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. 1997 Dec 1;16(23):7019–7031. doi: 10.1093/emboj/16.23.7019

Control of B cell development by Ras-mediated activation of Raf.

B M Iritani 1, K A Forbush 1, M A Farrar 1, R M Perlmutter 1
PMCID: PMC1170305  PMID: 9384581

Abstract

Cell fate commitment in a variety of lineages requires signals conveyed via p21ras. To examine the role of p21ras in the development of B lymphocytes, we generated transgenic mice expressing a dominant-negative form of Ras in B lymphocyte progenitors, using a novel transcriptional element consisting of the Emu enhancer and the lck proximal promoter. Expression of dominant-negative Ras arrests B cell development at a very early stage, prior to formation of the pre-B cell receptor. Furthermore, an activated form of Raf expressed in the same experimental system could both drive the maturation of normal pro-B cells and rescue development of progenitors expressing dominant-negative Ras. Hence p21ras normally regulates early development of B lymphocytes by a mechanism that involves activation of the serine/threonine kinase Raf.

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Selected References

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  1. Adari H., Lowy D. R., Willumsen B. M., Der C. J., McCormick F. Guanosine triphosphatase activating protein (GAP) interacts with the p21 ras effector binding domain. Science. 1988 Apr 22;240(4851):518–521. doi: 10.1126/science.2833817. [DOI] [PubMed] [Google Scholar]
  2. Alberola-Ila J., Forbush K. A., Seger R., Krebs E. G., Perlmutter R. M. Selective requirement for MAP kinase activation in thymocyte differentiation. Nature. 1995 Feb 16;373(6515):620–623. doi: 10.1038/373620a0. [DOI] [PubMed] [Google Scholar]
  3. Alberola-Ila J., Hogquist K. A., Swan K. A., Bevan M. J., Perlmutter R. M. Positive and negative selection invoke distinct signaling pathways. J Exp Med. 1996 Jul 1;184(1):9–18. doi: 10.1084/jem.184.1.9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Alexander W. S., Schrader J. W., Adams J. M. Expression of the c-myc oncogene under control of an immunoglobulin enhancer in E mu-myc transgenic mice. Mol Cell Biol. 1987 Apr;7(4):1436–1444. doi: 10.1128/mcb.7.4.1436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Allen J. M., Forbush K. A., Perlmutter R. M. Functional dissection of the lck proximal promoter. Mol Cell Biol. 1992 Jun;12(6):2758–2768. doi: 10.1128/mcb.12.6.2758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Appleby M. W., Kerner J. D., Chien S., Maliszewski C. R., Bondada S., Perlmutter R. M., Bondadaa S [corrected to Bondada S. ]. Involvement of p59fynT in interleukin-5 receptor signaling. J Exp Med. 1995 Sep 1;182(3):811–820. doi: 10.1084/jem.182.3.811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bain G., Maandag E. C., Izon D. J., Amsen D., Kruisbeek A. M., Weintraub B. C., Krop I., Schlissel M. S., Feeney A. J., van Roon M. E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements. Cell. 1994 Dec 2;79(5):885–892. doi: 10.1016/0092-8674(94)90077-9. [DOI] [PubMed] [Google Scholar]
  8. Baker D. A., Maher J., Roberts I. A., Dibb N. J. Evidence that ras and myc mediate the synergy between SCF or M-CSF and other haemopoietic growth factors. Leukemia. 1994 Nov;8(11):1970–1981. [PubMed] [Google Scholar]
  9. Baldari C. T., Heguy A., Telford J. L. ras protein activity is essential for T-cell antigen receptor signal transduction. J Biol Chem. 1993 Feb 5;268(4):2693–2698. [PubMed] [Google Scholar]
  10. Bradford A. P., Conrad K. E., Wasylyk C., Wasylyk B., Gutierrez-Hartmann A. Functional interaction of c-Ets-1 and GHF-1/Pit-1 mediates Ras activation of pituitary-specific gene expression: mapping of the essential c-Ets-1 domain. Mol Cell Biol. 1995 May;15(5):2849–2857. doi: 10.1128/mcb.15.5.2849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Brasel K., McKenna H. J., Morrissey P. J., Charrier K., Morris A. E., Lee C. C., Williams D. E., Lyman S. D. Hematologic effects of flt3 ligand in vivo in mice. Blood. 1996 Sep 15;88(6):2004–2012. [PubMed] [Google Scholar]
  12. Cahill M. A., Janknecht R., Nordheim A. Signalling pathways: jack of all cascades. Curr Biol. 1996 Jan 1;6(1):16–19. doi: 10.1016/s0960-9822(02)00410-4. [DOI] [PubMed] [Google Scholar]
  13. Calés C., Hancock J. F., Marshall C. J., Hall A. The cytoplasmic protein GAP is implicated as the target for regulation by the ras gene product. Nature. 1988 Apr 7;332(6164):548–551. doi: 10.1038/332548a0. [DOI] [PubMed] [Google Scholar]
  14. Cao X., Shores E. W., Hu-Li J., Anver M. R., Kelsall B. L., Russell S. M., Drago J., Noguchi M., Grinberg A., Bloom E. T. Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity. 1995 Mar;2(3):223–238. doi: 10.1016/1074-7613(95)90047-0. [DOI] [PubMed] [Google Scholar]
  15. Chaffin K. E., Beals C. R., Wilkie T. M., Forbush K. A., Simon M. I., Perlmutter R. M. Dissection of thymocyte signaling pathways by in vivo expression of pertussis toxin ADP-ribosyltransferase. EMBO J. 1990 Dec;9(12):3821–3829. doi: 10.1002/j.1460-2075.1990.tb07600.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Chen S. Y., Huff S. Y., Lai C. C., Der C. J., Powers S. Ras-15A protein shares highly similar dominant-negative biological properties with Ras-17N and forms a stable, guanine-nucleotide resistant complex with CDC25 exchange factor. Oncogene. 1994 Sep;9(9):2691–2698. [PubMed] [Google Scholar]
  17. Cooke M. P., Abraham K. M., Forbush K. A., Perlmutter R. M. Regulation of T cell receptor signaling by a src family protein-tyrosine kinase (p59fyn). Cell. 1991 Apr 19;65(2):281–291. doi: 10.1016/0092-8674(91)90162-r. [DOI] [PubMed] [Google Scholar]
  18. Cumano A., Paige C. J. Enrichment and characterization of uncommitted B-cell precursors from fetal liver at day 12 of gestation. EMBO J. 1992 Feb;11(2):593–601. doi: 10.1002/j.1460-2075.1992.tb05091.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. David M., Petricoin E., 3rd, Benjamin C., Pine R., Weber M. J., Larner A. C. Requirement for MAP kinase (ERK2) activity in interferon alpha- and interferon beta-stimulated gene expression through STAT proteins. Science. 1995 Sep 22;269(5231):1721–1723. doi: 10.1126/science.7569900. [DOI] [PubMed] [Google Scholar]
  20. Dickson B. Nuclear factors in sevenless signalling. Trends Genet. 1995 Mar;11(3):106–111. doi: 10.1016/S0168-9525(00)89011-3. [DOI] [PubMed] [Google Scholar]
  21. Duronio V., Welham M. J., Abraham S., Dryden P., Schrader J. W. p21ras activation via hemopoietin receptors and c-kit requires tyrosine kinase activity but not tyrosine phosphorylation of p21ras GTPase-activating protein. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1587–1591. doi: 10.1073/pnas.89.5.1587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Eisenmann D. M., Kim S. K. Signal transduction and cell fate specification during Caenorhabditis elegans vulval development. Curr Opin Genet Dev. 1994 Aug;4(4):508–516. doi: 10.1016/0959-437x(94)90065-b. [DOI] [PubMed] [Google Scholar]
  23. Furth M. E., Aldrich T. H., Cordon-Cardo C. Expression of ras proto-oncogene proteins in normal human tissues. Oncogene. 1987 Mar;1(1):47–58. [PubMed] [Google Scholar]
  24. Garvin A. M., Abraham K. M., Forbush K. A., Farr A. G., Davison B. L., Perlmutter R. M. Disruption of thymocyte development and lymphomagenesis induced by SV40 T-antigen. Int Immunol. 1990;2(2):173–180. doi: 10.1093/intimm/2.2.173. [DOI] [PubMed] [Google Scholar]
  25. Gong S., Nussenzweig M. C. Regulation of an early developmental checkpoint in the B cell pathway by Ig beta. Science. 1996 Apr 19;272(5260):411–414. doi: 10.1126/science.272.5260.411. [DOI] [PubMed] [Google Scholar]
  26. Grabstein K. H., Waldschmidt T. J., Finkelman F. D., Hess B. W., Alpert A. R., Boiani N. E., Namen A. E., Morrissey P. J. Inhibition of murine B and T lymphopoiesis in vivo by an anti-interleukin 7 monoclonal antibody. J Exp Med. 1993 Jul 1;178(1):257–264. doi: 10.1084/jem.178.1.257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. Gross J. A., Appleby M. W., Chien S., Nada S., Bartelmez S. H., Okada M., Aizawa S., Perlmutter R. M. Control of lymphopoiesis by p50csk, a regulatory protein tyrosine kinase. J Exp Med. 1995 Feb 1;181(2):463–473. doi: 10.1084/jem.181.2.463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Guerrero I., Villasante A., Corces V., Pellicer A. Loss of the normal N-ras allele in a mouse thymic lymphoma induced by a chemical carcinogen. Proc Natl Acad Sci U S A. 1985 Dec;82(23):7810–7814. doi: 10.1073/pnas.82.23.7810. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Guerrero I., Villasante A., D'Eustachio P., Pellicer A. Isolation, characterization, and chromosome assignment of mouse N-ras gene from carcinogen-induced thymic lymphoma. Science. 1984 Sep 7;225(4666):1041–1043. doi: 10.1126/science.6089339. [DOI] [PubMed] [Google Scholar]
  31. Hagman J., Grosschedl R. Regulation of gene expression at early stages of B-cell differentiation. Curr Opin Immunol. 1994 Apr;6(2):222–230. doi: 10.1016/0952-7915(94)90095-7. [DOI] [PubMed] [Google Scholar]
  32. Hardy R. R., Carmack C. E., Li Y. S., Hayakawa K. Distinctive developmental origins and specificities of murine CD5+ B cells. Immunol Rev. 1994 Feb;137:91–118. doi: 10.1111/j.1600-065x.1994.tb00660.x. [DOI] [PubMed] [Google Scholar]
  33. Hardy R. R., Carmack C. E., Shinton S. A., Kemp J. D., Hayakawa K. Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow. J Exp Med. 1991 May 1;173(5):1213–1225. doi: 10.1084/jem.173.5.1213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. 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]
  35. Hofer F., Fields S., Schneider C., Martin G. S. Activated Ras interacts with the Ral guanine nucleotide dissociation stimulator. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11089–11093. doi: 10.1073/pnas.91.23.11089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Howe L. R., Leevers S. J., Gómez N., Nakielny S., Cohen P., Marshall C. J. Activation of the MAP kinase pathway by the protein kinase raf. Cell. 1992 Oct 16;71(2):335–342. doi: 10.1016/0092-8674(92)90361-f. [DOI] [PubMed] [Google Scholar]
  37. Hunte B. E., Hudak S., Campbell D., Xu Y., Rennick D. flk2/flt3 ligand is a potent cofactor for the growth of primitive B cell progenitors. J Immunol. 1996 Jan 15;156(2):489–496. [PubMed] [Google Scholar]
  38. Izquierdo Pastor M., Reif K., Cantrell D. The regulation and function of p21ras during T-cell activation and growth. Immunol Today. 1995 Mar;16(3):159–164. doi: 10.1016/0167-5699(95)80134-0. [DOI] [PubMed] [Google Scholar]
  39. Jin D. I., Jameson S. B., Reddy M. A., Schenkman D., Ostrowski M. C. Alterations in differentiation and behavior of monocytic phagocytes in transgenic mice that express dominant suppressors of ras signaling. Mol Cell Biol. 1995 Feb;15(2):693–703. doi: 10.1128/mcb.15.2.693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Kantor A. B., Herzenberg L. A. Origin of murine B cell lineages. Annu Rev Immunol. 1993;11:501–538. doi: 10.1146/annurev.iy.11.040193.002441. [DOI] [PubMed] [Google Scholar]
  41. Karasuyama H., Rolink A., Melchers F. Surrogate light chain in B cell development. Adv Immunol. 1996;63:1–41. doi: 10.1016/s0065-2776(08)60853-6. [DOI] [PubMed] [Google Scholar]
  42. Kitamura D., Roes J., Kühn R., Rajewsky K. A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature. 1991 Apr 4;350(6317):423–426. doi: 10.1038/350423a0. [DOI] [PubMed] [Google Scholar]
  43. 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]
  44. Langer S. J., Bortner D. M., Roussel M. F., Sherr C. J., Ostrowski M. C. Mitogenic signaling by colony-stimulating factor 1 and ras is suppressed by the ets-2 DNA-binding domain and restored by myc overexpression. Mol Cell Biol. 1992 Dec;12(12):5355–5362. doi: 10.1128/mcb.12.12.5355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. 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]
  46. 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]
  47. Leon J., Guerrero I., Pellicer A. Differential expression of the ras gene family in mice. Mol Cell Biol. 1987 Apr;7(4):1535–1540. doi: 10.1128/mcb.7.4.1535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Li Y. S., Hayakawa K., Hardy R. R. The regulated expression of B lineage associated genes during B cell differentiation in bone marrow and fetal liver. J Exp Med. 1993 Sep 1;178(3):951–960. doi: 10.1084/jem.178.3.951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Li Y. S., Wasserman R., Hayakawa K., Hardy R. R. Identification of the earliest B lineage stage in mouse bone marrow. Immunity. 1996 Dec;5(6):527–535. doi: 10.1016/s1074-7613(00)80268-x. [DOI] [PubMed] [Google Scholar]
  50. Lin H., Grosschedl R. Failure of B-cell differentiation in mice lacking the transcription factor EBF. Nature. 1995 Jul 20;376(6537):263–267. doi: 10.1038/376263a0. [DOI] [PubMed] [Google Scholar]
  51. Marais R., Light Y., Paterson H. F., Marshall C. J. Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation. EMBO J. 1995 Jul 3;14(13):3136–3145. doi: 10.1002/j.1460-2075.1995.tb07316.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. McKercher S. R., Torbett B. E., Anderson K. L., Henkel G. W., Vestal D. J., Baribault H., Klemsz M., Feeney A. J., Wu G. E., Paige C. J. Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J. 1996 Oct 15;15(20):5647–5658. [PMC free article] [PubMed] [Google Scholar]
  53. Medema R. H., de Vries-Smits A. M., van der Zon G. C., Maassen J. A., Bos J. L. Ras activation by insulin and epidermal growth factor through enhanced exchange of guanine nucleotides on p21ras. Mol Cell Biol. 1993 Jan;13(1):155–162. doi: 10.1128/mcb.13.1.155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Melchers F., Haasner D., Grawunder U., Kalberer C., Karasuyama H., Winkler T., Rolink A. G. Roles of IgH and L chains and of surrogate H and L chains in the development of cells of the B lymphocyte lineage. Annu Rev Immunol. 1994;12:209–225. doi: 10.1146/annurev.iy.12.040194.001233. [DOI] [PubMed] [Google Scholar]
  55. Mombaerts P., Clarke A. R., Rudnicki M. A., Iacomini J., Itohara S., Lafaille J. J., Wang L., Ichikawa Y., Jaenisch R., Hooper M. L. Mutations in T-cell antigen receptor genes alpha and beta block thymocyte development at different stages. Nature. 1992 Nov 19;360(6401):225–231. doi: 10.1038/360225a0. [DOI] [PubMed] [Google Scholar]
  56. Mombaerts P. Lymphocyte development and function in T-cell receptor and RAG-1 mutant mice. Int Rev Immunol. 1995;13(1):43–63. doi: 10.3109/08830189509061737. [DOI] [PubMed] [Google Scholar]
  57. Moodie S. A., Willumsen B. M., Weber M. J., Wolfman A. Complexes of Ras.GTP with Raf-1 and mitogen-activated protein kinase kinase. Science. 1993 Jun 11;260(5114):1658–1661. doi: 10.1126/science.8503013. [DOI] [PubMed] [Google Scholar]
  58. Nagasawa T., Hirota S., Tachibana K., Takakura N., Nishikawa S., Kitamura Y., Yoshida N., Kikutani H., Kishimoto T. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature. 1996 Aug 15;382(6592):635–638. doi: 10.1038/382635a0. [DOI] [PubMed] [Google Scholar]
  59. Nagasawa T., Kikutani H., Kishimoto T. Molecular cloning and structure of a pre-B-cell growth-stimulating factor. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2305–2309. doi: 10.1073/pnas.91.6.2305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Nemazee D. Can receptor editing play an important role in normal B-cell development? J Autoimmun. 1996 Apr;9(2):259–261. doi: 10.1006/jaut.1996.0032. [DOI] [PubMed] [Google Scholar]
  61. Nosaka T., van Deursen J. M., Tripp R. A., Thierfelder W. E., Witthuhn B. A., McMickle A. P., Doherty P. C., Grosveld G. C., Ihle J. N. Defective lymphoid development in mice lacking Jak3. Science. 1995 Nov 3;270(5237):800–802. doi: 10.1126/science.270.5237.800. [DOI] [PubMed] [Google Scholar]
  62. O'Shea C. C., Crompton T., Rosewell I. R., Hayday A. C., Owen M. J. Raf regulates positive selection. Eur J Immunol. 1996 Oct;26(10):2350–2355. doi: 10.1002/eji.1830261012. [DOI] [PubMed] [Google Scholar]
  63. Osmond D. G., Rico-Vargas S., Valenzona H., Fauteux L., Liu L., Janani R., Lu L., Jacobsen K. Apoptosis and macrophage-mediated cell deletion in the regulation of B lymphopoiesis in mouse bone marrow. Immunol Rev. 1994 Dec;142:209–230. doi: 10.1111/j.1600-065x.1994.tb00891.x. [DOI] [PubMed] [Google Scholar]
  64. Park S. Y., Saijo K., Takahashi T., Osawa M., Arase H., Hirayama N., Miyake K., Nakauchi H., Shirasawa T., Saito T. Developmental defects of lymphoid cells in Jak3 kinase-deficient mice. Immunity. 1995 Dec;3(6):771–782. doi: 10.1016/1074-7613(95)90066-7. [DOI] [PubMed] [Google Scholar]
  65. Perlmutter R. M., Alberola-Ila J. The use of dominant-negative mutations to elucidate signal transduction pathways in lymphocytes. Curr Opin Immunol. 1996 Apr;8(2):285–290. doi: 10.1016/s0952-7915(96)80069-0. [DOI] [PubMed] [Google Scholar]
  66. Peschon J. J., Morrissey P. J., Grabstein K. H., Ramsdell F. J., Maraskovsky E., Gliniak B. C., Park L. S., Ziegler S. F., Williams D. E., Ware C. B. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med. 1994 Nov 1;180(5):1955–1960. doi: 10.1084/jem.180.5.1955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Prendergast G. C., Khosravi-Far R., Solski P. A., Kurzawa H., Lebowitz P. F., Der C. J. Critical role of Rho in cell transformation by oncogenic Ras. Oncogene. 1995 Jun 15;10(12):2289–2296. [PubMed] [Google Scholar]
  68. Pronk G. J., Bos J. L. The role of p21ras in receptor tyrosine kinase signalling. Biochim Biophys Acta. 1994 Dec 30;1198(2-3):131–147. doi: 10.1016/0304-419x(94)90010-8. [DOI] [PubMed] [Google Scholar]
  69. Qiu R. G., Chen J., Kirn D., McCormick F., Symons M. An essential role for Rac in Ras transformation. Nature. 1995 Mar 30;374(6521):457–459. doi: 10.1038/374457a0. [DOI] [PubMed] [Google Scholar]
  70. Rayter S. I., Woodrow M., Lucas S. C., Cantrell D. A., Downward J. p21ras mediates control of IL-2 gene promoter function in T cell activation. EMBO J. 1992 Dec;11(12):4549–4556. doi: 10.1002/j.1460-2075.1992.tb05556.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Rodewald H. R., Ogawa M., Haller C., Waskow C., DiSanto J. P. Pro-thymocyte expansion by c-kit and the common cytokine receptor gamma chain is essential for repertoire formation. Immunity. 1997 Mar;6(3):265–272. doi: 10.1016/s1074-7613(00)80329-5. [DOI] [PubMed] [Google Scholar]
  72. Rodriguez-Viciana P., Warne P. H., Dhand R., Vanhaesebroeck B., Gout I., Fry M. J., Waterfield M. D., Downward J. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature. 1994 Aug 18;370(6490):527–532. doi: 10.1038/370527a0. [DOI] [PubMed] [Google Scholar]
  73. Russell S. M., Johnston J. A., Noguchi M., Kawamura M., Bacon C. M., Friedmann M., Berg M., McVicar D. W., Witthuhn B. A., Silvennoinen O. Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID. Science. 1994 Nov 11;266(5187):1042–1045. doi: 10.1126/science.7973658. [DOI] [PubMed] [Google Scholar]
  74. Scharff M. D., Poltoratsky V., Green N. S. The promotion of V region hypermutation. J Exp Med. 1997 Jan 20;185(2):185–188. doi: 10.1084/jem.185.2.185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Schlessinger J. SH2/SH3 signaling proteins. Curr Opin Genet Dev. 1994 Feb;4(1):25–30. doi: 10.1016/0959-437x(94)90087-6. [DOI] [PubMed] [Google Scholar]
  76. Schweighoffer F., Cai H., Chevallier-Multon M. C., Fath I., Cooper G., Tocque B. The Saccharomyces cerevisiae SDC25 C-domain gene product overcomes the dominant inhibitory activity of Ha-Ras Asn-17. Mol Cell Biol. 1993 Jan;13(1):39–43. doi: 10.1128/mcb.13.1.39. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Seger R., Seger D., Reszka A. A., Munar E. S., Eldar-Finkelman H., Dobrowolska G., Jensen A. M., Campbell J. S., Fischer E. H., Krebs E. G. Overexpression of mitogen-activated protein kinase kinase (MAPKK) and its mutants in NIH 3T3 cells. Evidence that MAPKK involvement in cellular proliferation is regulated by phosphorylation of serine residues in its kinase subdomains VII and VIII. J Biol Chem. 1994 Oct 14;269(41):25699–25709. [PubMed] [Google Scholar]
  78. Shinkai Y., Rathbun G., Lam K. P., Oltz E. M., Stewart V., Mendelsohn M., Charron J., Datta M., Young F., Stall A. M. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992 Mar 6;68(5):855–867. doi: 10.1016/0092-8674(92)90029-c. [DOI] [PubMed] [Google Scholar]
  79. 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]
  80. Sudo T., Nishikawa S., Ohno N., Akiyama N., Tamakoshi M., Yoshida H., Nishikawa S. Expression and function of the interleukin 7 receptor in murine lymphocytes. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9125–9129. doi: 10.1073/pnas.90.19.9125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Sun X. H. Constitutive expression of the Id1 gene impairs mouse B cell development. Cell. 1994 Dec 2;79(5):893–900. doi: 10.1016/0092-8674(94)90078-7. [DOI] [PubMed] [Google Scholar]
  82. Swan K. A., Alberola-Ila J., Gross J. A., Appleby M. W., Forbush K. A., Thomas J. F., Perlmutter R. M. Involvement of p21ras distinguishes positive and negative selection in thymocytes. EMBO J. 1995 Jan 16;14(2):276–285. doi: 10.1002/j.1460-2075.1995.tb07001.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Szeberényi J., Cai H., Cooper G. M. Effect of a dominant inhibitory Ha-ras mutation on neuronal differentiation of PC12 cells. Mol Cell Biol. 1990 Oct;10(10):5324–5332. doi: 10.1128/mcb.10.10.5324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Takeda S., Shimizu T., Rodewald H. R. Interactions between c-kit and stem cell factor are not required for B-cell development in vivo. Blood. 1997 Jan 15;89(2):518–525. [PubMed] [Google Scholar]
  85. Thomis D. C., Gurniak C. B., Tivol E., Sharpe A. H., Berg L. J. Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science. 1995 Nov 3;270(5237):794–797. doi: 10.1126/science.270.5237.794. [DOI] [PubMed] [Google Scholar]
  86. Umanoff H., Edelmann W., Pellicer A., Kucherlapati R. The murine N-ras gene is not essential for growth and development. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1709–1713. doi: 10.1073/pnas.92.5.1709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Urbánek P., Wang Z. Q., Fetka I., Wagner E. F., Busslinger M. Complete block of early B cell differentiation and altered patterning of the posterior midbrain in mice lacking Pax5/BSAP. Cell. 1994 Dec 2;79(5):901–912. doi: 10.1016/0092-8674(94)90079-5. [DOI] [PubMed] [Google Scholar]
  88. Veiby O. P., Lyman S. D., Jacobsen S. E. Combined signaling through interleukin-7 receptors and flt3 but not c-kit potently and selectively promotes B-cell commitment and differentiation from uncommitted murine bone marrow progenitor cells. Blood. 1996 Aug 15;88(4):1256–1265. [PubMed] [Google Scholar]
  89. 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]
  90. Warne P. H., Viciana P. R., Downward J. Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature. 1993 Jul 22;364(6435):352–355. doi: 10.1038/364352a0. [DOI] [PubMed] [Google Scholar]
  91. Wassarman D. A., Therrien M., Rubin G. M. The Ras signaling pathway in Drosophila. Curr Opin Genet Dev. 1995 Feb;5(1):44–50. doi: 10.1016/s0959-437x(95)90052-7. [DOI] [PubMed] [Google Scholar]
  92. Wasylyk B., Hahn S. L., Giovane A. The Ets family of transcription factors. Eur J Biochem. 1993 Jan 15;211(1-2):7–18. doi: 10.1007/978-3-642-78757-7_2. [DOI] [PubMed] [Google Scholar]
  93. Wasylyk C., Maira S. M., Sobieszczuk P., Wasylyk B. Reversion of Ras transformed cells by Ets transdominant mutants. Oncogene. 1994 Dec;9(12):3665–3673. [PubMed] [Google Scholar]
  94. Weiss A., Littman D. R. Signal transduction by lymphocyte antigen receptors. Cell. 1994 Jan 28;76(2):263–274. doi: 10.1016/0092-8674(94)90334-4. [DOI] [PubMed] [Google Scholar]
  95. Wen Z., Zhong Z., Darnell J. E., Jr Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995 Jul 28;82(2):241–250. doi: 10.1016/0092-8674(95)90311-9. [DOI] [PubMed] [Google Scholar]
  96. Wildin R. S., Garvin A. M., Pawar S., Lewis D. B., Abraham K. M., Forbush K. A., Ziegler S. F., Allen J. M., Perlmutter R. M. Developmental regulation of lck gene expression in T lymphocytes. J Exp Med. 1991 Feb 1;173(2):383–393. doi: 10.1084/jem.173.2.383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Woodrow M. A., Rayter S., Downward J., Cantrell D. A. p21ras function is important for T cell antigen receptor and protein kinase C regulation of nuclear factor of activated T cells. J Immunol. 1993 May 1;150(9):3853–3861. [PubMed] [Google Scholar]
  98. Zhang X. F., Settleman J., Kyriakis J. M., Takeuchi-Suzuki E., Elledge S. J., Marshall M. S., Bruder J. T., Rapp U. R., Avruch J. Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1. Nature. 1993 Jul 22;364(6435):308–313. doi: 10.1038/364308a0. [DOI] [PubMed] [Google Scholar]
  99. Zhang X., Blenis J., Li H. C., Schindler C., Chen-Kiang S. Requirement of serine phosphorylation for formation of STAT-promoter complexes. Science. 1995 Mar 31;267(5206):1990–1994. doi: 10.1126/science.7701321. [DOI] [PubMed] [Google Scholar]
  100. Zheng B., Xue W., Kelsoe G. Locus-specific somatic hypermutation in germinal centre T cells. Nature. 1994 Dec 8;372(6506):556–559. doi: 10.1038/372556a0. [DOI] [PubMed] [Google Scholar]
  101. Zhuang Y., Cheng P., Weintraub H. B-lymphocyte development is regulated by the combined dosage of three basic helix-loop-helix genes, E2A, E2-2, and HEB. Mol Cell Biol. 1996 Jun;16(6):2898–2905. doi: 10.1128/mcb.16.6.2898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. Zhuang Y., Soriano P., Weintraub H. The helix-loop-helix gene E2A is required for B cell formation. Cell. 1994 Dec 2;79(5):875–884. doi: 10.1016/0092-8674(94)90076-0. [DOI] [PubMed] [Google Scholar]
  103. de Vries-Smits A. M., Burgering B. M., Leevers S. J., Marshall C. J., Bos J. L. Involvement of p21ras in activation of extracellular signal-regulated kinase 2. Nature. 1992 Jun 18;357(6379):602–604. doi: 10.1038/357602a0. [DOI] [PubMed] [Google Scholar]
  104. van Corven E. J., Hordijk P. L., Medema R. H., Bos J. L., Moolenaar W. H. Pertussis toxin-sensitive activation of p21ras by G protein-coupled receptor agonists in fibroblasts. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1257–1261. doi: 10.1073/pnas.90.4.1257. [DOI] [PMC free article] [PubMed] [Google Scholar]

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