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Engagement of the B-cell antigen receptor activates STAT through Lyn in a Jak-independent pathway

Oncogene volume 26, pages 2851–2859 (2007)Cite this article

Abstract

Engagement of the B-cell antigen receptor (BCR) initiated by the Src kinase Lyn triggers rapid signaling cascades, leading to proliferation, differentiation or growth arrest of B cells. The Janus kinase (JAK)–STAT (signal transducer and activator of transcription) pathway, activated through cytokine receptors, mediates similar responses. Hypothesizing that Src and JAK pathways engage in crosstalk in B-cell signaling, we studied wild-type and Lyn-null B-cell lines, which express BCR. We found that activated BCR results in tyrosine phosphorylation of JAK–STAT, which required Lyn. To confirm that STAT activation is not due to JAK, we cloned the chicken homologs of JAK1 and JAK2 and made their antisense constructs. In cells expressing antisense JAK1 and JAK2, tyrosine phosphorylation of STAT was not inhibited following BCR stimulation. Using activation loop-specific phosphotyrosine antibodies, we did not detect phospho-JAK1 and phospho-JAK2 after BCR stimulation. The JAK inhibitor AG490 did not inhibit the tyrosine phosphorylation of Lyn or STAT after BCR simulation. An in vitro phosphorylation assay showed that Lyn directly phosphorylates STAT3. In an electrophoretic mobility shift assay, BCR stimulation led to enhanced DNA binding of the STAT3 in DT40, but not in the Lyn-null cells. We conclude that BCR engagement activates the STAT pathway via Lyn, independent of JAK.

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References

  • Cao X, Tay A, Guy GR, Tan YH . (1996). Activation and association of Stat3 with Src in v-Src-transformed cell lines. Mol Cell Biol 16: 1595–1603.

    Article  CAS  Google Scholar 

  • Chaturvedi P, Reddy MV, Reddy EP . (1998). Src kinases and not JAKs activate STATs during IL-3 induced myeloid cell proliferation. Oncogene 16: 1749–1758.

    Article  CAS  Google Scholar 

  • Chin H, Arai A, Wakao H, Kamiyama R, Miyasaka N, Miura O . (1998). Lyn physically associates with the erythropoietin receptor and may play a role in activation of the Stat5 pathway. Blood 91: 3734–3745.

    CAS  PubMed  Google Scholar 

  • Cirri P, Chiarugi P, Marra F, Raugei G, Camici G, Manao G et al. (1997). c-Src activates both STAT1 and STAT3 in PDGF-stimulated NIH3T3 cells. Biochem Biophys Res Commun 239: 493–497.

    Article  CAS  Google Scholar 

  • Coppo P, Dusanter-Fourt I, Millot G, Nogueira MM, Dugray A, Bonnet ML et al. (2003). Constitutive and specific activation of STAT3 by BCR-ABL in embryonic stem cells. Oncogene 22: 4102–4110.

    Article  CAS  Google Scholar 

  • Corey SJ, Dombrosky-Ferlan PM, Zuo S, Krohn E, Donnenberg AD, Zorich P et al. (1998). Requirement of Src kinase Lyn for induction of DNA synthesis by granulocyte colony-stimulating factor. J Biol Chem 273: 3230–3235.

    Article  CAS  Google Scholar 

  • de Groot RP, Raaijmakers JA, Lammers JW, Jove R, Koenderman L . (1999). STAT5 activation by BCR-Abl contributes to transformation of K562 leukemia cells. Blood 94: 1108–1112.

    CAS  PubMed  Google Scholar 

  • DeFranco AL, Richards JD, Blum JH, Stevens TL, Law DA, Chan VW et al. (1995). Signal transduction by the B-cell antigen receptor. Ann NY Acad Sci 766: 195–201.

    Article  CAS  Google Scholar 

  • Dorsey JF, Cunnick JM, Lanehart R, Huang M, Kraker AJ, Bhalla KN et al. (2002). Interleukin-3 protects Bcr-Abl-transformed hematopoietic progenitor cells from apoptosis induced by Bcr-Abl tyrosine kinase inhibitors. Leukemia 16: 1589–1595.

    Article  CAS  Google Scholar 

  • Fan H, Rothstein TL . (2001). Lymphokine dependence of STAT3 activation produced by surface immunoglobulin cross-linking and by phorbol ester plus calcium ionophore treatment in B cells. Eur J Immunol 31: 665–671.

    Article  CAS  Google Scholar 

  • Finbloom DS, Larner AC . (1995). Regulation of the Jak/STAT signalling pathway. Cell Signal 7: 739–745.

    Article  CAS  Google Scholar 

  • Hibbs ML, Harder KW, Armes J, Kountouri N, Quilici C, Casagranda F et al. (2002). Sustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity. J Exp Med 196: 1593–1604.

    Article  CAS  Google Scholar 

  • Ihle JN . (1995). The Janus protein tyrosine kinases in hematopoietic cytokine signaling. Semin Immunol 7: 247–254.

    Article  CAS  Google Scholar 

  • Imada K, Leonard WJ . (2000). The Jak–STAT pathway. Mol Immunol 37: 1–11.

    Article  CAS  Google Scholar 

  • Ishikawa H, Tsuyama N, Abroun S, Liu S, Li FJ, Taniguchi O et al. (2002). Requirements of src family kinase activity associated with CD45 for myeloma cell proliferation by interleukin-6. Blood 99: 2172–2178.

    Article  CAS  Google Scholar 

  • Kaptein A, Paillard V, Saunders M . (1996). Dominant negative stat3 mutant inhibits interleukin-6-induced Jak-STAT signal transduction. J Biol Chem 271: 5961–5964.

    Article  CAS  Google Scholar 

  • Karras JG, Huo L, Wang Z, Frank DA, Zimmet JM, Rothstein TL . (1996a). Delayed tyrosine phosphorylation and nuclear expression of STAT1 following antigen receptor stimulation of B lymphocytes. J Immunol 157: 2299–2309.

    CAS  PubMed  Google Scholar 

  • Karras JG, Wang Z, Coniglio SJ, Frank DA, Rothstein TL . (1996b). Antigen-receptor engagement in B cells induces nuclear expression of STAT5 and STAT6 proteins that bind and transactivate an IFN-gamma activation site. J Immunol 157: 39–47.

    CAS  PubMed  Google Scholar 

  • Keshvara LM, Isaacson CC, Yankee TM, Sarac R, Harrison ML, Geahlen RL . (1998). Syk- and Lyn-dependent phosphorylation of Syk on multiple tyrosines following B cell activation includes a site that negatively regulates signaling. J Immunol 161: 5276–5283.

    CAS  PubMed  Google Scholar 

  • Koay DC, Nguyen T, Sartorelli AC . (2002). Distinct region of the granulocyte colony-stimulating factor receptor mediates proliferative signaling through activation of Janus kinase 2 and p44/42 mitogen-activated protein kinase. Cell Signal 14: 239–247.

    Article  CAS  Google Scholar 

  • Kurosaki T, Maeda A, Ishiai M, Hashimoto A, Inabe K, Takata M . (2000). Regulation of the phospholipase C-gamma2 pathway in B cells. Immunol Rev 176: 19–29.

    Article  CAS  Google Scholar 

  • Leonard WJ, O'Shea JJ . (1998). Jaks and STATs: biological implications. Annu Rev Immunol 16: 293–322.

    Article  CAS  Google Scholar 

  • Lund TC, Coleman C, Horvath E, Sefton BM, Jove R, Medveczky MM et al. (1999). The Src-family kinase Lck can induce STAT3 phosphorylation and DNA binding activity. Cell Signal 11: 789–796.

    Article  CAS  Google Scholar 

  • Mirnics ZK, Caudell E, Gao Y, Kuwahara K, Sakaguchi N, Kurosaki T et al. (2004). Microarray analysis of Lyn-deficient B cells reveals germinal center-associated nuclear protein and other genes associated with the lymphoid germinal center. J Immunol 172: 4133–4141.

    Article  CAS  Google Scholar 

  • Nelson KL, Rogers JA, Bowman TL, Jove R, Smithgall TE . (1998). Activation of STAT3 by the c-Fes protein-tyrosine kinase. J Biol Chem 273: 7072–7077.

    Article  CAS  Google Scholar 

  • Nicholson SE, Novak U, Ziegler SF, Layton JE . (1995). Distinct regions of the granulocyte colony-stimulating factor receptor are required for tyrosine phosphorylation of the signaling molecules JAK2, Stat3, and p42, p44MAPK. Blood 86: 3698–3704.

    CAS  PubMed  Google Scholar 

  • Okutani Y, Kitanaka A, Tanaka T, Kamano H, Ohnishi H, Kubota Y et al. (2001). Src directly tyrosine-phosphorylates STAT5 on its activation site and is involved in erythropoietin-induced signaling pathway. Oncogene 20: 6643–6650.

    Article  CAS  Google Scholar 

  • Pereira S, Lowell C . (2003). The Lyn tyrosine kinase negatively regulates neutrophil integrin signaling. J Immunol 171: 1319–1327.

    Article  CAS  Google Scholar 

  • Saharinen P, Vihinen M, Silvennoinen O . (2003). Autoinhibition of Jak2 tyrosine kinase is dependent on specific regions in its pseudokinase domain. Mol Biol Cell 14: 1448–1459.

    Article  CAS  Google Scholar 

  • Saouaf SJ, Mahajan S, Rowley RB, Kut SA, Fargnoli J, Burkhardt AL et al. (1994). 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 USA 91: 9524–9528.

    Article  CAS  Google Scholar 

  • Sarmay G, Koncz G, Pecht I, Gergely J . (1997). Fc gamma receptor type IIb induced recruitment of inositol and protein phosphatases to the signal transductory complex of human B-cell. Immunol Lett 57: 159–164.

    Article  CAS  Google Scholar 

  • Scheeren FA, Naspetti M, Diehl S, Schotte R, Nagasawa M, Wijnands E et al. (2005). STAT5 regulates the self-renewal capacity and differentiation of human memory B cells and controls Bcl-6 expression. Nat Immunol 6: 303–313.

    Article  CAS  Google Scholar 

  • Sternberg DW, Gilliland DG . (2004). The role of signal transducer and activator of transcription factors in leukemogenesis. J Clin Oncol 22: 361–371.

    Article  CAS  Google Scholar 

  • Su L, Rickert RC, David M . (1999). Rapid STAT phosphorylation via the B cell receptor. Modulatory role of CD19. J Biol Chem 274: 31770–31774.

    Article  CAS  Google Scholar 

  • Takata M, Sabe H, Hata A, Inazu T, Homma Y, Nukada T et al. (1994). Tyrosine kinases Lyn and Syk regulate B cell receptor-coupled Ca2+ mobilization through distinct pathways. EMBO J 13: 1341–1349.

    Article  CAS  Google Scholar 

  • Tweardy DJ, Wright TM, Ziegler SF, Baumann H, Chakraborty A, White SM et al. (1995). Granulocyte colony-stimulating factor rapidly activates a distinct STAT-like protein in normal myeloid cells. Blood 86: 4409–4416.

    CAS  PubMed  Google Scholar 

  • Wahl MI, Fluckiger AC, Kato RM, Park H, Witte ON, Rawlings DJ . (1997). Phosphorylation of two regulatory tyrosine residues in the activation of Bruton's tyrosine kinase via alternative receptors. Proc Natl Acad Sci USA 94: 11526–11533.

    Article  CAS  Google Scholar 

  • Winding P, Berchtold MW . (2001). The chicken B cell line DT40: a novel tool for gene disruption experiments. J Immunol Methods 249: 1–16.

    Article  CAS  Google Scholar 

  • Yi TL, Bolen JB, Ihle JN . (1991). Hematopoietic cells express two forms of lyn kinase differing by 21 amino acids in the amino terminus. Mol Cell Biol 11: 2391–2398.

    Article  CAS  Google Scholar 

  • You M, Yu DH, Feng GS . (1999). Shp2-tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak/STAT pathway. Mol Cell Biol 19: 2416–2424.

    Article  CAS  Google Scholar 

  • Yu CL, Jove R, Burakoff SJ . (1997). Constitutive activation of the Janus kinase-STAT pathway in T lymphoma overexpressing the Lck protein tyrosine kinase. J Immunol 159: 5206–5210.

    CAS  PubMed  Google Scholar 

  • Yu CL, Meyer DJ, Campbell GS, Larner AC, Carter-Su C, Schwartz J et al. (1995). Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science 269: 81–83.

    Article  CAS  Google Scholar 

  • Yu H, Jove R . (2004). The STATs of cancer – new molecular targets come of age. Nat Rev Cancer 4: 97–105.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work is supported by grants from the National Institutes of Health and the American Cancer Society. Seth J Corey is a recipient of an NIH Independent Scientist Award.

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Authors and Affiliations

  1. Division of Pediatrics, University of Texas-MD Anderson Cancer Center, Houston, TX, USA

    L Wang & S J Corey

  2. Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, Japan

    T Kurosaki

  3. Lymphocyte Differentiation RIKEN Research Center for Allergy and Immunology, Yokohama, Japan

    T Kurosaki

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  1. L Wang
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Correspondence to S J Corey.

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Wang, L., Kurosaki, T. & Corey, S. Engagement of the B-cell antigen receptor activates STAT through Lyn in a Jak-independent pathway. Oncogene 26, 2851–2859 (2007). https://doi.org/10.1038/sj.onc.1210092

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