receptor induces tyrosine phosphorylation of several CD4-associated proteins, including the phosphatidylinositol 3-kinaseG Briand
Centre de Recherche en Infectiologie, Centre Hospitalier Universitaire de Quebec, Canada
Virology 228:171-9. 1997..Immunoblot analysis permitted the identification of two of these proteins, p56lck and phosphatidylinositol 3-kinase (PI 3-kinase) p85 alpha...
- A 10-aa-long sequence in SLP-76 upstream of the Gads binding site is essential for T cell development and functionLalit Kumar
Division of Immunology, Children s Hospital, CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115, USA
Proc Natl Acad Sci U S A 102:19063-8. 2005The adapter SLP-76 is essential for T cell development and function. SLP-76 binds to the src homology 3 domain of Lck in vitro. This interaction depends on amino acids 185-194 of SLP-76...
- Dok-3, a novel adapter molecule involved in the negative regulation of immunoreceptor signalingS Lemay
McGill Cancer Centre, McGill University, Montreal, Quebec, Canada H3G 1Y6
Mol Cell Biol 20:2743-54. 2000....
- Lad, an adapter protein interacting with the SH2 domain of p56lck, is required for T cell activationY B Choi
Signal Transduction Laboratory Mogam Biotechnology Research Institute, Koosungmyon, Yonginsi, Kyunggido, Korea
J Immunol 163:5242-9. 1999T cell-specific Src family tyrosine kinase, p56lck, plays crucial roles in T cell differentiation, activation, and proliferation...
- SHP-1 regulates Lck-induced phosphatidylinositol 3-kinase phosphorylation and activityB Cuevas
Division of Medicine, and the Cell Growth Regulation Laboratory, University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA
J Biol Chem 274:27583-9. 1999Ligation of the T cell antigen receptor (TCR) activates the Src family tyrosine kinase p56 Lck, which, in turn, phosphorylates a variety of intracellular substrates...
- Regulation of the Src family kinase Lck by Hsp90 and ubiquitinationAna Giannini
Department of Immunobiology, Guy s Hospital, King s College London, United Kingdom
Mol Cell Biol 24:5667-76. 2004Regulation of the Src-related tyrosine kinase Lck is crucial to the outcome of T-cell receptor (TCR) stimulation. It was previously shown that the stability of the constitutively active mutant LckY505F is controlled by Hsp90 (M. J...
- Unc119, a novel activator of Lck/Fyn, is essential for T cell activationMagdalena M Gorska
Division of Allergy and Immunology, Department of Internal Medicine, University of Texas Medical Branch, Galveston 77555, USA
J Exp Med 199:369-79. 2004The first step in T cell receptor for antigen (TCR) signaling is the activation of the receptor-bound Src kinases, Lck and Fyn. The exact mechanism of this process is unknown...
- Proline residues in CD28 and the Src homology (SH)3 domain of Lck are required for T cell costimulationA D Holdorf
Department of Pathology, Center for Immunology, Pulmonary Division, Washington University School of Medicine, St Louis, Missouri 63110, USA
J Exp Med 190:375-84. 1999The Src family tyrosine kinases Lck and Fyn are critical for signaling via the T cell receptor. However, the exact mechanism of their activation is unknown...
- Profound block in thymocyte development in mice lacking p56lckT J Molina
Ontario Cancer Institute, University of Toronto, Canada
Nature 357:161-4. 1992The protein Lck (p56lck) has a relative molecular mass of 56,000 and belongs to the Src family of tyrosine kinases. It is expressed exclusively in lymphoid cells, predominantly in thymocytes and peripheral T cells...
- Activation of phosphatidylinositol-3-kinase in Jurkat T cells depends on the presence of the p56lck tyrosine kinaseM von Willebrand
Division of Cell Biology, Institute for Allergy and Immunology, La Jolla, CA 92037
Eur J Immunol 24:234-8. 1994..tyrosine phosphorylation and activation of PI3K in Jurkat T leukemia cells depend on the presence of the p56lck tyrosine kinase: in a variant of the Jurkat T cell line lacking p56lck, JCaM1, these responses were absent...
- The SH3 domain of p56lck binds to proline-rich sequences in the cytoplasmic domain of CD2G M Bell
Department of Medicine, Veterans Affairs Medical Center, San Francisco, California, USA
J Exp Med 183:169-78. 1996..An Src-like protein tyrosine kinase, p56lck, coprecipitates with CD2, and perturbation of CD2 by monoclonal antibodies results in an increase in the activity ..
- Syk and ZAP-70 mediate recruitment of p56lck/CD4 to the activated T cell receptor/CD3/zeta complexM Thome
Department of Immunology, Institut Pasteur, Paris, France
J Exp Med 181:1997-2006. 1995..suggested that the association of CD4 with TCR/CD3/zeta requires the interaction of the protein tyrosine kinase p56lck with CD4...
- Identification of two SH3-binding motifs in the regulatory subunit of phosphatidylinositol 3-kinaseR Kapeller
Department of Physiology, Tufts University Medical School, Boston, Massachusetts 02111
J Biol Chem 269:1927-33. 1994..Here we show that p85, the regulatory subunit of PI 3-kinase, binds directly to the SH3 domains of Abl, Lck, Fyn, and p85 itself...
- The association of the protein tyrosine kinases p56lck and p60fyn with the glycosyl phosphatidylinositol-anchored proteins Thy-1 and CD48 in rat thymocytes is dependent on the state of cellular activationD Garnett
MRC Cellular Immunology Unit, Sir William Dunn School of Pathology, University of Oxford, GB
Eur J Immunol 23:2540-4. 1993..are shown to be associated with multimolecular complexes of phosphoproteins including the protein tyrosine kinases p56lck and p60fyn in both rat and mouse thymocytes...
- Regulation of Bcl-3 through interaction with the Lck tyrosine kinaseYujie Zhao
Center for Advanced Biotechnology and Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA
Biochem Biophys Res Commun 335:865-73. 2005..that Bcl-3 interacts with the Fyn tyrosine kinase in platelets, we investigated possible interactions of Bcl-3 with Lck, a related tyrosine kinase important in lymphoid cells...
- Modification of phosphatidylinositol 3-kinase SH2 domain binding properties by Abl- or Lck-mediated tyrosine phosphorylation at Tyr-688M von Willebrand
Divisions of Cell Biology and Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA
J Biol Chem 273:3994-4000. 1998..We report that this phosphorylation event is readily catalyzed by the Abl and Lck protein-tyrosine kinases in vitro, by Bcr-Abl or a catalytically activated Lck-Y505F in co-transfected COS cells, ..
- Association between mitogen-activated protein kinase and the zeta chain of the T cell receptor (TcR) with the SH2,3 domain of p56lck. Differential regulation by TcR cross-linkingA August
Immunology Program, Sloan Kettering Institute for Cancer Research, New York, New York 10021, USA
J Biol Chem 271:10054-9. 1996A number of protein-tyrosine kinases have been shown to be important in T cell activation. One such kinase, Lck, has been demonstrated genetically to be essential for T cell receptor (TcR) signaling, and the SH2 and SH3 (src homology 2 ..
- LCK-phosphorylated human killer cell-inhibitory receptors recruit and activate phosphatidylinositol 3-kinaseF Marti
The Immunology Program, Memorial Sloan Kettering Cancer Center, Cornell University Medical Center, New York, NY 10021, USA
Proc Natl Acad Sci U S A 95:11810-5. 1998..Using these systems, we show that KIR CYT, once phosphorylated by the src-family tyrosine kinase LCK, additionally bind the p85alpha regulatory subunit of phosphatidylinositol (PI) 3-kinase...
- A membrane proximal domain of the human interleukin-3 receptor beta c subunit that signals DNA synthesis in NIH 3T3 cells specifically binds a complex of Src and Janus family tyrosine kinases and phosphatidylinositol 3-kinaseP Rao
Holland Laboratory for BioMedical Science, American Red Cross, Rockville, Maryland 20855
J Biol Chem 270:6886-93. 1995..Purified Lyn and Lck kinase, but not Fes, could phosphorylate tyrosines in both domains...
- Sequential involvement of Lck and SHP-1 with MHC-recognizing receptors on NK cells inhibits FcR-initiated tyrosine kinase activationB A Binstadt
Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA
Immunity 5:629-38. 1996..Using a somatic genetic model, we first define a requirement for the Src family protein tyrosine kinase (PTK) Lck in mediating KIR tyrosine phosphorylation...
- Activation of rabbit platelets by Ca2+ influx and thromboxane A2 release in an external Ca(2+)-dependent manner by zooxanthellatoxin-A, a novel polyolM C Rho
Department of Pharmaceutical Molecular Biology, Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
Br J Pharmacol 115:433-40. 1995..The resulting increase in [Ca2+]i subsequently stimulates the secondary release of TXA2 from platelets. Furthermore, the response to ZT-A may be associated with tyrosine phosphorylation...
- Detection of a physical and functional interaction between Csk and Lck which involves the SH2 domain of Csk and is mediated by autophosphorylation of Lck on tyrosine 394C Bougeret
INSERM, , France
J Biol Chem 271:7465-72. 1996..analysis (BIAcore(TM)), we detected in vitro a specific interaction between Csk and one of its substrates Lck, a lymphocyte-specific member of the Src family...
- Signaling mechanisms of basic fibroblast growth factor in arterial cells from genetically hypertensive ratD L Zhu
CNRS URA 1482, Laboratoire de Pharmacologie, , Paris, France
Am J Hypertens 7:351-6. 1994..Therefore, one may envisage that bFGF contributes, through paracrine/autocrine mechanisms, to the vascular smooth muscle hyperplasia/hypertrophy in SHR...
- Platelet-derived growth factor. Structure, function and implications in normal and malignant cell growthB Westermark
Department of Pathology, University Hospital, Uppsala, Sweden
Acta Oncol 32:101-5. 1993..This view is supported by our recent finding that human melanoma cells that have been stably transfected with a PDGF B-chain cDNA, elicit a stroma response when transplanted to nude mice...
- Protein tyrosine kinase in colorectal adenomaT Hatada
Department of Surgery, Hyogo College of Medicine, Japan
Acta Oncol 32:23-8. 1993....
- Protein tyrosine kinase activity in human thyroid papillary carcinomaY Yasuda
Second Department of Surgery, Hyogo College of Medicine, Japan
Acta Oncol 31:409-12. 1992..These findings indicate that elevated cytosolic PTK activity may be a potentially useful marker for papillary thyroid carcinoma...
- Activation of p58c-fgr and p53/56lyn in adherent human neutrophils: evidence for a role of divalent cations in regulating neutrophil adhesion and protein tyrosine kinase activitiesS R Yan
Institute of General Pathology, University of Verona, Italy
J Inflamm 45:297-311. 1995....
- Effect of hypoxia on protein tyrosine kinase activity in cortical membranes of newborn piglets--the role of nitric oxideOm Prakash Mishra
Department of Pediatrics, Neonatal Research Laboratory, Drexel University College of Medicine, MCP, Room 701, 7th Floor Heritage Building, 3300 Henry Avenue, Philadelphia, PA 19129, USA
Neurosci Lett 372:114-8. 2004..We propose that the hypoxia-induced increase in protein tyrosine kinase activity leading to increased phosphorylation of Bcl-2 is a critical link to hypoxic neuronal injury pathway...
- Demonstration of selective protein kinase C-dependent activation of Src and Lck tyrosine kinases during ischemic preconditioning in conscious rabbitsP Ping
Experimental Research Laboratory, Division of Cardiology and the Department of Physiology and Biophysics, University of Louisville and Jewish Hospital Heart and Lung Institute, KY 40202, USA
Circ Res 85:542-50. 1999..and 4-minute reperfusion) induces selective activation of 2 members of the Src family of tyrosine kinases, Src and Lck, in the heart of conscious rabbits...
- L-selectin activates the Ras pathway via the tyrosine kinase p56lckB Brenner
Department of Pediatrics, University of Heidelberg, Germany
Proc Natl Acad Sci U S A 93:15376-81. 1996..of Jurkat cells using different antibodies or glycomimetics resulted in activation of the src-tyrosine kinase p56lck; tyrosine phosphorylation of intracellular proteins, in particular mitogen-activating protein kinase and L-..
- Effects of the novel and potent lymphocyte-specific protein tyrosine kinase inhibitor TKM0150 on mixed lymphocyte reaction and contact hypersensitivity in miceTetsuo Takayama
Medicinal Research Laboratories, Taisho Pharmaceutical Co, Ltd, Saitama, Japan
Arzneimittelforschung 60:282-5. 2010Lymphocyte-specific protein tyrosine kinase (Lck) plays a critical role in T cell activation...
- Properties of tripartite chimeras between Src and LckA Kashishian
Fred Hutchinson Cancer Research Center, Seattle, Washington 98104
Oncogene 5:1463-70. 1990..domains of Src-family kinases, we have assembled five chimeric molecules containing parts of p60c-src (Src) and p56lck (Lck)...
- Calcium-induced ERK activation in human T lymphocytes occurs via p56(Lck) and CaM-kinaseR A Franklin
Department of Microbiology and Immunology, East Carolina University School of Medicine, Brody Building, Greenville, NC 27858, USA
Mol Immunol 37:675-83. 2000..of T lymphocytes with ionomycin or A23187 resulted in a CaM-kinase-dependent shift in the mobility of p56(Lck)...
- Differential effects of expression of the CD45 tyrosine protein phosphatase on the tyrosine phosphorylation of the lck, fyn, and c-src tyrosine protein kinasesT R Hurley
Molecular Biology and Virology Laboratory, Salk Institute, San Diego, California 92186
Mol Cell Biol 13:1651-6. 1993..We have studied the phosphorylation of the closely related lck, fyn, and c-src tyrosine protein kinases in leukemic murine T-cell lines that have lost the expression of CD45...
- Partial purification and characterization of the lck protein-tyrosine kinase from bovine thymusQ M Wang
Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy, Purdue University, West Lafayette, IN 47907
Biochem J 279:567-74. 1991..were also recognized by polyclonal anti-peptide antibodies raised against the C-terminal 33 amino acids of p56lck, a major T lymphocyte protein-tyrosine kinase...
- Zap70 signaling pathway mediates glucocorticoid receptor-dependent transcriptional activation: role in the regulation of annexin 1 expression in T cellsMohammad Ishaq
Laboratory of Molecular Cell Biology, SAIC Frederick, National Cancer Institute, Frederick, MD 21702, USA
J Immunol 179:3851-8. 2007..b>Lck-lacking Jurkat cells were also found to show markedly reduced GR activation, and reconstitution with Lck restored ..
- Neocortical neurons lacking the protein-tyrosine kinase B receptor display abnormal differentiation and process elongation in vitro and in vivoM A Gates
Division of Neuroscience, Children s Hospital, Harvard Medical School, Boston, MA 02115, USA
Neuroscience 98:437-47. 2000....
- Regulation of eicosanoid biosynthesis in the macrophage. Involvement of protein tyrosine phosphorylation and modulation by selective protein tyrosine kinase inhibitorsK B Glaser
Division of Immunopharmacology, Wyeth Ayerst Research, Princeton, NJ 08543 8000
Biochem Pharmacol 45:711-21. 1993..The use of selective PTK inhibitors suggests a common role for PTK and tyrosine phosphorylation in eicosanoid biosynthesis in the murine peritoneal macrophage...
- Differential regulation of fyn-associated protein tyrosine kinase activity by macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF)Y Li
Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201
J Leukoc Biol 57:484-90. 1995..Collectively, our data suggest that the activation of fyn kinase is closely associated with the acquisition of adherent capacity in maturing macrophages...
- Differential regulation of T cell receptor-mediated Th1 cell IFN-gamma production and proliferation by divergent cAMP-mediated redox pathwaysR Cochrane
Department of Pathology, The University of Connecticut Health Center, Farmington, CT 06030 3105, USA
J Interferon Cytokine Res 21:797-807. 2001..Immunoblotting of lysates from an FSK-treated Th1 clone with antibodies to a carboxy-terminal epitope of p56(lck), a signal transduction enzyme upstream from ERK-1 and ERK2, did not detect p56(lck) unless the lysates were ..
- Increased ubiquitination and reduced expression of LCK in T lymphocytes from patients with systemic lupus erythematosusElizabeth C Jury
Royal Free and University College Medical School, University College, London, UK
Arthritis Rheum 48:1343-54. 2003..To explore regulation of proximal signaling and composition of lipid rafts in T lymphocytes from patients with systemic lupus erythematosus (SLE)...
- Association of herpesvirus saimiri tip with lipid raft is essential for downregulation of T-cell receptor and CD4 coreceptorNam Hyuk Cho
Department of Microbiology and Molecular Genetics and Tumor Virology Division, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772 9102, USA
J Virol 80:108-18. 2006..HVS), which is a T-lymphotropic tumor virus, is constitutively targeted to lipid rafts and interacts with cellular Lck tyrosine kinase and p80 WD repeat-containing endosomal protein...
- Transcriptional activation of lck by retrovirus promoter insertion between two lymphoid-specific promotersH T Adler
Molecular Biology and Virology Laboratory, Salk Institute, San Diego, California 92138
J Virol 62:4113-22. 1988b>p56lck, a member of the src family of cytoplasmic tyrosine protein kinases, is expressed primarily in lymphoid cells...
- Genetic and Immunological Impact of the HRES-1/Rab4 Locus in SLEAndras Perl; Fiscal Year: 2010..The key intracellular transducer of T-cell activation, Lck, is brought to the IS via binding to CD4. TCR6 chain binds to the TFR...
- p56lck Inhibitors as Potential Immunosuppressive Drugs.ALEXANDER MACKERELL; Fiscal Year: 2004SH2 domains in non-receptor tyrosine kinases, such as p56lck, represent molecular targets that are central to cellular signaling pathways related to immune response...
- TYROSINE PROTEIN KINASES AND LYMPHOCYTE ACTIVATIONROBERT GEAHLEN; Fiscal Year: 1993..It is likely that the molecular mechanisms of signal transduction in B lymphocytes will serve as a prototype for receptor signaling pathways in a variety of cell types...
- TYROSINE PROTEIN KINASES AND LYMPHOCYTE ACTIVATIONROBERT GEAHLEN; Fiscal Year: 1991..It is our contention that a greater understanding of the biochemical pathways that regulate normal cell growth and development is necessary to begin to define the lesions within this pathway that can lead to malignant growth...
- Phosphoproteomic Analysis of T Cell Activation PathwaysARTHUR ROBERT SALOMON; Fiscal Year: 2010..within the pathway through quantitative phosphoproteomic analysis of T cells with disrupted pathway proteins LCK, PLC1, VAV, and ERK...
- Role of Src Kinases in T Cell Receptor SignalingDavid Straus; Fiscal Year: 2004..We will take advantage of our ability to express mutants of the Src-family kinase Lck in an Lck-deficient T cell line to determine what steps in the activation process are dependent upon particular ..
- Negative regulation of TCR-associated PTKsROBERT RICKERT; Fiscal Year: 2007..We will determine to what extent TCR signaling is altered in the absence of PEP and if Lck and Fyn are hyperactive...
- Negative regulation of TCR-associated PTKsTomas Mustelin; Fiscal Year: 2006..We will determine to what extent TCR signaling is altered in the absence of PEP and if Lck and Fyn are hyperactive...
- INTERFERON SIGNAL TRANSDUCTION IN T CELLSAndrew Larner; Fiscal Year: 2001..a rapid association with the alpha chain of the IFNalpha receptor (IFNalphaR1) of the protein tyrosine kinases Lck and ZAP-70 and the protein tyrosine phosphatase, CD-45...
- Src Family Kinases as Molecular Targets for HIV/NefTHOMAS SMITHGALL; Fiscal Year: 2007..Our work is focused on the interaction of Nef with protein kinases in infected cells. Completion of these experiments will validate these Nef-kinase complexes as targets for the discovery of new anti-HIV therapeutics. ..
- Src Family Kinases as Molecular Targets for HIV/NefTHOMAS EDWARD SMITHGALL; Fiscal Year: 2010..Our work is focused on the interaction of Nef with protein kinases in infected cells. Completion of these experiments will validate these Nef-kinase complexes as targets for the discovery of new anti-HIV therapeutics. ..
- SIGNAL TRANSDUCTION IN T LYMPHOCYTE ACTIVATIONAmnon Altman; Fiscal Year: 1993..the following approaches will be undertaken to elucidate the roles of two T cell-expressed TPKs, p59fyn and p56lck, that are associated with the TCR/CD3 complex or the CD4/CD8 coreceptors, respectively, in T cell signaling, in ..
- Focal Adhesion Kinase - Tumor Biology and TherapeuticsWilliam G Cance; Fiscal Year: 2010..Thus, this application will provide novel molecular cancer therapeutics that target the focal adhesion kinase. ..
- OSTEOCLASTIC PHOSPHOTYROSYL PHOSPHATASE AND RESORPTIONKIN HING LAU; Fiscal Year: 2002....
- PROTEIN TYROSINE KINASE TYRO-3ANNE PRIETO; Fiscal Year: 2003..Through these efforts we hope to uncover the role of Tyro-3 in molecular mechanisms of cell adhesion, intracellular signaling and neuroplasticity in the normal and diseases nervous system. ..
- REGULATION OF BCR MEDIATED SIGNAL TRANSDUCTION BY CD45LOUIS JUSTEMENT; Fiscal Year: 2002..Thus, the studies proposed above may provide information that enhances our understanding of the events which result in aberrant activation of the B cell. ..
- T cell regulation by N-glycosylationMichael Demetriou; Fiscal Year: 2010..This in turn blocks recruitment of Nck, WASp, SLP-76 and CD4-Lck to TCR, F-actin remodeling and transfer of the complex to GM1/cholesterol-enriched microdomains (GEMs)...
- T cell regulation by N-glycosylationMichael Demetriou; Fiscal Year: 2010..This in turn blocks recruitment of Nck, WASp, SLP-76 and CD4-Lck to TCR, F-actin remodeling and transfer of the complex to GM1/cholesterol-enriched microdomains (GEMs)...
- Mechanisms of Breast Tumor Cell Growth, Motility, and Antiestrogen ResponseAmy H Bouton; Fiscal Year: 2010....
- Mechanisms of Breast Tumor Cell Growth, Motility, and Antiestrogen ResponseAmy Bouton; Fiscal Year: 2009....
- A Tumor Suppressor Function for the c-Fes Tyrosine Kinase in Colon CancerTHOMAS EDWARD SMITHGALL; Fiscal Year: 2010..If c-fes is a true tumor suppressor, then mice lacking c-fes function are expected to develop more severe disease in terms of tumor size, number, and invasiveness. ..
- MITOGENIC SIGNALING BY ENDOTHELIN PEPTIDESMichael Simonson; Fiscal Year: 1993..Because ET-1 has been implicated the vascular response to injury and in renal failure, the ability to block the mitogenic actions of ET might be relevant in clinical settings...