Home LiteratureArticle Details
PMID: 8887682 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Binding of human immunodeficiency virus type 1 to CD4 induces association of Lck and Raf-1 and activates Raf-1 by a Ras-independent pathway.

Molecular and cellular biology ·Vol. 16 ·No. 11 ·1996-11-00 ·Pages 6532-41

Popik W, Pitha PM

Abstract

We have analyzed CD4-mediated signaling during the early stages of human immunodeficiency virus type 1 (HIV-1) infection. Binding of purified HIV-1 virions or recombinant HIV-1 glycoprotein gp120 to CD4 receptors resulted in association and tyrosine phosphorylation and activation of tyrosine kinase Lck and serine/threonine kinase Raf-1. The association between Lck and Raf-1 was mediated by stimulation of the CD4 receptors, since it was abolished by preincubation of the virus with soluble CD4 and was not detected in CD4-negative A201 T cells. However, the Lck-Raf-1 association was restored in A201 cells permanently transfected with human CD4 cDNA and stimulated with anti-CD4 antibodies. In addition, a catalytically active Lck was required for the association of Lck and Raf-1. Surprisingly, the CD4-mediated signaling, induced by the HIV-1 binding, did not result in stimulation of the Ras GTP-binding activity or its association with Raf-1, indicating that the signaling pathway generated by the HIV-1 binding is not identical to the classical Ras/Raf-1 pathway. Furthermore, overexpression of activated Raf-1 in Jurkat T cells stimulated the HIV long terminal repeat promoter activity and significantly enhanced HIV-1 replication. This suggests that the Lck-Raf-1 pathway, rapidly stimulated by the binding of HIV-1 or gp120 to CD4 receptors, may play an essential role in the transcriptional activation of the integrated HIV-1 provirus as well as in its pathogenicity.

MeSH Terms
Antibodies Antigens, CD/physiology CD4 Antigens/physiology Cell Line Enzyme Activation HIV Envelope Protein gp120/metabolism HIV Long Terminal Repeat HIV-1/physiology Humans Kinetics Lymphocyte Specific Protein Tyrosine Kinase p56(lck) Phosphorylation Promoter Regions, Genetic Protein Serine-Threonine Kinases/metabolism Proto-Oncogene Proteins/metabolism Proto-Oncogene Proteins c-raf Recombinant Proteins/metabolism Tumor Cells, Cultured Virion/physiology Virus Replication ras Proteins/metabolism src-Family Kinases/metabolism
Chemicals
Antibodies Antigens, CD CD4 Antigens HIV Envelope Protein gp120 Proto-Oncogene Proteins Recombinant Proteins Lymphocyte Specific Protein Tyrosine Kinase p56(lck) src-Family Kinases Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-raf ras Proteins
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Popik W
Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Pitha P M
References (88)
88 references, click to expand
  1. A kinase-independent function of Lck in potentiating antigen-specific T cell activation.
    Cell. 1993 Aug 27;74(4):633-43 PMID: 8358792
  2. The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun.
    Nature. 1993 Sep 23;365(6444):352-5 PMID: 8397339
  3. Conditional transformation of cells and rapid activation of the mitogen-activated protein kinase cascade by an estradiol-dependent human raf-1 protein kinase.
    Mol Cell Biol. 1993 Oct;13(10):6241-52 PMID: 8413224
  4. 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-kinase.
    Mol Cell Biol. 1993 Dec;13(12):7708-17 PMID: 8246987
  5. Oncogene activation of HIV-LTR-driven expression via the NF-kappa B binding sites.
    Nucleic Acids Res. 1993 Nov 11;21(22):5229-34 PMID: 8255780
  6. The mitogenic response of T cells to interleukin-2 requires Raf-1.
    Eur J Immunol. 1993 Dec;23(12):3146-50 PMID: 8258328
  7. A new function for a phosphotyrosine phosphatase: linking GRB2-Sos to a receptor tyrosine kinase.
    Mol Cell Biol. 1994 Jan;14(1):509-17 PMID: 8264620
  8. Protein kinase C-mediated serine phosphorylation directly activates Raf-1 in murine hematopoietic cells.
    J Biol Chem. 1994 Jan 14;269(2):1249-56 PMID: 8288587
  9. Interaction of Ras and Raf in intact mammalian cells upon extracellular stimulation.
    J Biol Chem. 1994 Feb 11;269(6):3913-6 PMID: 8307946
  10. Human immunodeficiency virus type 1 Nef associates with a cellular serine kinase in T lymphocytes.
    Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1539-43 PMID: 8108442
  11. Association of p56lck with the cytoplasmic domain of CD4 modulates HIV-1 expression.
    EMBO J. 1994 Feb 15;13(4):774-83 PMID: 8112293
  12. Trk receptors use redundant signal transduction pathways involving SHC and PLC-gamma 1 to mediate NGF responses.
    Neuron. 1994 Mar;12(3):691-705 PMID: 8155326
  13. Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane.
    Nature. 1994 Jun 2;369(6479):411-4 PMID: 8196769
  14. Molecular and functional analysis of a lymphocyte chemoattractant factor: association of biologic function with CD4 expression.
    Proc Natl Acad Sci U S A. 1994 May 24;91(11):5109-13 PMID: 7910967
  15. Activation of Raf as a result of recruitment to the plasma membrane.
    Science. 1994 Jun 3;264(5164):1463-7 PMID: 7811320
  16. The T-cell antigen receptor utilizes Lck, Raf-1, and MEK-1 for activating mitogen-activated protein kinase. Evidence for the existence of a second protein kinase C-dependent pathway in an Lck-negative Jurkat cell mutant.
    J Biol Chem. 1994 Jun 24;269(25):17349-57 PMID: 7516337
  17. A single amino acid change in Raf-1 inhibits Ras binding and alters Raf-1 function.
    Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):5982-6 PMID: 8016101
  18. Raf-1 is a necessary component of the mitogenic response of the human megakaryoblastic leukemia cell line MO7 to human stem cell factor, granulocyte-macrophage colony-stimulating factor, interleukin 3, and interleukin 9.
    Cell Growth Differ. 1994 Apr;5(4):367-72 PMID: 7519043
  19. Involvement of human leukocyte antigen class I molecules in human immunodeficiency virus infection of CD4-positive cells.
    J Virol. 1994 Oct;68(10):6332-9 PMID: 7916059
  20. Direct activation of the serine/threonine kinase activity of Raf-1 through tyrosine phosphorylation by the PDGF beta-receptor.
    Cell. 1989 Aug 25;58(4):649-57 PMID: 2475255
  21. Insulin activates the kinase activity of the Raf-1 proto-oncogene by increasing its serine phosphorylation.
    J Biol Chem. 1990 Jul 25;265(21):12115-8 PMID: 2197270
  22. Colony stimulating factor-1 (CSF-1) stimulates temperature dependent phosphorylation and activation of the RAF-1 proto-oncogene product.
    EMBO J. 1990 Nov;9(11):3649-57 PMID: 1698619
  23. T cell antigen receptor engagement stimulates c-raf phosphorylation and induces c-raf-associated kinase activity via a protein kinase C-dependent pathway.
    J Biol Chem. 1990 Oct 25;265(30):18472-80 PMID: 2170413
  24. No T-cell tyrosine protein kinase signalling or calcium mobilization after CD4 association with HIV-1 or HIV-1 gp120.
    Nature. 1990 Dec 6;348(6301):557-60 PMID: 1701034
  25. gp120 ligation of CD4 induces p56lck activation and TCR desensitization independent of TCR tyrosine phosphorylation.
    J Immunol. 1994 Oct 1;153(7):2905-17 PMID: 7522245
  26. Cross-linking of CD4 molecules upregulates Fas antigen expression in lymphocytes by inducing interferon-gamma and tumor necrosis factor-alpha secretion.
    Blood. 1994 Oct 15;84(8):2622-31 PMID: 7522637
  27. Inhibition of human immunodeficiency virus type 1 replication by a Tat-activated, transduced interferon gene: targeted expression to human immunodeficiency virus type 1-infected cells.
    J Virol. 1995 Jan;69(1):110-21 PMID: 7983701
  28. Induction of interleukin-10 by human immunodeficiency virus type 1 and its gp120 protein in human monocytes/macrophages.
    J Virol. 1995 Feb;69(2):1284-7 PMID: 7815507
  29. Human immunodeficiency virus type 1 Nef and p56lck protein-tyrosine kinase interact with a common element in CD4 cytoplasmic tail.
    Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):349-53 PMID: 7831289
  30. HIV-1 infection of nondividing cells: C-terminal tyrosine phosphorylation of the viral matrix protein is a key regulator.
    Cell. 1995 Feb 10;80(3):379-88 PMID: 7859280
  31. 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 CD4.
    EMBO J. 1995 Feb 1;14(3):484-91 PMID: 7859737
  32. Multiple Ras functions can contribute to mammalian cell transformation.
    Cell. 1995 Feb 24;80(4):533-41 PMID: 7867061
  33. Identification of human immunodeficiency virus primary isolates resistant to interferon-alpha and correlation of prevalence to disease progression.
    J Infect Dis. 1995 Apr;171(4):822-8 PMID: 7706808
  34. The torso receptor tyrosine kinase can activate Raf in a Ras-independent pathway.
    Cell. 1995 Apr 7;81(1):63-71 PMID: 7720074
  35. Absolute dependence on kappa B responsive elements for initiation and Tat-mediated amplification of HIV transcription in blood CD4 T lymphocytes.
    EMBO J. 1995 Apr 3;14(7):1552-60 PMID: 7729429
  36. Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation.
    EMBO J. 1995 Jul 3;14(13):3136-45 PMID: 7542586
  37. LckBP1, a proline-rich protein expressed in haematopoietic lineage cells, directly associates with the SH3 domain of protein tyrosine kinase p56lck.
    EMBO J. 1995 Jul 17;14(14):3403-14 PMID: 7628441
  38. HIV-1 envelope glycoproteins induce activation of activated protein-1 in CD4+ T cells.
    J Biol Chem. 1995 Aug 18;270(33):19364-9 PMID: 7642615
  39. Identification of Lck-binding elements in tip of herpesvirus saimiri.
    J Biol Chem. 1995 Sep 1;270(35):20660-7 PMID: 7544793
  40. The cytoplasmic tail of CD4 is required for inhibition of human immunodeficiency virus type 1 replication by antibodies that bind to the immunoglobulin CDR3-like region in domain 1 of CD4.
    J Virol. 1995 Nov;69(11):6904-10 PMID: 7474107
  41. A single amino acid in the SH3 domain of Hck determines its high affinity and specificity in binding to HIV-1 Nef protein.
    EMBO J. 1995 Oct 16;14(20):5006-15 PMID: 7588629
  42. Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes.
    Nat Med. 1995 Feb;1(2):129-34 PMID: 7585008
  43. The immune response to HIV: potential for immunotherapy?
    Immunol Today. 1995 Jul;16(7):356-8 PMID: 7576075
  44. KSR: a novel player in the RAS pathway.
    Cell. 1995 Dec 15;83(6):831-4 PMID: 8521506
  45. Raf-1 kinase targets GA-binding protein in transcriptional regulation of the human immunodeficiency virus type 1 promoter.
    J Virol. 1996 Apr;70(4):2260-8 PMID: 8642652
  46. Physical and functional interaction of Nef with Lck. HIV-1 Nef-induced T-cell signaling defects.
    J Biol Chem. 1996 Mar 15;271(11):6333-41 PMID: 8626429
  47. Binding of HIV-1 virions or gp120-anti-gp120 immune complexes to HIV-1-infected quiescent peripheral blood mononuclear cells reveals latent infection.
    J Immunol. 1996 May 15;156(10):3994-4004 PMID: 8621941
  48. Human immunodeficiency virus type 1 Nef protein is incorporated into virus particles and specifically cleaved by the viral proteinase.
    Virology. 1996 May 1;219(1):228-36 PMID: 8623533
  49. Interleukin-2 (IL-2) induces tyrosine kinase-dependent translocation of active raf-1 from the IL-2 receptor into the cytosol.
    J Biol Chem. 1992 Aug 5;267(22):15281-4 PMID: 1639773
  50. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells.
    Mol Cell Biol. 1982 Sep;2(9):1044-51 PMID: 6960240
  51. The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus.
    Nature. 1984 Dec 20-1985 Jan 2;312(5996):763-7 PMID: 6096719
  52. T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV.
    Nature. 1984 Dec 20-1985 Jan 2;312(5996):767-8 PMID: 6083454
  53. Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone.
    J Virol. 1986 Aug;59(2):284-91 PMID: 3016298
  54. The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain.
    Cell. 1986 Nov 7;47(3):333-48 PMID: 3094962
  55. Functional interaction between human T-cell protein CD4 and the major histocompatibility complex HLA-DR antigen.
    Nature. 1987 Aug 13-19;328(6131):626-9 PMID: 3112582
  56. Interaction between CD4 and class II MHC molecules mediates cell adhesion.
    Nature. 1987 Nov 19-25;330(6145):256-9 PMID: 2823150
  57. The human immunodeficiency virus: infectivity and mechanisms of pathogenesis.
    Science. 1988 Feb 5;239(4840):617-22 PMID: 3277274
  58. The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes.
    Proc Natl Acad Sci U S A. 1988 Jul;85(14):5190-4 PMID: 2455897
  59. Contingent genetic regulatory events in T lymphocyte activation.
    Science. 1989 Jan 20;243(4889):355-61 PMID: 2783497
  60. Signal transduction through the CD4 receptor involves the activation of the internal membrane tyrosine-protein kinase p56lck.
    Nature. 1989 Mar 16;338(6212):257-9 PMID: 2784195
  61. HIV-1 GP120-mediated immune suppression and lymphocyte destruction in the absence of viral infection.
    J Immunol. 1989 May 1;142(9):3091-7 PMID: 2468713
  62. NF-kappa B: a pleiotropic mediator of inducible and tissue-specific gene control.
    Cell. 1989 Jul 28;58(2):227-9 PMID: 2665943
  63. Granulocyte-macrophage colony-stimulating factor and interleukin-3 induce rapid phosphorylation and activation of the proto-oncogene Raf-1 in a human factor-dependent myeloid cell line.
    Blood. 1991 Jan 15;77(2):243-8 PMID: 1845931
  64. Epidermal growth factor (EGF) stimulates association and kinase activity of Raf-1 with the EGF receptor.
    Mol Cell Biol. 1991 Feb;11(2):913-9 PMID: 1990291
  65. Interleukin 2 induces tyrosine phosphorylation and activation of p72-74 Raf-1 kinase in a T-cell line.
    Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1227-31 PMID: 1996324
  66. Linker-scanning mutational analysis of the transcriptional activity of the human immunodeficiency virus type 1 long terminal repeat.
    J Virol. 1991 May;65(5):2436-44 PMID: 2016766
  67. Human immunodeficiency virus type 1 envelope glycoproteins gp120 and gp160 induce interleukin-6 production in CD4+ T-cell clones.
    J Virol. 1991 Nov;65(11):6277-82 PMID: 1656094
  68. The zeta chain is associated with a tyrosine kinase and upon T-cell antigen receptor stimulation associates with ZAP-70, a 70-kDa tyrosine phosphoprotein.
    Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9166-70 PMID: 1717999
  69. Tyrosyl phosphorylation and activation of MAP kinases by p56lck.
    Science. 1992 Feb 14;255(5046):853-5 PMID: 1311128
  70. Both p21ras and pp60v-src are required, but neither alone is sufficient, to activate the Raf-1 kinase.
    Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2922-6 PMID: 1372995
  71. Serum-, TPA-, and Ras-induced expression from Ap-1/Ets-driven promoters requires Raf-1 kinase.
    Genes Dev. 1992 Apr;6(4):545-56 PMID: 1313769
  72. Ras GTPase-activating protein: a substrate and a potential binding protein of the protein-tyrosine kinase p56lck.
    Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3343-6 PMID: 1565625
  73. The effect of p56lck, a lymphocyte specific protein tyrosine kinase, on the syncytium formation induced by human immunodeficiency virus envelope glycoprotein.
    Int Immunol. 1992 Feb;4(2):233-42 PMID: 1622897
  74. Interaction of human immunodeficiency virus glycoprotein 160 with CD4 in Jurkat cells increases p56lck autophosphorylation and kinase activity.
    Int Immunol. 1992 Feb;4(2):295-9 PMID: 1535787
  75. Oncoprotein-mediated signalling cascade stimulates c-Jun activity by phosphorylation of serines 63 and 73.
    Mol Cell Biol. 1992 Aug;12(8):3507-13 PMID: 1630458
  76. Transcriptional activation of the tat-defective human immunodeficiency virus type-1 provirus: effect of interferon.
    Virology. 1992 Aug;189(2):435-47 PMID: 1641975
  77. Association of the tyrosine kinase LCK with phospholipase C-gamma 1 after stimulation of the T cell antigen receptor.
    J Exp Med. 1992 Aug 1;176(2):373-9 PMID: 1500851
  78. Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor.
    Cell. 1992 Aug 21;70(4):585-93 PMID: 1505025
  79. The HIV-1 surface protein gp120 has no effect on transmembrane signal transduction in T cells.
    J Acquir Immune Defic Syndr. 1992;5(8):760-70 PMID: 1325556
  80. Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis.
    J Exp Med. 1992 Oct 1;176(4):1099-106 PMID: 1402655
  81. Activation of the MAP kinase pathway by the protein kinase raf.
    Cell. 1992 Oct 16;71(2):335-42 PMID: 1330321
  82. Role of tumor necrosis factor alpha in activation and replication of the tat-defective human immunodeficiency virus type 1.
    J Virol. 1993 Feb;67(2):1094-9 PMID: 8419639
  83. CD45 specifically modulates binding of Lck to a phosphopeptide encompassing the negative regulatory tyrosine of Lck.
    EMBO J. 1993 Jan;12(1):315-21 PMID: 8428589
  84. Characterization of the nuclear and cytoplasmic components of the lymphoid-specific nuclear factor of activated T cells (NF-AT) complex.
    J Biol Chem. 1993 Feb 5;268(4):2917-23 PMID: 8428966
  85. Human immunodeficiency virus gp120 and derived peptides activate protein tyrosine kinase p56lck in human CD4 T lymphocytes.
    Eur J Immunol. 1993 Mar;23(3):600-7 PMID: 7680610
  86. Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor.
    Cell. 1993 May 7;73(3):611-20 PMID: 8490966
  87. Protein kinase C alpha activates RAF-1 by direct phosphorylation.
    Nature. 1993 Jul 15;364(6434):249-52 PMID: 8321321
  88. Kappa B site-dependent induction of gene expression by diverse inducers of nuclear factor kappa B requires Raf-1.
    J Biol Chem. 1993 Aug 25;268(24):17676-9 PMID: 8349650
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.16.11.6532
Published
1996-11-00
Pages
6532-41
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC231655
Subset
IM
Grants
NIAID NIH HHS · AI26123 · United States
External Links
PubMed source DOI: 10.1128/MCB.16.11.6532 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2