• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jexpmedHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
J Exp Med. Aug 1, 1995; 182(2): 611–615.
PMCID: PMC2192133

The protein product of the c-cbl protooncogene is phosphorylated after B cell receptor stimulation and binds the SH3 domain of Bruton's tyrosine kinase

Abstract

X-linked agammaglobulinemia, a B cell immunodeficiency, is caused by mutations in the Bruton's tyrosine kinase (Btk) gene. The absence of a functional Btk protein leads to a failure of B cell differentiation and antibody production. B cell receptor stimulation leads to the phosphorylation of the Btk protein and it is, therefore, likely that Btk is involved in B cell receptor signaling. As a nonreceptor tyrosine kinase, Btk is likely to interact with several proteins within the context of a signal transduction pathway. To understand such interactions, we have generated glutathione S-transferase fusion proteins corresponding to different domains of the human Btk protein. We have identified a 120-kD protein present in human B cells as being bound by the SH3 domain of Btk and which, after B cell receptor stimulation, is one of the major substrates of tyrosine phosphorylation. We have shown that this 120-kD protein is the protein product of c-cbl, a protooncogene, which is known to be phosphorylated in response to T cell receptor stimulation and to interact with several other tyrosine kinases. Association of the SH3 domain of Btk with p120cbl provides evidence for an analogous role for p120cbl in B cell signaling pathways. The p120cbl protein is the first identified ligand of the Btk SH3 domain.

Full Text

The Full Text of this article is available as a PDF (695K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Vetrie D, Vorechovský I, Sideras P, Holland J, Davies A, Flinter F, Hammarström L, Kinnon C, Levinsky R, Bobrow M, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. 1993 Jan 21;361(6409):226–233. [PubMed]
  • Bradley LA, Sweatman AK, Lovering RC, Jones AM, Morgan G, Levinsky RJ, Kinnon C. Mutation detection in the X-linked agammaglobulinemia gene, BTK, using single strand conformation polymorphism analysis. Hum Mol Genet. 1994 Jan;3(1):79–83. [PubMed]
  • de Weers M, Mensink RG, Kraakman ME, Schuurman RK, Hendriks RW. Mutation analysis of the Bruton's tyrosine kinase gene in X-linked agammaglobulinemia: identification of a mutation which affects the same codon as is altered in immunodeficient xid mice. Hum Mol Genet. 1994 Jan;3(1):161–166. [PubMed]
  • de Weers M, Verschuren MC, Kraakman ME, Mensink RG, Schuurman RK, van Dongen JJ, Hendriks RW. The Bruton's tyrosine kinase gene is expressed throughout B cell differentiation, from early precursor B cell stages preceding immunoglobulin gene rearrangement up to mature B cell stages. Eur J Immunol. 1993 Dec;23(12):3109–3114. [PubMed]
  • Smith CI, Baskin B, Humire-Greiff P, Zhou JN, Olsson PG, Maniar HS, Kjellén P, Lambris JD, Christensson B, Hammarström L, et al. Expression of Bruton's agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells. J Immunol. 1994 Jan 15;152(2):557–565. [PubMed]
  • de Weers M, Brouns GS, Hinshelwood S, Kinnon C, Schuurman RK, Hendriks RW, Borst J. B-cell antigen receptor stimulation activates the human Bruton's tyrosine kinase, which is deficient in X-linked agammaglobulinemia. J Biol Chem. 1994 Sep 30;269(39):23857–23860. [PubMed]
  • Saouaf SJ, Mahajan S, Rowley RB, Kut SA, Fargnoli J, Burkhardt AL, Tsukada S, Witte ON, Bolen JB. Temporal differences in the activation of three classes of non-transmembrane protein tyrosine kinases following B-cell antigen receptor surface engagement. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9524–9528. [PMC free article] [PubMed]
  • Aoki Y, Isselbacher KJ, Pillai S. Bruton tyrosine kinase is tyrosine phosphorylated and activated in pre-B lymphocytes and receptor-ligated B cells. Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10606–10609. [PMC free article] [PubMed]
  • Hinshelwood S, Lovering RC, Genevier HC, Levinsky RJ, Kinnon C. The protein defective in X-linked agammaglobulinemia, Bruton's tyrosine kinase, shows increased autophosphorylation activity in vitro when isolated from cells in which the B cell receptor has been cross-linked. Eur J Immunol. 1995 Apr;25(4):1113–1116. [PubMed]
  • Pawson T, Gish GD. SH2 and SH3 domains: from structure to function. Cell. 1992 Oct 30;71(3):359–362. [PubMed]
  • Koch CA, Anderson D, Moran MF, Ellis C, Pawson T. SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins. Science. 1991 May 3;252(5006):668–674. [PubMed]
  • Songyang Z, Shoelson SE, Chaudhuri M, Gish G, Pawson T, Haser WG, King F, Roberts T, Ratnofsky S, Lechleider RJ, et al. SH2 domains recognize specific phosphopeptide sequences. Cell. 1993 Mar 12;72(5):767–778. [PubMed]
  • Bar-Sagi D, Rotin D, Batzer A, Mandiyan V, Schlessinger J. SH3 domains direct cellular localization of signaling molecules. Cell. 1993 Jul 16;74(1):83–91. [PubMed]
  • Ren R, Mayer BJ, Cicchetti P, Baltimore D. Identification of a ten-amino acid proline-rich SH3 binding site. Science. 1993 Feb 19;259(5098):1157–1161. [PubMed]
  • Yu H, Chen JK, Feng S, Dalgarno DC, Brauer AW, Schreiber SL. Structural basis for the binding of proline-rich peptides to SH3 domains. Cell. 1994 Mar 11;76(5):933–945. [PubMed]
  • Cheng G, Ye ZS, Baltimore D. Binding of Bruton's tyrosine kinase to Fyn, Lyn, or Hck through a Src homology 3 domain-mediated interaction. Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8152–8155. [PMC free article] [PubMed]
  • Blake TJ, Heath KG, Langdon WY. The truncation that generated the v-cbl oncogene reveals an ability for nuclear transport, DNA binding and acute transformation. EMBO J. 1993 May;12(5):2017–2026. [PMC free article] [PubMed]
  • Donovan JA, Wange RL, Langdon WY, Samelson LE. The protein product of the c-cbl protooncogene is the 120-kDa tyrosine-phosphorylated protein in Jurkat cells activated via the T cell antigen receptor. J Biol Chem. 1994 Sep 16;269(37):22921–22924. [PubMed]
  • Rivero-Lezcano OM, Sameshima JH, Marcilla A, Robbins KC. Physical association between Src homology 3 elements and the protein product of the c-cbl proto-oncogene. J Biol Chem. 1994 Jul 1;269(26):17363–17366. [PubMed]
  • Frangioni JV, Neel BG. Solubilization and purification of enzymatically active glutathione S-transferase (pGEX) fusion proteins. Anal Biochem. 1993 Apr;210(1):179–187. [PubMed]
  • Feng S, Chen JK, Yu H, Simon JA, Schreiber SL. Two binding orientations for peptides to the Src SH3 domain: development of a general model for SH3-ligand interactions. Science. 1994 Nov 18;266(5188):1241–1247. [PubMed]
  • Lim WA, Richards FM, Fox RO. Structural determinants of peptide-binding orientation and of sequence specificity in SH3 domains. Nature. 1994 Nov 24;372(6504):375–379. [PubMed]
  • Burkhardt AL, Costa T, Misulovin Z, Stealy B, Bolen JB, Nussenzweig MC. Ig alpha and Ig beta are functionally homologous to the signaling proteins of the T-cell receptor. Mol Cell Biol. 1994 Feb;14(2):1095–1103. [PMC free article] [PubMed]
  • Janeway CA, Jr, Golstein P. Lymphocyte activation and effector functions. Editorial overview. The role of cell surface molecules. Curr Opin Immunol. 1993 Jun;5(3):313–323. [PubMed]
  • Andoniou CE, Thien CB, Langdon WY. Tumour induction by activated abl involves tyrosine phosphorylation of the product of the cbl oncogene. EMBO J. 1994 Oct 3;13(19):4515–4523. [PMC free article] [PubMed]
  • Langdon WY, Hartley JW, Klinken SP, Ruscetti SK, Morse HC., 3rd v-cbl, an oncogene from a dual-recombinant murine retrovirus that induces early B-lineage lymphomas. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1168–1172. [PMC free article] [PubMed]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...