Advertisement

Erythropoietin, Thrombopoietin and Leptin Receptors

  • Fabrice Gouilleux
Part of the Endocrine Updates book series (ENDO, volume 17)

Abstract

Erythropoietin (Epo), Thrombopoietin (Tpo) and leptin are hormones with distinct physiological properties. While the first two regulate survival, growth and differentiation of erythroid and megakaryocytic progenitors respectively, leptin is crucial for mammalian body weight regulation[1–3]. Receptors for these ligands have been isolated and well- characterized; they belong to the class I cytokine receptor family that includes most interleukin receptors involved in hematopoiesis as well as those for prolactin and growth hormone (see Chapter 7) which play an important role in metabolism and reproduction [4]. This family of receptors shares structural similarities both in their extracellular and intracellular domains and is characterized by the absence of an intrinsic tyrosine kinase. Nevertheless, ligand binding to this type of receptor induces the tyrosine phosphorylation of many cellular substrates including the receptor itself, leading to the activation of distinct signaling pathways. This review will focus first on the structure and biological properties of Epo, Tpo, leptin and their receptors. The second part will summarize the signal transduction pathways induced by these three ligands and their roles in cell proliferation, differentiation and survival.

Keywords

Tyrosine Phosphorylation Erythroid Progenitor Erythroid Differentiation Erythropoietin Receptor Megakaryocytic Differentiation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Lacombe, C. and Mayeux, P. 1998 Biology of erythropoietin. Haematologica 83: 724–32.PubMedGoogle Scholar
  2. 2.
    Wendling, F. 1999 Thrombopoietin: its role from early hematopoiesis to platelet production. Haematologica 84: 158–66.PubMedGoogle Scholar
  3. 3.
    White, D.W. and Tartaglia, L.A. 1996 Leptin and OB-R: body weight regulation by a cytokine receptor. Cytokine Growth Factor Rev 7: 303–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Bazan, J.F. 1990 Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci U S A 87: 6934–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Recny, M.A., Scoble, H.A. and Kim, Y. 1987 Structural characterization of natural human urinary and recombinant DNA-derived erythropoietin. Identification of desarginine 166 erythropoietin. J Biol Chem 262: 17156–63.PubMedGoogle Scholar
  6. 6.
    Bazan, J.F. 1990 Haemopoietic receptors and helical cytokines. Immunol Today 11: 350–4.Google Scholar
  7. 7.
    Wu, H., Liu, X., Jaenisch, R. and Lodish, H.F. 1995 Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell 83: 59–67.PubMedCrossRefGoogle Scholar
  8. 8.
    Methia, N., Louache, F., Vainchenker, W. and Wendling, F. 1993 Oligodeoxynucleotides antisense to the proto-oncogene c-mpl specifically inhibit in vitro megakaryocytopoiesis. Blood 82: 1395–401.PubMedGoogle Scholar
  9. 9.
    Wendling, F. and Vainchenker, W. 1998 Thrombopoietin and its receptor. Eur Cytokine Netw 9: 221–31.PubMedGoogle Scholar
  10. 10.
    Alexander, W.S. 1999 Thrombopoietin and the c-Mpl receptor: insights from gene targeting. Int J Biochem Cell Biol 31: 1027–35.PubMedCrossRefGoogle Scholar
  11. 11.
    Ingalls, A.M., Dickie, M.M. and Snell, G.D. 1996 Obese, a new mutation in the house mouse. Obes Res 4: 101.PubMedGoogle Scholar
  12. 12.
    Hummel, K.P., Dickie, M.M. and Coleman, D.L. 1966 Diabetes, a new mutation in the mouse. Science 153: 1127–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L. and Friedman, J.M. 1994 Positional cloning of the mouse obese gene and its human homologue. Nature 372: 42532.Google Scholar
  14. 14.
    Madej, T., Boguski, M.S. and Bryant, S.H. 1995 Threading analysis suggests that the obese gene product may be a helical cytokine. FEBS Lett 373: 13–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Fantuzzi, G. and Faggioni, R. 2000 Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol 68: 437–46.PubMedGoogle Scholar
  16. 16.
    D’Andrea, A.D., Lodish, H.F. and Wong, G.G. 1989 Expression cloning of the murine erythropoietin receptor. Cell 57: 277–85.PubMedCrossRefGoogle Scholar
  17. 17.
    Jones, S.S., D’Andrea, A.D., Haines, L.L. and Wong, G.G. 1990 Human erythropoietin receptor: cloning, expression, and biologic characterization. Blood 76: 31–5.PubMedGoogle Scholar
  18. 18.
    Constantinescu, S.N., Ghaffari, S. and Lodish, H.F. 1999 The Erythropoietin Receptor: Structure, Activation and Intracellular Signal Transduction. Trends Endocrinol Metab 10: 18–23.Google Scholar
  19. 19.
    Jiang, N., He, T.C., Miyajima, A. and Wojchowski, D.M. 1996 The boxi domain of the erythropoietin receptor specifies Janus kinase 2 activation and functions mitogenically within an interleukin 2 beta-receptor chimera. J Biol Chem 271: 16472–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Miura, O., D’Andrea, A., Kabat, D. and Ihle, J.N. 1991 Induction of tyrosine phosphorylation by the erythropoietin receptor correlates with mitogenesis. Mol Cell Biol 11: 4895–902.PubMedGoogle Scholar
  21. 21.
    Miura, O., Cleveland, J.L. and Ihle, J.N. 1993 Inactivation of erythropoietin receptor function by point mutations in a region having homology with other cytokine receptors. Mol Cell Biol 13: 1788–95.PubMedGoogle Scholar
  22. 22.
    Dusanter-Fourt, I., Casadevall, N., Lacombe, C., Muller, O., Billat, C., Fischer, S. and Mayeux, P. 1992 Erythropoietin induces the tyrosine phosphorylation of its own receptor in human erythropoietin-responsive cells. J Biol Chem 267: 10670–5.PubMedGoogle Scholar
  23. 23.
    Lin, C.S., Lim, S.K., D’Agati, V. and Costantini, F. 1996 Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis. Genes Dev 10: 154–64.PubMedCrossRefGoogle Scholar
  24. 24.
    Souyri, M., Vigon, I., Penciolelli, J.F., Heard, J.M., Tambourin, P. and Wendling, F. 1990 A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors. Cell 63: 1137–47.PubMedCrossRefGoogle Scholar
  25. 25.
    Skoda, R.C., Seldin, D.C., Chiang, M.K., Peichel, C.L., Vogt, T.F. and Leder, P. 1993 Murine c-mpl: a member of the hematopoietic growth factor receptor superfamily that transduces a proliferative signal. Embo J 12: 2645–53.PubMedGoogle Scholar
  26. 26.
    Vigon, I., Mornon, J.P., Cocault, L., Mitjavila, M.T., Tambourin, P., Gisselbrecht, S. and Souyri M. 1992 Molecular cloning and characterization of MPL, the human homolog of the v-mpl oncogene: identification of a member of the hematopoietic growth factor receptor superfamily. Proc Natl Acad Sci U S A 89: 5640–4.PubMedCrossRefGoogle Scholar
  27. 27.
    Souyri, M. 1998 Mpl: from an acute myeloproliferative virus to the isolation of the long sought thrombopoietin. Semin Hematol 35: 222–31.PubMedGoogle Scholar
  28. 28.
    Gurney, A.L., Wong, S.C., Henzel, W.J. and de Sauvage, F.J. 1995 Distinct regions of c-Mpl cytoplasmic domain are coupled to the JAK-STAT signal transduction pathway and Shc phosphorylation. Proc Natl Acad Sci U S A 92: 5292–6.Google Scholar
  29. 29.
    Drachman, J.G. and Kaushansky, K. 1997 Dissecting the thrombopoietin receptor: functional elements of the Mpl cytoplasmic domain. Proc Natl Acad Sci U S A 94, 2350–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Kaushansky, K. 1999 Thrombopoietin and hematopoietic stem cell development. Ann N Y Acad Sci 872: 314–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Ihara, K., Ishii, E., Eguchi, M., Takada, H., Suminoe, A., Good, R.A. and Hara, T. 1999 Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia. Proc Natl Acad Sci U S A 96: 3132–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Tartaglia, L.A., Dembski, M., Weng, X., Deng, N., Culpepper, J., Devos, R., Richards, G.J., Campfield, L.A., Clark, F.T., Deeds, J. and et al. 1995 Identification and expression cloning of a leptin receptor, OB-R. Cell 83: 1263–71.Google Scholar
  33. 33.
    Tartaglia, L.A. 1997 The leptin receptor. J Biol Chem 272: 6093–6.PubMedGoogle Scholar
  34. 34.
    Huang, L., Wang, Z. and Li, C. 2000 Modulation of Circulating Leptin Levels by Its Soluble Receptor. J Biol Chem.Google Scholar
  35. 35.
    Baumann, H., Morella, K.K., White, D.W., Dembski, M., Bailon, P.S., Kim, H., Lai, C.F. and Tartaglia, L.A. 1996 The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors. Proc Natl Acad Sci U S A 93: 8374–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Wang, Y., Kuropatwinski, K.K., White, D.W., Hawley, T.S., Hawley, R.G., Tartaglia, L.A. and Baumann, H. 1997 Leptin receptor action in hepatic cells. J Biol Chem 272: 16216–23.PubMedCrossRefGoogle Scholar
  37. 37.
    Bjorbaek, C., Uotani, S., da Silva, B. and Flier, J.S. 1997 Divergent signaling capacities of the long and short isoforms of the leptin receptor. J Biol Chem 272: 32686–95.PubMedCrossRefGoogle Scholar
  38. 38.
    Chen, H., Charlat, O., Tartaglia, L.A., Woolf, E.A., Weng, X., Ellis, S.J., Lakey, N.D., Culpepper, J., Moore, K.J., Breitbart, R.E., Duyk, G.M., Tepper, R.I. and Morgenstern, J.P. 1996 Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84: 491–5.PubMedCrossRefGoogle Scholar
  39. 39.
    Lee, G.H., Proenca, R., Montez, J.M., Carroll, K.M., Darvishzadeh, J.G., Lee, J.I. and Friedman, J.M. 1996 Abnormal splicing of the leptin receptor in diabetic mice. Nature 379: 632–5.PubMedCrossRefGoogle Scholar
  40. 40.
    Watowich, S.S., Yoshimura, A., Longmore, G.D., Hilton, D.J., Yoshimura, Y. and Lodish, H.F. 1992 Homodimerization and constitutive activation of the erythropoietin receptor. Proc Natl Acad Sci U S A 89: 2140–4.PubMedCrossRefGoogle Scholar
  41. 41.
    Watowich, S.S., Hilton, D.J. and Lodish, H.F. 1994 Activation and inhibition of erythropoietin receptor function: role of receptor dimerization. Mol Cell Biol 14: 3535–49.PubMedGoogle Scholar
  42. 42.
    Remy, I., Wilson, I.A. and Michnick, S.W. 1999 Erythropoietin receptor activation by a ligand-induced conformation change. Science 283: 990–3.PubMedCrossRefGoogle Scholar
  43. 43.
    Alexander, W.S., Metcalf, D. and Dunn, A.R. 1995 Point mutations within a dimer interface homology domain of c-Mpl induce constitutive receptor activity and tumorigenicity. Embo J 14: 5569–78.PubMedGoogle Scholar
  44. 44.
    Ihle, J.N., Thierfelder, W., Teglund, S., Stravapodis, D., Wang, D., Feng, J. and Parganas, E. 1998 Signaling by the cytokine receptor superfamily. Ann N Y Acad Sci 865: 1–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Pellegrini, S. and Dusanter-Fourt I. 1997 The structure, regulation and function of the Janus kinases (JAKs) and the signal transducers and activators of transcription ( STATs ). Eur J Biochem 248: 615–33.Google Scholar
  46. 46.
    Witthuhn, B.A., Quelle, F.W., Silvennoinen, O., Yi, T., Tang, B., Miura, O. and Ihle, J.N. 1993 JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell 74: 227–36.PubMedCrossRefGoogle Scholar
  47. 47.
    Drachman, J.G., Griffin, J.D. and Kaushansky, K. 1995 The c-Mpl ligand (thrombopoietin) stimulates tyrosine phosphorylation of Jak2, Shc, and c-Mpl. J Biol Chem 270: 4979–82.Google Scholar
  48. 48.
    Miyakawa, Y., Oda, A., Druker, B.J., Kato, T., Miyazaki, H., Handa, M. and Ikeda, Y. 1995 Recombinant thrombopoietin induces rapid protein tyrosine phosphorylation of Janus kinase 2 and Shc in human blood platelets. Blood 86: 23–7.PubMedGoogle Scholar
  49. 49.
    Ghilardi, N. and Skoda, R.C. 1997 The leptin receptor activates janus kinase 2 and signals for proliferation in a factor-dependent cell line. Mol Endocrinol 11: 393–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Banks, A.S., Davis, S.M., Bates, S.H. and Myers, M.G., Jr. 2000 Activation of downstream signals by the long form of the leptin receptor. J Biol Chem 275: 14563–72.PubMedCrossRefGoogle Scholar
  51. 51.
    Sattler, M., Durstin, M.A., Frank, D.A., Okuda, K., Kaushansky, K., Salgia, R. and Griffin, J.D. 1995 The thrombopoietin receptor c-MPL activates JAK2 and TYK2 tyrosine kinases. Exp Hematol 23: 1040–8.PubMedGoogle Scholar
  52. 52.
    Parganas, E., Wang, D., Stravopodis, D., Topham, D.J., Marine, J.C., Teglund, S., Vanin, E.F., Bodner, S., Colamonici, O.R., van Deursen, J.M., Grosveld, G. and Ihle, J.N. 1998 Jak2 is essential for signaling through a variety of cytokine receptors. Cell 93: 385–95.PubMedCrossRefGoogle Scholar
  53. 53.
    Neubauer, H., Cumano, A., Muller, M., Wu, H., Huffstadt, U. and Pfeffer, K. 1998 Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 93: 397–409.PubMedCrossRefGoogle Scholar
  54. 54.
    Drachman, J.G., Millett, K.M. and Kaushansky, K. 1999 Thrombopoietin signal transduction requires functional JAK2, not TYK2. J Biol Chem 274: 13480–4.PubMedCrossRefGoogle Scholar
  55. 55.
    Dorsch, M., Fan, P.D., Dania, N.N., Rothman, P.B. and Goff, S.P. 1997 The thrombopoietin receptor can mediate proliferation without activation of the Jak-STAT pathway. J Exp Med 186: 1947–55.PubMedCrossRefGoogle Scholar
  56. 56.
    Oda, A., Sawada, K., Druker, B.J., Ozaki, K., Takano, H., Koizumi, K., Fukada, Y., Handa, M., Koike, T. and Ikeda, Y. 1998 Erythropoietin induces tyrosine phosphorylation of Jak2, STATSA, and STAT5B in primary cultured human erythroid precursors. Blood 92: 443–51.PubMedGoogle Scholar
  57. 57.
    Miyakawa, Y., Oda, A., Druker, B.J., Miyazaki, H., Handa, M., Ohashi, H. and Ikeda, Y. 1996 Thrombopoietin induces tyrosine phosphorylation of Stat3 and Stat5 in human blood platelets. Blood 87: 439–46.PubMedGoogle Scholar
  58. 58.
    Pallard, C., Gouilleux, F., Benit, L., Cocault, L., Souyri, M., Levy, D., Groner, B., Gisselbrecht, S. and Dusanter-Fourt, I. 1995 Thrombopoietin activates a STATS-like factor in hematopoietic cells. Embo J 14: 2847–56.PubMedGoogle Scholar
  59. 59.
    Schulze, H., Ballmaier, M., Welte, K. and Germeshausen, M. 2000 Thrombopoietin induces the generation of distinct Statl, Stat3, Stat5a and Stat5b homo-and heterodimeric complexes with different kinetics in human platelets. Exp Hematol 28: 294–304.PubMedCrossRefGoogle Scholar
  60. 60.
    Ghilardi, N., Ziegler, S., Wiestner, A., Stoffel, R., Heim, M.H. and Skoda, R.C. 1996 Defective STAT signaling by the leptin receptor in diabetic mice. Proc Natl Acad Sci U S A 93: 6231–5.PubMedCrossRefGoogle Scholar
  61. 61.
    Rosenblum, C.I., Tota, M., Cully, D., Smith, T., Collum, R., Qureshi, S., Hess, J.F., Phillips, M.S., Hey, P.J., Vongs, A., Fong, T.M., Xu, L., Chen, H.Y., Smith, R.G., Schindler, C. and Van der Ploeg, L.H. 1996 Functional STAT 1 and 3 signaling by the leptin receptor ( OB-R); reduced expression of the rat fatty leptin receptor in transfected cells. Endocrinology 137: 5178–81.Google Scholar
  62. 62.
    Drachman, J.G., Rojnuckarin, P. and Kaushansky, K. 1999 Thrombopoietin signal transduction: studies from cell lines and primary cells. Methods 17: 238–49.PubMedCrossRefGoogle Scholar
  63. 63.
    Vaisse, C., Halaas, J.L., Horvath, C.M., Darnell, J.E., Jr., Stoffel, M. and Friedman, J.M. 1996 Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat Genet 14: 95–7.PubMedCrossRefGoogle Scholar
  64. 64.
    Damen, J.E., Wakao, H., Miyajima, A., Krosl, J., Humphries, R.K., Cutler, R.L. and Krystal, G. 1995 Tyrosine 343 in the erythropoietin receptor positively regulates erythropoietin-induced cell proliferation and Stat5 activation. Embo J 14: 5557–68.PubMedGoogle Scholar
  65. 65.
    Gobert, S., Chretien, S., Gouilleux, F., Muller, O., Pallard, C., Dusanter-Fourt, I., Groner, B., Lacombe, C., Gisselbrecht, S. and Mayeux, P. 1996 Identification of tyrosine residues within the intracellular domain of the erythropoietin receptor crucial for STATS activation. Embo J 15: 2434–41.PubMedGoogle Scholar
  66. 66.
    Klingmuller, U. 1997 The role of tyrosine phosphorylation in proliferation and maturation of erythroid progenitor cells-signals emanating from the erythropoietin receptor. Eur J Biochem 249: 637–47.PubMedCrossRefGoogle Scholar
  67. 67.
    Fujitani, Y., Hibi, M., Fukada, T., Takahashi-Tezuka, M., Yoshida, H., Yamaguchi, T., Sugiyama, K., Yamanaka, Y., Nakajima, K. and Hirano, T. 1997 An alternative pathway for STAT activation that is mediated by the direct interaction between JAK and STAT. Oncogene 14: 751–61.PubMedCrossRefGoogle Scholar
  68. 68.
    Chretien, S., Varlet, P., Verdier, F., Gobert, S., Cartron, J.P., Gisselbrecht, S., Mayeux, P. and Lacombe, C. 1996 Erythropoietin-induced erythroid differentiation of the human erythroleukemia cell line TF-1 correlates with impaired STAT5 activation. Embo J 15: 4174–81.PubMedGoogle Scholar
  69. 69.
    Bittorf, T., Seiler, J., Ludtke, B., Buchse, T., Jaster, R. and Brock, J. 2000 Activation of STAT5 during EPO-directed suppression of apoptosis. Cell Signal 12: 23–30.PubMedCrossRefGoogle Scholar
  70. 70.
    Iwatsuki, K., Endo, T., Misawa, H., Yokouchi, M., Matsumoto, A., Ohtsubo, M., Mori, K.J. and Yoshimura, A. 1997 STAT5 activation correlates with erythropoietin receptor-mediated erythroid differentiation of an erythroleukemia cell line. J Biol Chem 272: 8149–52.PubMedCrossRefGoogle Scholar
  71. 71.
    Gregory, R.C., Jiang, N., Todokoro, K., Crouse, J., Pacifici, R.E. and Wojchowski, D.M. 1998 Erythropoietin receptor and STAT5-specific pathways promote SKT6 cell hemoglobinization. Blood 92: 1104–18.PubMedGoogle Scholar
  72. 72.
    Teglund, S., McKay, C., Schuetz, E., van Deursen, J.M., Stravopodis, D., Wang, D., Brown, M., Bodner, S., Grosveld, G. and Ihle, J.N. 1998 Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 93: 841–50.PubMedCrossRefGoogle Scholar
  73. 73.
    Socolovsky, M., Fallon, A.E., Wang, S., Brugnara, C. and Lodish, H.F. 1999 Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/- mice: a direct role for StatS in Bcl-X(L) induction. Cell 98: 181–91.PubMedCrossRefGoogle Scholar
  74. 74.
    >Matsumura, I., Ishikawa, J., Nakajima, K., Oritani, K., Tomiyama, Y., Miyagawa, J., Kato, T., Miyazaki, H., Matsuzawa, Y. and Kanakura, Y. 1997 Thrombopoietininduced differentiation of a human megakaryoblastic leukemia cell line, CMK, involves transcriptional activation of p21(WAF1/Cipl) by STAT5. Mol Cell Biol 17: 2933–43.PubMedGoogle Scholar
  75. 75.
    Liu, R.Y., Fan, C., Garcia, R., Jove, R. and Zuckerman, K.S. 1999 Constitutive activation of the JAK2/STAT5 signal transduction pathway correlates with growth factor independence of megakaryocytic leukemic cell lines. Blood 93: 2369–79.PubMedGoogle Scholar
  76. 76.
    Hanazono, Y., Chiba, S., Sasaki, K., Mano, H., Yazaki, Y. and Hirai, H. 1993 Erythropoietin induces tyrosine phosphorylation and kinase activity of the c-fps/fes proto-oncogene product in human erythropoietin-responsive cells. Blood 81: 3193–6.PubMedGoogle Scholar
  77. 77.
    Duprez, V., Blank, U., Chretien, S., Gisselbrecht, S. and Mayeux, P. 1998 Physical and functional interaction between p72(syk) and erythropoietin receptor. J Biol Chem 273: 33985–90.PubMedCrossRefGoogle Scholar
  78. 78.
    Machide, M., Mano, H. and Todokoro, K. 1995 Interleukin 3 and erythropoietin induce association of Vav with Tec kinase through Tec homology domain. Oncogene 11: 619–25.PubMedGoogle Scholar
  79. 79.
    Tilbrook, P.A., Ingley, E., Williams, J.H., Hibbs, M.L. and Klinken, S.P. 1997 Lyn tyrosine kinase is essential for erythropoietin-induced differentiation of J2E erythroid cells. Embo J 16: 1610–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Chin, H., Arai, A., Wakao, H., Kamiyama, R., Miyasaka, N. and Miura, O. 1998 Lyn physically associates with the erythropoietin receptor and may play a role in activation of the StatS pathway. Blood 91: 3734–45.PubMedGoogle Scholar
  81. 81.
    Ingley, E., Sarna, M.K., Beaumont, J.G., Tilbrook, P.A., Tsai, S., Takemoto, Y., Williams, J.H. and Klinken, S.P. 2000 HS1 interacts with Lyn and is critical for erythropoietin-induced differentiation of erythroid cells. J Biol Chem 275: 7887–93.PubMedCrossRefGoogle Scholar
  82. 82.
    Yamashita, Y.,Miyazato, A.,Shimizu, R.,Komatsu, N., Miura, Y., Ozawa, K., Mano, H. 1997 Tec protein-tyrosine kinase is involved in the thrombopoietin/c-Mpl signaling pathway. Exp Hematol 25: 211–16.PubMedGoogle Scholar
  83. 83.
    Wu, H., Klingmuller, U., Besmer, P. and Lodish, H.F. 1995 Interaction of the erythropoietin and stem-cell-factor receptors. Nature 377 242–6.PubMedCrossRefGoogle Scholar
  84. 84.
    Wu, H., Klingmuller, U., Acurio, A., Hsiao, J.G. and Lodish, H.F. 1997 Functional interaction of erythropoietin and stem cell factor receptors is essential for erythroid colony formation. Proc Natl Acad Sci U S A 94: 1806–10.PubMedCrossRefGoogle Scholar
  85. 85.
    Kapur, R. and Zhang, L. 2001 A Novel Mechanism of Cooperation between c-Kit and Erythropoietin Receptor. Stem Cell Factor induces the expression of Stat5 and erythropoietin receptor, resulting in efficient proliferation and survival by erythropoietin. J Biol Chem 276: 1099–1106.PubMedCrossRefGoogle Scholar
  86. 86.
    Pircher, T.J., Geiger, J.N., Miller, C.P., Zhang, D., Gaines, P. and Wojchowski, D.M. 2000 Integrative signaling by minimal EPO receptor forms and C-kit. J Biol Chem.Google Scholar
  87. 87.
    Damen, J.E., Krosl, J., Morrison, D., Pelech, S. and Krystal, G. 1998 The hyperresponsiveness of cells expressing truncated erythropoietin receptors is contingent on insulin-like growth factor-1 in fetal calf serum. Blood 92: 425–33.PubMedGoogle Scholar
  88. 88.
    Datta, S.R., Brunet, A. and Greenberg, M.E. 1999 Cellular survival: a play in three Akts. Genes Dev 13: 2905–27.PubMedCrossRefGoogle Scholar
  89. 89.
    Uddin, S., Kottegoda, S., Stigger, D., Platanias, L.C. and Wickrema, A. 2000 Activation of the Akt/FKHRL1 pathway mediates the antiapoptotic effects of erythropoietin in primary human erythroid progenitors. Biochem Biophys Res Commun 275: 16–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Haseyama, Y., Sawada, K., Oda, A., Koizumi, K., Takano, H., Tarumi, T., Nishio, M., Handa, M., Ikeda, Y. and Koike, T. 1999 Phosphatidylinositol 3-kinase is involved in the protection of primary cultured human erythroid precursor cells from apoptosis. Blood 94: 1568–77.PubMedGoogle Scholar
  91. 91.
    Miura, O., Nakamura, N., Ihle, J.N. and Aoki, N. 1994 Erythropoietin-dependent association of phosphatidylinositol 3-kinase with tyrosine-phosphorylated erythropoietin receptor. J Biol Chem 269: 614–20.PubMedGoogle Scholar
  92. 92.
    Klingmuller, U., Wu, H., Hsiao, J.G., Toker, A., Duckworth, B.C., Cantley, L.C. and Lodish, H.F. 1997 Identification of a novel pathway important for proliferation and differentiation of primary erythroid progenitors. Proc Natl Acad Sci U S A 94: 3016–21.PubMedCrossRefGoogle Scholar
  93. 93.
    Shigematsu, H., Iwasaki, H., Otsuka, T., Ohno, Y., Arima, F. and Niho, Y. 1997 Role of the vav proto-oncogene product (Vav) in erythropoietin-mediated cell proliferation and phosphatidylinositol 3-kinase activity. J Biol Chem 272: 14334–40.PubMedCrossRefGoogle Scholar
  94. 94.
    Verdier, F., Chretien, S., Billat, C., Gisselbrecht, S., Lacombe, C. and Mayeux, P. 1997 Erythropoietin induces the tyrosine phosphorylation of insulin receptor substrate-2. An alternate pathway for erythropoietin-induced phosphatidylinositol 3-kinase activation. J Biol Chem 272: 26173–8.PubMedCrossRefGoogle Scholar
  95. 95.
    Lecoq-Lafon, C., Verdier, F., Fichelson, S., Chretien, S., Gisselbrecht, S., Lacombe, C. and Mayeux, P. 1999 Erythropoietin induces the tyrosine phosphorylation of GAB1 and its association with SHC, SHP2, SHIP, and phosphatidylinositol 3-kinase. Blood 93: 2578–85.PubMedGoogle Scholar
  96. 96.
    Wickrema, A., Uddin, S., Sharma, A., Chen, F., Alsayed, Y., Ahmad, S., Sawyer, S.T., Krystal, G., Yi, T., Nishada, K., Hibi, M., Hirano, T. and Platanias, L.C. 1999 Engagement of Gab and Gab2 in erythropoietin signaling. J Biol Chem 274: 24469–74.PubMedCrossRefGoogle Scholar
  97. 97.
    Sattler, M., Salgia, R., Durstin, M.A., Prasad, K.V. and Griffin, J.D. 1997 Thrombopoietin induces activation of the phosphatidylinositol-3’ kinase pathway and formation of a complex containing p85PI3K and the protooncoprotein p120CBL. J Cell Physiol 171: 28–33.PubMedCrossRefGoogle Scholar
  98. 98.
    Oda, A., Miyakawa, Y., Druker, B.J., Ozaki, K., Ohashi, H., Kato, T., Miyazaki, H., Handa, M., Ikebuchi, K. and Ikeda, Y. 1999 Thrombopoietin-induced signal transduction and potentiation of platelet activation. Thromb Haemost 82: 377–84.PubMedGoogle Scholar
  99. 99.
    Majka, M., Ratajczak, J., Gewirtz, A.M. and Ratajczak, M.Z. 2000 PI-3k-Akt axis inhibits apoptosis in normal human megakaryoblasts and is efficiently activated by thrombopoietin [In Process Citation]. Exp Hematol 28: 1492.CrossRefGoogle Scholar
  100. 100.
    Miyakawa, Y., Rojnuckarin, P., Habib, T. and Kaushansky, K. 2000 ) Thrombopoietin induces PI3K activation through SHP2, Gab and IRS proteins in BaF3 cells and primary murine megakaryocytes. J Biol Chem.Google Scholar
  101. 101.
    Bouscary, D., Lecoq-Lafon, C., Chretien, S., Zompi S., Fichelson S., Muller, O., Porteu F., Dusanter, I., Gisselbrecht, S., Mayeux, P. and Lacombe, C. Role of Gab proteins in phosphatidyl-inositol 3-kinase activation by thrombopoietin (Tpo). SubmittedGoogle Scholar
  102. 102.
    Kellerer, M., Koch, M., Metzinger, E., Mushack, J., Capp, E. and Haring, H.U. 1997 Leptin activates PI-3 kinase in C2C12 myotubes via janus kinase-2 (JAK-2) and insulin receptor substrate-2 (IRS-2) dependent pathways. Diabetologia 40: 1358–62.PubMedCrossRefGoogle Scholar
  103. 103.
    Harvey, J., McKay, N.G., Walker, K.S., Van der Kaay, J., Downes, C.P. and Ashford, M.L. 2000 Essential role of phosphoinositide 3-kinase in leptin-induced K(ATP) channel activation in the rat CRI-G1 insulinoma cell line. J Biol Chem 275: 4660–9.PubMedCrossRefGoogle Scholar
  104. 104.
    Ren, H.Y., Komatsu, N., Shimizu, R., Okada, K. and Miura, Y. 1994 Erythropoietin induces tyrosine phosphorylation and activation of phospholipase C-gamma 1 in a human erythropoietin-dependent cell line. J Biol Chem 269: 19633–8.PubMedGoogle Scholar
  105. 105.
    Boudot, C., Petitfrere, E., Kadri, Z., Chretien, S., Mayeux, P., Haye, B. and Billat, C. 1999 Erythropoietin induces glycosylphosphatidylinositol hydrolysis. Possible involvement of phospholipase c-gamma(2). J Biol Chem 274: 33966–72.PubMedCrossRefGoogle Scholar
  106. 106.
    Damen, J.E., Liu, L., Rosten, P., Humphries, R.K., Jefferson, A.B., Majerus, P.W. and Krystal, G. 1996 The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5phosphatase. Proc Natl Acad Sci U S A 93: 1689–93.PubMedCrossRefGoogle Scholar
  107. 107.
    Liu, L., Damen, J.E., Cutler, R.L. and Krystal, G. 1994 Multiple cytokines stimulate the binding of a common 145-kilodalton protein to She at the Grb2 recognition site of Shc. Mol Cell Biol 14: 6926–35.PubMedGoogle Scholar
  108. 108.
    Mason, J.M., Beattie, B.K., Liu, Q., Dumont, D.J. and Barber, D.L. 2000 The SH2 inositol 5-phosphatase Shipl is recruited in an SH2-dependent manner to the erythropoietin receptor. J Biol Chem 275: 4398–406.PubMedCrossRefGoogle Scholar
  109. 109.
    Bergelson, S., Klingmuller, U., Socolovsky, M., Hsiao, J.G. and Lodish, H.F. 1998 Tyrosine residues within the intracellular domain of the erythropoietin receptor mediate activation of AP-1 transcription factors. J Biol Chem 273: 2396–401.PubMedCrossRefGoogle Scholar
  110. 110.
    Helgason, C.D., Damen, J.E., Rosten, P., Grewal, R., Sorensen, P., Chappel, S.M., Borowski, A., Jirik, F., Krystal, G. and Humphries, R.K. 1998 Targeted disruption of SHIP leads to hemopoietic perturbations, lung pathology, and a shortened life span. Genes Dev 12: 1610–20.PubMedCrossRefGoogle Scholar
  111. 111.
    Marais, R. and Marshall, C.J. 1996 Control of the ERK MAP kinase cascade by Ras and Raf. Cancer Sury 27: 101–25.Google Scholar
  112. 112.
    Miura, Y., Miura, O., Ihle, J.N. and Aoki, N. 1994 Activation of the mitogen-activated protein kinase pathway by the erythropoietin receptor. J Biol Chem 269: 29962–9.PubMedGoogle Scholar
  113. 113.
    He, T.C., Jiang, N., Zhuang, H. and Wojchowski, D.M. 1995 Erythropoietin-induced recruitment of Shc via a receptor phosphotyrosine-independent, Jak2-associated pathway. J Biol Chem 270: 11055–61.PubMedCrossRefGoogle Scholar
  114. 114.
    Barber, D.L., Corless, C.N., Xia, K., Roberts, T.M. and D’Andrea, A.D. 1997 Erythropoietin activates Rafl by an Shc-independent pathway in CTLL-EPO-R cells. Blood 89: 55–64.PubMedGoogle Scholar
  115. 115.
    Nosaka, Y., Arai, A., Miyasaka, N. and Miura, O. 1999 CrkL mediates Ras-dependent activation of the Raf/ERK pathway through the guanine nucleotide exchange factor C3G in hematopoietic cells stimulated with erythropoietin or interleukin-3. J Biol Chem 274: 30154–62.PubMedCrossRefGoogle Scholar
  116. 116.
    Sakamoto, H., Kitamura, T. and Yoshimura, A. 2000 Mitogen-activated Protein Kinase Plays an Essential Role in the Erythropoietin-dependent Proliferation of CTLL-2 Cells. J Biol Chem 275: 35857–35862.PubMedCrossRefGoogle Scholar
  117. 117.
    Jacobs-Helber, S.M., Ryan, J.J. and Sawyer, S.T. 2000 JNK and p38 are activated by erythropoietin (EPO) but are not induced in apoptosis following EPO withdrawal in EPOdependent HCD57 cells. Blood 96: 933–40.PubMedGoogle Scholar
  118. 118.
    Alexander, W.S., Maurer, A.B., Novak, U. and Harrison-Smith, M. 1996 Tyrosine-599 of the c-Mpl receptor is required for Shc phosphorylation and the induction of cellular differentiation. Embo J 15: 6531–40.PubMedGoogle Scholar
  119. 119.
    Hill, R.J., Zozulya, S., Lu, Y.L., Hollenbach, P.W., Joyce-Shaikh, B., Bogenberger, J. and Gishizky, M.L. 1996 Differentiation induced by the c-Mpl cytokine receptor is blocked by mutant Shc adaptor protein. Cell Growth Differ 7: 1125–34.PubMedGoogle Scholar
  120. 120.
    Challier, C., Cocault, L., Flon, M., Pauchard, M., Porteu, F., Gisselbrecht, S. and Souyri, M. 2000 A new feature of Mpl receptor: ligand-induced transforming activity in FRE rat fibroblasts. Oncogene 19: 2033–42.PubMedCrossRefGoogle Scholar
  121. 121.
    Porteu, F., Rouyez, M.C., Cocault, L., Benit, L., Charon, M., Picard, F., Gisselbrecht, S., Souyri, M. and Dusanter-Fourt, I. 1996 Functional regions of the mouse thrombopoietin receptor cytoplasmic domain: evidence for a critical region which is involved in differentiation and can be complemented by erythropoietin. Mol Cell Biol 16: 2473–82.PubMedGoogle Scholar
  122. 122.
    Rouyez, M.C., Boucheron, C., Gisselbrecht, S., Dusanter-Fourt, I. and Porteu, F. 1997 Control of thrombopoietin-induced megakaryocytic differentiation by the mitogenactivated protein kinase pathway. Mol Cell Biol 17: 4991–5000.PubMedGoogle Scholar
  123. 123.
    Matsumura, I., Nakajima, K., Wakao, H., Hattori, S., Hashimoto, K., Sugahara, H., Kato, T., Miyazaki, H., Hirano, T. and Kanakura, Y. 1998 Involvement of prolonged ras activation in thrombopoietin-induced megakaryocytic differentiation of a human factor-dependent hematopoietic cell line. Mol Cell Biol 18: 4282–90.PubMedGoogle Scholar
  124. 124.
    Rojnuckarin, P., Drachman, J.G. and Kaushansky, K. 1999 Thrombopoietin-induced activation of the mitogen-activated protein kinase (MAPK) pathway in normal megakaryocytes: role in endomitosis. Blood 94: 1273–82.PubMedGoogle Scholar
  125. 125.
    Fichelson, S., Freyssinier, J.M., Picard, F., Fontenay-Roupie, M., Guesnu, M., Cherai, M., Gisselbrecht, S. and Porteu, F. 1999 Megakaryocyte growth and development factor-induced proliferation and differentiation are regulated by the mitogen-activated protein kinase pathway in primitive cord blood hematopoietic progenitors. Blood 94: 1601–13.PubMedGoogle Scholar
  126. 126.
    Luoh, S.M., Stefanich, E., Solar, G., Steinmetz, H., Lipari, T., Pestina, T.I., Jackson, C.W. and de Sauvage, F.J. 2000 Role of the distal half of the c-Mpl intracellular domain in control of platelet production by thrombopoietin in vivo. Mol Cell Biol 20: 507–15.PubMedCrossRefGoogle Scholar
  127. 127.
    Tanabe, K., Okuya, S., Tanizawa, Y., Matsutani, A. and Oka, Y. 1997 Leptin induces proliferation of pancreatic beta cell line MIN6 through activation of mitogen-activated protein kinase. Biochem Biophys Res Commun 241: 765–8.PubMedCrossRefGoogle Scholar
  128. 128.
    Takahashi, Y., Okimura, Y., Mizuno, I., Iida, K., Takahashi, T., Kaji, H., Abe, H. and Chihara, K. 1997 Leptin induces mitogen-activated protein kinase-dependent proliferation of C3H10T1/2 cells. J Biol Chem 272: 12897–900.PubMedCrossRefGoogle Scholar
  129. 129.
    Bjorbak, C., Buchholz, R.M., Davis, S.M., Bates, S.H., Pierroz, D.D., Gu, H., Neel, B.G., Myers, M.G., Jr. and Flier, J.S. 2000 The role of SHP-2 in MAPK activation by leptin receptors. J Biol Chem.Google Scholar
  130. 130.
    Berti, L. and Gammeltoft, S. 1999 Leptin stimulates glucose uptake in C2C12 muscle cells by activation of ERK2. Mol Cell Endocrinol 157: 121–30.PubMedCrossRefGoogle Scholar
  131. 131.
    Nagata, Y., Moriguchi, T., Nishida, E. and Todokoro, K. 1997 Activation of p38 MAP kinase pathway by erythropoietin and interleukin-3. Blood 90: 929–34.PubMedGoogle Scholar
  132. 132.
    Nagata, Y., Nishida, E. and Todokoro, K. 1997 Activation of JNK signaling pathway by erythropoietin, thrombopoietin, and interleukin-3. Blood 89: 2664–9.PubMedGoogle Scholar
  133. 133.
    Ezumi, Y., Nishida, E., Uchiyama, T. and Takayama, H. 1999 Thrombopoietin potentiates agonist-stimulated activation of p38 mitogen-activated protein kinase in human platelets. Biochem Biophys Res Commun 261: 58–63.PubMedCrossRefGoogle Scholar
  134. 134.
    Nagata, Y., Takahashi, N., Davis, R.J. and Todokoro, K. 1998 Activation of p38 MAP kinase and JNK but not ERK is required for erythropoietin-induced erythroid differentiation. Blood 92: 1859–69.PubMedGoogle Scholar
  135. 135.
    Tamura, K., Sudo, T., Senftleben, U., Dadak, A.M., Johnson, R. and Karin, M. 2000 Requirement for p38alpha in erythropoietin expression: a role for stress kinases in erythropoiesis. Cell 102: 221–31.PubMedCrossRefGoogle Scholar
  136. 136.
    Feller, S.M., Posern, G., Voss, J., Kardinal, C., Sakkab, D., Zheng, J. and Knudsen, B.S. 1998 Physiological signals and oncogenesis mediated through Crk family adapter proteins. J Cell Physiol 177: 535–52.PubMedCrossRefGoogle Scholar
  137. 137.
    Chin, H., Saito, T., Arai, A., Yamamoto, K., Kamiyama, R., Miyasaka, N. and Miura, O. 1997 Erythropoietin and IL-3 induce tyrosine phosphorylation of CrkL and its association with Shc, SHP-2, and Cbl in hematopoietic cells. Biochem Biophys Res Commun 239: 412–7.PubMedCrossRefGoogle Scholar
  138. 138.
    Arai, A., Nosaka, Y., Kanda, E., Yamamoto, K., Miyasaka, N. and Miura, O. 2000 Rapt is activated by erythropoietin or interleukin-3 and is involved in regulation of {beta} 1 integrin-mediated hematopoietic cell adhesion. J Biol Chem.Google Scholar
  139. 139.
    Ota, J., Kimura, F., Sato, K., Wakimoto, N., Nakamura, Y., Nagata, N., Suzu, S., Yamada, M., Shimamura, S. and Motoyoshi, K. 1998 Association of CrkL with STAT5 in hematopoietic cells stimulated by granulocyte-macrophage colony-stimulating factor or erythropoietin. Biochem Biophys Res Commun 252: 779–86.PubMedCrossRefGoogle Scholar
  140. 140.
    Oda, A., Wakao, H., Fujihara, M., Ozaki, K., Komatsu, N., Tanaka, S., Ikeda, H., Miyajima, A. and Ikebuchi, K. 2000 Thrombopoietin and interleukin-2 induce association of CRK with STAT5 [In Process Citation]. Biochem Biophys Res Commun 278: 299–305.PubMedCrossRefGoogle Scholar
  141. 141.
    Barber, D.L., Mason, J.M., Fukazawa, T., Reedquist, K.A., Druker, B.J., Band, H. and D’Andrea, A.D 1997 Erythropoietin and interleukin-3 activate tyrosine phosphorylation of CBL and association with CRK adaptor proteins. Blood 89: 3166–74.PubMedGoogle Scholar
  142. 142.
    Rudd, C.E. and Schneider, H 2000 Lymphocyte signaling: Cbl sets the threshold for autoimmunity. Curr Biol 10: R344–7.PubMedCrossRefGoogle Scholar
  143. 143.
    Hanazono, Y., Odai, H., Sasaki, K., Iwamatsu, A., Yazaki, Y. and Hirai, H 1996 Proto-oncogene products Vav and c-Cbl are involved in the signal transduction through Grb2/Ash in hematopoietic cells. Acta Haematol 95: 236–42.PubMedCrossRefGoogle Scholar
  144. 144.
    Sasaki, K., Odai, H., Hanazono, Y., Ueno, H., Ogawa, S., Langdon, W.Y., Tanaka, T., Miyagawa, K., Mitani, K., Yazaki, Y. and et al. 1995 TPO/c-mpl ligand induces tyrosine phosphorylation of multiple cellular proteins including proto-oncogene products, Vav and c-Cbl, and Ras signaling molecules. Biochem Biophys Res Commun 216: 338–47.Google Scholar
  145. 145.
    Brizzi, M.F., Dentelli, P., Lanfrancone, L., Rosso, A., Pelicci, P.G. and Pegoraro, L. 1996 Discrete protein interactions with the Grb2/c-Cbl complex in SCF- and TPOmediated myeloid cell proliferation. Oncogene 13: 2067–76.PubMedGoogle Scholar
  146. 146.
    Oda, A., Ozaki, K., Druker, B.J., Miyakawa, Y., Miyazaki, H., Handa, M., Morita, H., Ohashi, H. and Ikeda, Y. 1996 p120c-cbl is present in human blood platelets and is differentially involved in signaling by thrombopoietin and thrombin. Blood 88: 1330–8.Google Scholar
  147. 147.
    Wakioka, T., Sasaki, A., Mitsui, K., Yokouchi, M., Inoue, A., Komiya, S. and Yoshimura, A. 1999 APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with cCbl. Leukemia 13: 760–7.PubMedCrossRefGoogle Scholar
  148. 148.
    Lumelsky, N.L. and Schwartz, B.S. 1997 Protein kinase C in erythroid and megakaryocytic differentiation: possible role in lineage determination. Biochim Biophys Acta 1358: 79–92.PubMedCrossRefGoogle Scholar
  149. 149.
    Patrone, M., Pessino, A., Passalacqua, M., Sparatore, B., Melloni, E. and Pontremoli, S. 1996 Correlation between levels of delta protein kinase C and resistance to differentiation in mutine erythroleukemia cells. Biochem Biophys Res Commun 220: 2630.CrossRefGoogle Scholar
  150. 150.
    Patrone, M., Pessino, A., Passalacqua, M., Sparatore, B., Melloni, E. and Pontremoli, S. 1994 Protein kinase C isoforms in mutine erythroleukemia cells and their involvement in the differentiation process. FEBS Lett 344: 91–5.PubMedCrossRefGoogle Scholar
  151. 151.
    Li, Y., Davis, K.L. and Sytkowski, A.J. 1996 Protein kinase C-epsilon is necessary for erythropoietin’s up-regulation of c-myc and for factor-dependent DNA synthesis. Evidence for discrete signals for growth and differentiation. J Biol Chem 271: 27025–30.Google Scholar
  152. 152.
    Myklebust, J.H., Smeland, E.B., Josefsen, D. and Sioud, M. 2000 Protein kinase C-alpha isoform is involved in erythropoietin-induced erythroid differentiation of CD34(+) progenitor cells from human bone marrow. Blood 95: 510–8.PubMedGoogle Scholar
  153. 153.
    von Lindern, M., Amelsvoort, M.P., van Dijk, T., Deiner, E., van Den Akker, E., van Ernst-De Vries, S., Willems, P., Beug, H. and Lowenberg, B. 2000 Protein kinase C alpha controls erythropoietin receptor signaling [In Process Citation]. J Biol Chem 275: 34719–27.CrossRefGoogle Scholar
  154. 154.
    Hong, Y., Dumenil, D., van der Loo, B., Goncalves, F., Vainchenker, W. and Erusalimsky, J.D. 1998 Protein kinase C mediates the mitogenic action of thrombopoietin in c-Mpl-expressing UT-7 cells. Blood 91: 813–22.PubMedGoogle Scholar
  155. 155.
    Kunitama, M., Shimizu, R., Yamada, M., Kato, T., Miyazaki, H., Okada, K., Miura, Y. and Komatsu, N. 1997 Protein kinase C and c-myc gene activation pathways in thrombopoietin signal transduction. Biochem Biophys Res Commun 231: 290–4.PubMedCrossRefGoogle Scholar
  156. 156.
    Ezumi, Y., Uchiyama, T. and Takayama, H. 1998 Thrombopoietin potentiates the protein-kinase-C-mediated activation of mitogen-activated protein kinase/ERK kinases and extracellular signal-regulated kinases in human platelets. Eur J Biochem 258: 976–85.PubMedCrossRefGoogle Scholar
  157. 157.
    Bignon, J.S. and Siminovitch, K.A. 1994 Identification of PTP1C mutation as the genetic defect in motheaten and viable motheaten mice: a step toward defining the roles of protein tyrosine phosphatases in the regulation of hemopoietic cell differentiation and function. Clin Immunol Immunopathol 73: 168–79.PubMedCrossRefGoogle Scholar
  158. 158.
    Klingmuller, U., Lorenz, U., Cantley, L.C., Neel, B.G. and Lodish, H.F. 1995 Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell 80: 729–38.PubMedCrossRefGoogle Scholar
  159. 159.
    Bittorf, T., Seiler, J., Zhang, Z., Jaster, R. and Brock, J. 1999 SHP1 protein tyrosine phosphatase negatively modulates erythroid differentiation and suppression of apoptosis in J2E erythroleukemic cells. Biol Chem 380: 1201–9.PubMedCrossRefGoogle Scholar
  160. 160.
    Yoshimura, A. and Misawa, H. 1998 Physiology and function of the erythropoietin receptor. Curr Opin Hematol 5: 171–6.PubMedCrossRefGoogle Scholar
  161. 161.
    Tauchi, T., Damen, J.E., Toyama, K., Feng, G.S., Broxmeyer, H.E. and Krystal, G. 1996 Tyrosine 425 within the activated erythropoietin receptor binds Syp, reduces the erythropoietin required for Syp tyrosine phosphorylation, and promotes mitogenesis. Blood 87: 4495–501.PubMedGoogle Scholar
  162. 162.
    Tauchi, T., Feng, G.S., Shen, R., Hoatlin, M., Bagby, G.C., Jr., Kabat, D., Lu, L. and Broxmeyer, H.E. 1995 Involvement of SH2-containing phosphotyrosine phosphatase Syp in erythropoietin receptor signal transduction pathways. J Biol Chem 270: 5631–5.PubMedCrossRefGoogle Scholar
  163. 163.
    Carpenter, L.R., Farruggella, T.J., Symes, A., Karow, M.L., Yancopoulos, G.D. and Stahl, N. 1998 Enhancing leptin response by preventing SH2-containing phosphatase 2 interaction with Ob receptor. Proc Natl Acad Sci U S A 95: 6061–6.PubMedCrossRefGoogle Scholar
  164. 164.
    Yoshimura, A. 1998 The CIS family: negative regulators of JAK-STAT signaling. Cytokine Growth Factor Rev 9: 197–204.PubMedCrossRefGoogle Scholar
  165. 165.
    Yoshimura, A., Ohkubo, T., Kiguchi, T., Jenkins, N.A., Gilbert, D.J., Copeland, N.G., Hara, T. and Miyajima, A. 1995 A novel cytokine-inducible gene CIS encodes an SH2containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. Embo J 14: 2816–26.PubMedGoogle Scholar
  166. 166.
    Verdier, F., Rabionet, R., Gouilleux, F., Beisenherz-Huss, C., Varlet, P., Muller, O., Mayeux, P., Lacombe, C., Gisselbrecht, S. and Chretien, S. 1998 A sequence of the CIS gene promoter interacts preferentially with two associated STAT5A dimers: a distinct biochemical difference between STAT5A and STAT5B. Mol Cell Biol 18: 5852–60.PubMedGoogle Scholar
  167. 167.
    Matsumoto, A., Masuhara, M., Mitsui, K., Yokouchi, M., Ohtsubo, M., Misawa, H., Miyajima, A. and Yoshimura, A. 1997 CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation. Blood 89: 3148–54.PubMedGoogle Scholar
  168. 168.
    Matsumoto, A., Seki, Y., Kubo, M., Ohtsuka, S., Suzuki, A., Hayashi, I., Tsuji, K., Nakahata, T., Okabe, M., Yamada, S. and Yoshimura, A. 1999 Suppression of STAT5 functions in liver, mammary glands, and T cells in cytokine-inducible SH2-containing protein 1 transgenic mice. Mol Cell Biol 19: 6396–407.PubMedGoogle Scholar
  169. 169.
    Verdier, F., Chretien, S., Muller, O., Varlet, P., Yoshimura, A., Gisselbrecht, S., Lacombe, C. and Mayeux, P. 1998 Proteasomes regulate erythropoietin receptor and signal transducer and activator of transcription 5 (STAT5) activation. Possible involvement of the ubiquitinated Cis protein. J Biol Chem 273: 28185–90.Google Scholar
  170. 170.
    Okabe, S., Tauchi, T., Morita, H., Ohashi, H., Yoshimura, A. and Ohyashiki, K. 1999 Thrombopoietin induces an SH2-containing protein, CIS1, which binds to Mpl: involvement of the ubiquitin proteosome pathway. Exp Hematol 27: 1542–7.PubMedCrossRefGoogle Scholar
  171. 171.
    Yasukawa, H., Misawa, H., Sakamoto, H., Masuhara, M., Sasaki, A., Wakioka, T., Ohtsuka, S., Imaizumi, T., Matsuda, T., Ihle, J.N. and Yoshimura, A. 1999 The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. Embo J 18: 1309–20.PubMedCrossRefGoogle Scholar
  172. 172.
    Sasaki, A., Yasukawa, H., Shouda, T., Kitamura, T., Dikic, I. and Yoshimura, A. 2000 CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2 [In Process Citation]. J Biol Chem 275: 29338–47.PubMedCrossRefGoogle Scholar
  173. 173.
    Marine, J.C., McKay, C., Wang, D., Topham, D.J., Parganas, E., Nakajima, H., Pendeville, H., Yasukawa, H., Sasaki, A., Yoshimura, A. and Ihle, J.N. 1999 SOCS3 is essential in the regulation of fetal liver erythropoiesis. Cell 98: 617–27.PubMedCrossRefGoogle Scholar
  174. 174.
    Alexander, W.S., Starr, R., Fenner, J.E., Scott, C.L., Handman, E., Sprigg, N.S., Corbin, J•E., Cornish, A.L., Darwiche, R., Owczarek, C.M., Kay, T.W., Nicola, N.A., Hertzog, P.J., Metcalf, D. and Hilton, D.J. 1999 SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 98: 597–608.PubMedCrossRefGoogle Scholar
  175. 175.
    Wang, Q., Miyakawa, Y., Fox, N. and Kaushansky, K. 2000 Interferon-alpha directly represses megakaryopoiesis by inhibiting thrombopoietin-induced signaling through induction of SOCS-1. Blood 96: 2093–9.PubMedGoogle Scholar
  176. 176.
    Bjorbaek, C.,Elmquist, J. K., Frantz, J. D., Shoelson, S. E., Flier, J. S. 1998 Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol. Cellules, 1: 619–25CrossRefGoogle Scholar
  177. 177.
    Bjorbaek, C., El-Haschimi, K., Frantz, J.D. and Flier, J.S. 1999 The role of SOCS-3 in leptin signaling and leptin resistance. J Biol Chem 274: 30059–65.PubMedCrossRefGoogle Scholar
  178. 178.
    Bjorbak, C., Lavery, H.J., Bates, S.H., Olson, R.K., Davis, S.M., Flier, J.S. and Myers, M.G., Jr. 2000 SOCS3 mediates feedback inhibition of the leptin receptor via tyr985 [In Process Citation]. J Biol Chem 275: 40649–57.PubMedCrossRefGoogle Scholar
  179. 179.
    Stoffel, R., Ziegler, S., Ghilardi, N., Ledermann, B., de Sauvage, F.J. and Skoda, R.C. 1999 Permissive role of thrombopoietin and granulocyte colony-stimulating factor receptors in hematopoietic cell fate decisions in vivo. Proc Natl Acad Sci U S A 96: 698702.Google Scholar
  180. 180.
    Socolovsky, M., Fallon, A.E. and Lodish, H.F. 1998 The prolactin receptor rescues EpoR-/- erythroid progenitors and replaces EpoR in a synergistic interaction with c-kit. Blood 92: 1491–6.PubMedGoogle Scholar
  181. 181.
    Socolovsky, M., Dusanter-Fourt, I. and Lodish, H.F. 1997 The prolactin receptor and severely truncated erythropoietin receptors support differentiation of erythroid progenitors. J Biol Chem 272: 14009–12.PubMedCrossRefGoogle Scholar
  182. 182.
    Chida, D., Miura, O., Yoshimura, A. and Miyajima, A. 1999 Role of cytokine signaling molecules in erythroid differentiation of mouse fetal liver hematopoietic cells: functional analysis of signaling molecules by retrovirus-mediated expression. Blood 93: 1567–78.PubMedGoogle Scholar
  183. 183.
    Fichelson, S., Chretien, S., Rokicka-Piotrowicz, M., Bouhanik, S., Gisselbrecht, S., Mayeux, P. and Lacombe, C. 1999 Tyrosine residues of the erythropoietin receptor are dispensable for erythroid differentiation of human CD34+ progenitors. Biochem Biophys Res Commun 256: 685–91.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Fabrice Gouilleux
    • 1
  1. 1.Laboratory of Immunology, School of MedicineUniversity of Picardie-Jules VerneAmiensFrance

Personalised recommendations