Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1995 Jan 1;181(1):417–422. doi: 10.1084/jem.181.1.417

Activation of the p21ras pathway couples antigen receptor stimulation to induction of the primary response gene egr-1 in B lymphocytes

PMCID: PMC2191844  PMID: 7807022

Abstract

The primary response gene egr-1 encodes a sequence-specific transcription factor whose expression is necessary for antigen receptor- stimulated activation of B lymphocytes. The molecular processes involved in linking egr-1 induction to antigen receptor signaling have not been defined. The present study demonstrates that expression of an activated form of p21ras results in egr-1 induction similar to that previously shown after antigen receptor cross-linking. In addition, both antigen receptor cross-linking and p21ras use the same element in the egr-1 promoter to exert their effects. Using dominant-negative mutants of p21ras and raf-1, we demonstrate that induction of egr-1 after antigen receptor cross-linking is mediated by activation of the p21ras/mitogen-activated protein kinase signaling pathway. While regulation of the p21ras pathway during B cell activation has been intensively studied, this report represents the first description of a biologically relevant event associated with its activation.

Full Text

The Full Text of this article is available as a PDF (639.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Boguski M. S., McCormick F. Proteins regulating Ras and its relatives. Nature. 1993 Dec 16;366(6456):643–654. doi: 10.1038/366643a0. [DOI] [PubMed] [Google Scholar]
  2. Boyer M. J., Gutmann D. H., Collins F. S., Bar-Sagi D. Crosslinking of the surface immunoglobulin receptor in B lymphocytes induces a redistribution of neurofibromin but not p120-GAP. Oncogene. 1994 Feb;9(2):349–357. [PubMed] [Google Scholar]
  3. Bustelo X. R., Barbacid M. Tyrosine phosphorylation of the vav proto-oncogene product in activated B cells. Science. 1992 May 22;256(5060):1196–1199. doi: 10.1126/science.256.5060.1196. [DOI] [PubMed] [Google Scholar]
  4. Cambier J. C., Pleiman C. M., Clark M. R. Signal transduction by the B cell antigen receptor and its coreceptors. Annu Rev Immunol. 1994;12:457–486. doi: 10.1146/annurev.iy.12.040194.002325. [DOI] [PubMed] [Google Scholar]
  5. DeFranco C., Damon D. H., Endoh M., Wagner J. A. Nerve growth factor induces transcription of NGFIA through complex regulatory elements that are also sensitive to serum and phorbol 12-myristate 13-acetate. Mol Endocrinol. 1993 Mar;7(3):365–379. doi: 10.1210/mend.7.3.8483478. [DOI] [PubMed] [Google Scholar]
  6. Feig L. A., Cooper G. M. Inhibition of NIH 3T3 cell proliferation by a mutant ras protein with preferential affinity for GDP. Mol Cell Biol. 1988 Aug;8(8):3235–3243. doi: 10.1128/mcb.8.8.3235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gold M. R., Crowley M. T., Martin G. A., McCormick F., DeFranco A. L. Targets of B lymphocyte antigen receptor signal transduction include the p21ras GTPase-activating protein (GAP) and two GAP-associated proteins. J Immunol. 1993 Jan 15;150(2):377–386. [PubMed] [Google Scholar]
  8. Graziadei L., Riabowol K., Bar-Sagi D. Co-capping of ras proteins with surface immunoglobulins in B lymphocytes. Nature. 1990 Sep 27;347(6291):396–400. doi: 10.1038/347396a0. [DOI] [PubMed] [Google Scholar]
  9. Gulbins E., Coggeshall K. M., Baier G., Telford D., Langlet C., Baier-Bitterlich G., Bonnefoy-Berard N., Burn P., Wittinghofer A., Altman A. Direct stimulation of Vav guanine nucleotide exchange activity for Ras by phorbol esters and diglycerides. Mol Cell Biol. 1994 Jul;14(7):4749–4758. doi: 10.1128/mcb.14.7.4749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gulbins E., Langlet C., Baier G., Bonnefoy-Berard N., Herbert E., Altman A., Coggeshall K. M. Tyrosine phosphorylation and activation of Vav GTP/GDP exchange activity in antigen receptor-triggered B cells. J Immunol. 1994 Mar 1;152(5):2123–2129. [PubMed] [Google Scholar]
  11. Harwood A. E., Cambier J. C. B cell antigen receptor cross-linking triggers rapid protein kinase C independent activation of p21ras1. J Immunol. 1993 Nov 1;151(9):4513–4522. [PubMed] [Google Scholar]
  12. Hill C. S., Marais R., John S., Wynne J., Dalton S., Treisman R. Functional analysis of a growth factor-responsive transcription factor complex. Cell. 1993 Apr 23;73(2):395–406. doi: 10.1016/0092-8674(93)90238-l. [DOI] [PubMed] [Google Scholar]
  13. Izquierdo M., Leevers S. J., Marshall C. J., Cantrell D. p21ras couples the T cell antigen receptor to extracellular signal-regulated kinase 2 in T lymphocytes. J Exp Med. 1993 Oct 1;178(4):1199–1208. doi: 10.1084/jem.178.4.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kharbanda S., Saleem A., Hirano M., Emoto Y., Sukhatme V., Blenis J., Kufe D. Activation of early growth response 1 gene transcription and pp90rsk during induction of monocytic differentiation. Cell Growth Differ. 1994 Mar;5(3):259–265. [PubMed] [Google Scholar]
  15. Kyriakis J. M., App H., Zhang X. F., Banerjee P., Brautigan D. L., Rapp U. R., Avruch J. Raf-1 activates MAP kinase-kinase. Nature. 1992 Jul 30;358(6385):417–421. doi: 10.1038/358417a0. [DOI] [PubMed] [Google Scholar]
  16. Lange-Carter C. A., Pleiman C. M., Gardner A. M., Blumer K. J., Johnson G. L. A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science. 1993 Apr 16;260(5106):315–319. doi: 10.1126/science.8385802. [DOI] [PubMed] [Google Scholar]
  17. Lazarus A. H., Kawauchi K., Rapoport M. J., Delovitch T. L. Antigen-induced B lymphocyte activation involves the p21ras and ras.GAP signaling pathway. J Exp Med. 1993 Nov 1;178(5):1765–1769. doi: 10.1084/jem.178.5.1765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Leevers S. J., Paterson H. F., Marshall C. J. Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. Nature. 1994 Jun 2;369(6479):411–414. doi: 10.1038/369411a0. [DOI] [PubMed] [Google Scholar]
  19. Luckow B., Schütz G. CAT constructions with multiple unique restriction sites for the functional analysis of eukaryotic promoters and regulatory elements. Nucleic Acids Res. 1987 Jul 10;15(13):5490–5490. doi: 10.1093/nar/15.13.5490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Owaki H., Varma R., Gillis B., Bruder J. T., Rapp U. R., Davis L. S., Geppert T. D. Raf-1 is required for T cell IL2 production. EMBO J. 1993 Nov;12(11):4367–4373. doi: 10.1002/j.1460-2075.1993.tb06121.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Payne D. M., Rossomando A. J., Martino P., Erickson A. K., Her J. H., Shabanowitz J., Hunt D. F., Weber M. J., Sturgill T. W. Identification of the regulatory phosphorylation sites in pp42/mitogen-activated protein kinase (MAP kinase). EMBO J. 1991 Apr;10(4):885–892. doi: 10.1002/j.1460-2075.1991.tb08021.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Perez-Castillo A., Pipaón C., García I., Alemany S. NGFI-A gene expression is necessary for T lymphocyte proliferation. J Biol Chem. 1993 Sep 15;268(26):19445–19450. [PubMed] [Google Scholar]
  23. Pulverer B. J., Kyriakis J. M., Avruch J., Nikolakaki E., Woodgett J. R. Phosphorylation of c-jun mediated by MAP kinases. Nature. 1991 Oct 17;353(6345):670–674. doi: 10.1038/353670a0. [DOI] [PubMed] [Google Scholar]
  24. Rim M., Qureshi S. A., Gius D., Nho J., Sukhatme V. P., Foster D. A. Evidence that activation of the Egr-1 promoter by v-Raf involves serum response elements. Oncogene. 1992 Oct;7(10):2065–2068. [PubMed] [Google Scholar]
  25. Saxton T. M., van Oostveen I., Bowtell D., Aebersold R., Gold M. R. B cell antigen receptor cross-linking induces phosphorylation of the p21ras oncoprotein activators SHC and mSOS1 as well as assembly of complexes containing SHC, GRB-2, mSOS1, and a 145-kDa tyrosine-phosphorylated protein. J Immunol. 1994 Jul 15;153(2):623–636. [PubMed] [Google Scholar]
  26. Schaap D., van der Wal J., Howe L. R., Marshall C. J., van Blitterswijk W. J. A dominant-negative mutant of raf blocks mitogen-activated protein kinase activation by growth factors and oncogenic p21ras. J Biol Chem. 1993 Sep 25;268(27):20232–20236. [PubMed] [Google Scholar]
  27. Seyfert V. L., McMahon S., Glenn W., Cao X. M., Sukhatme V. P., Monroe J. G. Egr-1 expression in surface Ig-mediated B cell activation. Kinetics and association with protein kinase C activation. J Immunol. 1990 Dec 1;145(11):3647–3653. [PubMed] [Google Scholar]
  28. Stokoe D., Macdonald S. G., Cadwallader K., Symons M., Hancock J. F. Activation of Raf as a result of recruitment to the plasma membrane. Science. 1994 Jun 3;264(5164):1463–1467. doi: 10.1126/science.7811320. [DOI] [PubMed] [Google Scholar]
  29. Tabin C. J., Bradley S. M., Bargmann C. I., Weinberg R. A., Papageorge A. G., Scolnick E. M., Dhar R., Lowy D. R., Chang E. H. Mechanism of activation of a human oncogene. Nature. 1982 Nov 11;300(5888):143–149. doi: 10.1038/300143a0. [DOI] [PubMed] [Google Scholar]
  30. Tordai A., Franklin R. A., Patel H., Gardner A. M., Johnson G. L., Gelfand E. W. Cross-linking of surface IgM stimulates the Ras/Raf-1/MEK/MAPK cascade in human B lymphocytes. J Biol Chem. 1994 Mar 11;269(10):7538–7543. [PubMed] [Google Scholar]
  31. Treisman R. Ternary complex factors: growth factor regulated transcriptional activators. Curr Opin Genet Dev. 1994 Feb;4(1):96–101. doi: 10.1016/0959-437x(94)90097-3. [DOI] [PubMed] [Google Scholar]
  32. Tsai-Morris C. H., Cao X. M., Sukhatme V. P. 5' flanking sequence and genomic structure of Egr-1, a murine mitogen inducible zinc finger encoding gene. Nucleic Acids Res. 1988 Sep 26;16(18):8835–8846. doi: 10.1093/nar/16.18.8835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Vojtek A. B., Hollenberg S. M., Cooper J. A. Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell. 1993 Jul 16;74(1):205–214. doi: 10.1016/0092-8674(93)90307-c. [DOI] [PubMed] [Google Scholar]

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

RESOURCES