Home LiteratureArticle Details
PMID: 9730885 Published · ppublish English Journal Article

Independent and opposing roles for Btk and lyn in B and myeloid signaling pathways.

The Journal of experimental medicine ·Vol. 188 ·No. 5 ·1998-09-07 ·Pages 833-44

Satterthwaite AB, Lowell CA, Khan WN, Sideras P, Alt FW, Witte ON

Abstract

Transphosphorylation by Src family kinases is required for the activation of Bruton's tyrosine kinase (Btk). Differences in the phenotypes of Btk-/- and lyn-/- mice suggest that these kinases may also have independent or opposing functions. B cell development and function were examined in Btk-/-lyn-/- mice to better understand the functional interaction of Btk and Lyn in vivo. The antigen-independent phase of B lymphopoiesis was normal in Btk-/-lyn-/- mice. However, Btk-/-lyn-/- animals had a more severe immunodeficiency than Btk-/- mice. B cell numbers and response to T cell-dependent antigens were reduced. Btk and Lyn therefore play independent or partially redundant roles in the maintenance and function of peripheral B cells. Autoimmunity, hypersensitivity to B cell receptor (BCR) cross-linking, and splenomegaly caused by myeloerythroid hyperplasia were alleviated by Btk deficiency in lyn-/- mice. A transgene expressing Btk at approximately 25% of endogenous levels (Btklo) was crossed onto Btk-/- and Btk-/-lyn-/- backgrounds to demonstrate that Btk is limiting for BCR signaling in the presence but not in the absence of Lyn. These observations indicate that the net outcome of Lyn function in vivo is to inhibit Btk-dependent pathways in B and myeloid cells, and that Btklo mice are a useful sensitized system to identify regulatory components of Btk signaling pathways.

MeSH Terms
Agammaglobulinaemia Tyrosine Kinase Agammaglobulinemia/enzymology,genetics,pathology Animals Autoimmune Diseases/enzymology,genetics B-Lymphocytes/enzymology,immunology,pathology Hematopoiesis/genetics,immunology Hematopoietic Stem Cells/enzymology,immunology Immunoglobulin Isotypes/biosynthesis,blood Immunoglobulins/biosynthesis,blood Lymphocyte Count Lymphopenia/enzymology,genetics,immunology Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Inbred Strains Mice, Knockout Protein-Tyrosine Kinases/deficiency,genetics,physiology Receptors, Antigen, B-Cell/antagonists & inhibitors,physiology Signal Transduction/genetics,immunology src-Family Kinases/deficiency,genetics,physiology
Chemicals
Immunoglobulin Isotypes Immunoglobulins Receptors, Antigen, B-Cell Protein-Tyrosine Kinases Agammaglobulinaemia Tyrosine Kinase Btk protein, mouse src-Family Kinases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Satterthwaite A B
Department of Microbiology and Molecular Genetics, University of California Los Angeles 90095, USA.
Lowell C A
Khan W N
Sideras P
Alt F W
Witte O N
References (60)
60 references, click to expand
  1. Ability of the xid gene to prevent autoimmunity in (NZB X NZW)F1 mice during the course of their natural history, after polyclonal stimulation, or following immunization with DNA.
    J Clin Invest. 1982 Sep;70(3):587-97 PMID: 6980900
  2. A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2.
    J Exp Med. 1996 Jul 1;184(1):31-40 PMID: 8691147
  3. Ly-1 B cells: functionally distinct lymphocytes that secrete IgM autoantibodies.
    Proc Natl Acad Sci U S A. 1984 Apr;81(8):2494-8 PMID: 6609363
  4. The interaction of the xid and me genes.
    J Immunol. 1987 Jun 1;138(11):3611-7 PMID: 2884254
  5. Immunodeficiency in protein kinase cbeta-deficient mice.
    Science. 1996 Aug 9;273(5276):788-91 PMID: 8670417
  6. Lessons from human genetic variants in the study of B-cell differentiation.
    Curr Opin Immunol. 1996 Aug;8(4):454-8 PMID: 8794006
  7. Inactivation of Btk by insertion of lacZ reveals defects in B cell development only past the pre-B cell stage.
    EMBO J. 1996 Sep 16;15(18):4862-72 PMID: 8890160
  8. Profound reduction of mature B cell numbers, reactivities and serum Ig levels in mice which simultaneously carry the XID and CD40 deficiency genes.
    Int Immunol. 1996 Nov;8(11):1675-85 PMID: 8943562
  9. Altered antigen receptor signaling and impaired Fas-mediated apoptosis of B cells in Lyn-deficient mice.
    J Exp Med. 1996 Sep 1;184(3):831-8 PMID: 9064343
  10. Impaired B cell maturation in mice lacking Bruton's tyrosine kinase (Btk) and CD40.
    Int Immunol. 1997 Mar;9(3):395-405 PMID: 9088978
  11. Influences on the lifespan of B cell subpopulations defined by different phenotypes.
    Eur J Immunol. 1997 May;27(5):1188-99 PMID: 9174610
  12. CBA/N X-linked B-cell defect prevents NZB B-cell hyperactivity in F1 mice.
    J Exp Med. 1979 Jul 1;150(1):31-43 PMID: 312908
  13. Synergistic genetic defect in B-lymphocyte function. I. Defective responses to B-cell stimulants and their genetic basis.
    J Exp Med. 1980 Jan 1;151(1):224-34 PMID: 6965307
  14. Transphosphorylation of Bruton's tyrosine kinase on tyrosine 551 is critical for B cell antigen receptor function.
    J Biol Chem. 1997 Jun 20;272(25):15595-8 PMID: 9188445
  15. xid affects events leading to B cell cycle entry.
    J Immunol. 1997 Jul 1;159(1):135-43 PMID: 9200448
  16. The complexity of signaling pathways activated by the BCR.
    Curr Opin Immunol. 1997 Jun;9(3):296-308 PMID: 9203421
  17. Characterization of the B lymphocyte populations in Lyn-deficient mice and the role of Lyn in signal initiation and down-regulation.
    Immunity. 1997 Jul;7(1):69-81 PMID: 9252121
  18. The motheaten mutation rescues B cell signaling and development in CD45-deficient mice.
    J Exp Med. 1997 Aug 18;186(4):581-8 PMID: 9254656
  19. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death.
    Cell. 1997 Sep 19;90(6):1073-83 PMID: 9323135
  20. Phosphorylation of two regulatory tyrosine residues in the activation of Bruton's tyrosine kinase via alternative receptors.
    Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11526-33 PMID: 9326643
  21. Btk dosage determines sensitivity to B cell antigen receptor cross-linking.
    Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13152-7 PMID: 9371815
  22. Itk and Fyn make independent contributions to T cell activation.
    J Exp Med. 1997 Dec 15;186(12):2069-73 PMID: 9396778
  23. Btk/Tec kinases regulate sustained increases in intracellular Ca2+ following B-cell receptor activation.
    EMBO J. 1998 Apr 1;17(7):1973-85 PMID: 9524120
  24. Involvement of Bruton's tyrosine kinase in FcepsilonRI-dependent mast cell degranulation and cytokine production.
    J Exp Med. 1998 Apr 20;187(8):1235-47 PMID: 9547335
  25. Interleukin 10, a novel B cell stimulatory factor: unresponsiveness of X chromosome-linked immunodeficiency B cells.
    J Exp Med. 1990 Dec 1;172(6):1625-31 PMID: 2124252
  26. A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene.
    Nature. 1991 Apr 4;350(6317):423-6 PMID: 1901381
  27. A critical role of lambda 5 protein in B cell development.
    Cell. 1992 May 29;69(5):823-31 PMID: 1591779
  28. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases.
    Nature. 1993 Jan 21;361(6409):226-33 PMID: 8380905
  29. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia.
    Cell. 1993 Jan 29;72(2):279-90 PMID: 8425221
  30. Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death.
    Cell. 1993 Feb 12;72(3):325-35 PMID: 8431943
  31. Colocalization of X-linked agammaglobulinemia and X-linked immunodeficiency genes.
    Science. 1993 Jul 16;261(5119):355-8 PMID: 8332900
  32. Mutation of unique region of Bruton's tyrosine kinase in immunodeficient XID mice.
    Science. 1993 Jul 16;261(5119):358-61 PMID: 8332901
  33. IL-5 receptor positive B cells, but not eosinophils, are functionally and numerically influenced in mice carrying the X-linked immune defect.
    Int Immunol. 1993 Sep;5(9):1183-90 PMID: 8241057
  34. Competition for follicular niches excludes self-reactive cells from the recirculating B-cell repertoire.
    Nature. 1994 Sep 29;371(6496):389-95 PMID: 7522305
  35. Humoral immune responses in CD40 ligand-deficient mice.
    J Exp Med. 1994 Nov 1;180(5):1889-900 PMID: 7964465
  36. CD40-deficient mice generated by recombination-activating gene-2-deficient blastocyst complementation.
    Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12135-9 PMID: 7527552
  37. Surface IgM-stimulated proliferation, inositol phospholipid hydrolysis, Ca2+ flux, and tyrosine phosphorylation are not altered in B cells from p59fyn-1- mice.
    J Leukoc Biol. 1994 Dec;56(6):812-6 PMID: 7996057
  38. Association and activation of Btk and Tec tyrosine kinases by gp130, a signal transducer of the interleukin-6 family of cytokines.
    Blood. 1995 Feb 1;85(3):627-33 PMID: 7530500
  39. Mice deficient for the CD40 ligand.
    Immunity. 1994 Aug;1(5):423-31 PMID: 7882172
  40. Defective antigen receptor-mediated proliferation of B and T cells in the absence of Vav.
    Nature. 1995 Mar 30;374(6521):467-70 PMID: 7700358
  41. Defective signalling through the T- and B-cell antigen receptors in lymphoid cells lacking the vav proto-oncogene.
    Nature. 1995 Mar 30;374(6521):470-3 PMID: 7700359
  42. Defective IL-5-receptor-mediated signaling in B cells of X-linked immunodeficient mice.
    Int Immunol. 1995 Jan;7(1):21-30 PMID: 7718512
  43. Activation of Bruton's tyrosine kinase (BTK) by a point mutation in its pleckstrin homology (PH) domain.
    Immunity. 1995 May;2(5):451-60 PMID: 7538439
  44. Protein tyrosine phosphatase 1C negatively regulates antigen receptor signaling in B lymphocytes and determines thresholds for negative selection.
    Immunity. 1995 Jan;2(1):13-24 PMID: 7600299
  45. Involvement of p59fynT in interleukin-5 receptor signaling.
    J Exp Med. 1995 Sep 1;182(3):811-20 PMID: 7650487
  46. Src family protein tyrosine kinases induce autoactivation of Bruton's tyrosine kinase.
    Mol Cell Biol. 1995 Oct;15(10):5304-11 PMID: 7565679
  47. Defective B cell development and function in Btk-deficient mice.
    Immunity. 1995 Sep;3(3):283-99 PMID: 7552994
  48. Impaired expansion of mouse B cell progenitors lacking Btk.
    Immunity. 1995 Sep;3(3):301-12 PMID: 7552995
  49. Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease.
    Cell. 1995 Oct 20;83(2):301-11 PMID: 7585947
  50. Prevention of autoimmune symptoms in autoimmune-prone mice by elimination of B-1 cells.
    Int Immunol. 1995 May;7(5):877-82 PMID: 7547714
  51. Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk.
    Nature. 1995 Nov 16;378(6554):298-302 PMID: 7477352
  52. Syk tyrosine kinase required for mouse viability and B-cell development.
    Nature. 1995 Nov 16;378(6554):303-6 PMID: 7477353
  53. Impaired proliferation of peripheral B cells and indication of autoimmune disease in lyn-deficient mice.
    Immunity. 1995 Nov;3(5):549-60 PMID: 7584145
  54. Regulation of an early developmental checkpoint in the B cell pathway by Ig beta.
    Science. 1996 Apr 19;272(5260):411-4 PMID: 8602530
  55. Balancing immunity and tolerance: deleting and tuning lymphocyte repertoires.
    Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2264-71 PMID: 8637861
  56. Discordant phenotype in siblings with X-linked agammaglobulinemia.
    Am J Hum Genet. 1996 Mar;58(3):477-83 PMID: 8644706
  57. Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases.
    Science. 1996 Feb 9;271(5250):822-5 PMID: 8629002
  58. Regulation of Btk by Src family tyrosine kinases.
    Mol Cell Biol. 1996 Jul;16(7):3465-71 PMID: 8668162
  59. Aberrant B cell development and immune response in mice with a compromised BCR complex.
    Science. 1996 Jun 21;272(5269):1804-8 PMID: 8650582
  60. Functional status of cells from lymphoid and myeloid tissues in mice with severe combined immunodeficiency disease.
    J Immunol. 1984 Apr;132(4):1804-8 PMID: 6607948
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.188.5.833
Published
1998-09-07
Pages
833-44
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2213392
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.188.5.833 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