Abstract
The recent identification and characterization of the c-mpl proto-oncogene set off an explosive wave of research that has advanced our understanding of megakaryocyte and platelet biology immensely. The mechanisms by which this member of the hemopoietic cytokine receptor family promotes the survival, proliferation, and differentiation of megakaryocytic progenitors resulting in platelet production will require many years, if not decades, to unravel completely. However, important insights into this process have already been achieved, and will be reviewed in this chapter.
Keywords
- Tyrosine Phosphorylation
- Cytokine Receptor
- Hemopoietic Cell
- Erythropoietin Receptor
- Induce Tyrosine Phosphorylation
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References
Wendling F, Varlet P, Charon M, Tambourin P. MPLV: a retrovirus complex inducing an acute myeloproliferative leukemic disorder in mice. Virology. 1986; 149: 242–246.
Souyri M, Vigon I, Penciolelli JF, Heard JM, Tambourin P, Wendling F. A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors. Cell. 1990; 63: 1137–1147.
Vigon I, Mornon JP, Cocault L, et al. 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 USA. 1992; 89: 5640–5644.
Skoda RC, Seldin DC, Chiang MK, Peichel CL, Vogt TF, Leder P. Murine c-mpl: a member of the hematopoietic growth factor receptor superfamily that transduces a proliferative signal. EMBO J. 1993; 12: 2645–2653.
Vigon I, Florindo C, Fichelson S, et al. Characterization of the murine Mpl proto-oncogene, a member of the hematopoietic cytokine receptor family: molecular cloning, chromosomal location and evidence for a function in cell growth. Oncogene. 1993; 8: 2607–2615.
Martin P, Papayannopoulou T. HEL cells: a new human erythroleukemia cell line with spontaneous and induced globin expression. Science. 1982; 216: 1233–1235.
Long MW, Heffner CH, Williams JL, Peters C, Prochownik EV. Regulation of megakaryocyte phenotype in human erythroleukemia cells. J Clin Invest. 1990; 85: 1072–1084.
Hong Y, Martin JF, Vainchenker W, Erusalimsky JD. Inhibition of Protein Kinase C suppresses megakaryocytic differentiation and stimulates erythroid differentiation in HEL cells. Blood. 1994; 87: 123–131.
Methia N, Louache F, Vainchenker W, Wendling F. Oligodeoxynucleotides antisense to the proto-oncogene c-mpl specifically inhibit in vitro megakaryocytopoiesis. Blood. 1993; 82: 1395–1401.
Vigon I, Dreyfus F, Melle J, et al. Expression of the c-mpl proto-oncogene in human hematologic malignancies. Blood. 1993; 82: 877–883.
Matsumura I, Kanakura Y, Kato T, et al. Growth response of acute myeloblasts leukemia cells to recombinant human thrombopoietin. Blood. 1995; 86: 703–709.
Berardi AC, Wang A, Levine JD, Lopez P, Scadden DT. Functional isolation and characterization of human hematopoietic stem cells. Science. 1995; 267: 104–108.
Debili N, Wendling F, Cosman D, et al. The mpl receptor is expressed in the megakaryocytic lineage from late progenitors to platelets. Blood. 1995; 85: 391–401.
Wolf NS, Kone A, Priestley GV, Bartelmez SH. In vivo and in vitro characterization of long-term repopulating primitive hematopoietic cells isolated by sequential Hoechst 33342-rhodamine 123 FACS selection. Exp Hematol. 1993; 21: 614–622.
Sitnicka E, Lin N, Priestley GV, et al. The effect of thrombopoietin on the proliferation and differentiation of murine hematopoietic stem cells. Blood. 1995; 86: 419a (abstract no 1664).
Kobayashi M, Laver JH, Kato T, Miyazaki H, Ogawa M. Recombinant human thrombopoietin (mpl ligand) enhances proliferation of erythroid progenitors. Blood. 1995; 86: 2494–2499.
Bazan JF. Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci USA. 1990; 87: 6934–6938.
Cosman D. The hematopoietin receptor superfamily. Cytokine. 1993; 5: 95–106.
Wells JA. Binding in the growth hormone receptor complex. Proc Natl Acad Sci USA. 1996; 93: 1–6.
Alexander WS, Dunn AR. Structure and transcription of the genomic locus encoding murine c-Mpl, a receptor for thrombopoietin. Oncogene. 1995; 10: 795–803.
Kiladjian JJ, Hetet G, Briere J, Grandchamp B, Gardin C. New mRNA isoforms of the c-mpl receptor in human platelets. Blood. 1995; 86: 366a (abstract no 1451).
Lofton-Day C, Buddie M, Berry J, Lok S. Differential binding of murine thrombopoietin to two isoforms of murine c-mpl. Blood. 1995; 86: 594a (abstract no 2362).
Kaushansky K, Broudy VC, Lin N, et al. Thrombopoietin, the Mpl-ligand, is essential for full megakaryocyte development. Proc Natl Acad Sci USA. 1995; 92: 3234–3238.
Lok S, Kaushansky K, Holly RD, et al. Cloning and expression of murine thrombopoietin cDNA and Stimulation of platelet production in vivo. Nature. 1994; 369: 565–568.
Ishibashi T, Kimura H, Uchida T, Kariyone S, Friese P, Burstein SA. Human interleukin 6 is a direct promoter of maturation of megakaryocytes in vitro. Proc Natl Acad Sci USA. 1989; 86: 5953–5957.
Burstein SA, Mei RL, Henthorn J, Friese P, Turner K. Leukemia inhibitory factor and interleukin-11 promote maturation of murine and human megakaryocytes in vitro. J Cell Physiol. 1992; 153:305–312.
Wallace PM, MacMaster JF, Rillema JR, Peng J, Burstein SA, Shoyab M. Thrombocytopoietic properties of oncostatin M. Blood. 1995; 86: 1310–1315.
Kishimoto T, Akira S, Narazaki M, Taga T. Interleukin-6 family of cytokines and gp130. Blood. 1995; 86: 1243–1254.
Saito M, Yoshida K, Hibi M, Taga T, Kishimoto T. Molecular cloning of a murine IL-6 receptor-associated signal transducer, gp130, and its regulated expression in vivo. J Immunol. 1992; 148:4066–4071.
Broudy VC, Lin N, Fox N, Taga T, Saito M, Kaushansky K. Thrombopoietin stimulates CFU-Meg proliferation and megakaryocyte maturation independently of cytokines that signal through the gp130 receptor subunit. Blood. 1996 (in press).
Segal GM, Stueve T, Adamson JW. Analysis of murine megakaryocyte colony size and ploidy: effects of interleukin-3. J Cell Physiol. 1988; 137: 537–544.
Miyajima A, Mui AL, Ogorochi T, Sakamaki K. Receptors for granulocyte-macrophage colony-stimulating factor, interleukin-3 and interleukin-5. Blood. 1993; 82: 1960–1974.
Broudy VC, Lin NL, Kaushansky K. Thrombopoietin (c-mpl ligand) acts synergistically with erythropoietin, stem cell factor, and interleukin-11 to enhance murine megakaryocyte colony growth and increases megakaryocyte ploidy in vitro. Blood. 1995; 85: 1719–1726.
Kaushansky K, Broudy VC, Grossmann A, et al. Thrombopoietin expands erythroid progenitors, increases red cell production, and enhances erythroid recovery after myelosuppressive therapy. J Clin Invest. 1995; 96: 1683–1687.
Ulich TR, del Castillo J, Yin S, et al. Megakaryocyte growth and development factor ameliorates carboplatin-induced thrombocytopenia in mice. Blood. 1995; 86: 911–916.
Watowich SS, Yoshimura A, Longmore GD, Hilton DJ, Yoshimura Y, Lodish HF. Homodimerization and constitutive activation of the erythropoietin receptor. Proc Natl Acad Sci USA. 1992; 89: 2140–2144.
de Sauvage FJ, Hass PE, Spencer SD, et al. Stimulation of megakaryocytopoiesis and throm-bopoiesis by the c-Mpl ligand. Nature. 1994; 369: 533–538.
Broudy VC, Lin N, Fox N, Atkins H, Iscove N, Kaushansky K. Hematopoietic cells display high affinity receptors for thrombopoietin. Blood. 1995; 86: 593a (abstract no 2361).
Bartley TD, Bogenberger J, Hunt P, et al. Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. Cell. 1994; 77: 1117–1124.
B’enit L, Courtois G, Charon M, Varlet P, Dusanter-Fourt I, Gisselbrecht S. Characterization of mpl cytoplasmic domain sequences required for myeloproliferative leukemia virus pathogenicity. J Virol. 1994; 68: 5270–5274.
Mignotte V, Vigon I, Boucher de Crevecoeur E, Roméo PH, Lemarchandel V, Chrétien S. Structure and transcription of the human c-mpl gene (MPL). Genomics. 1994; 20: 5–12.
Murakami M, Narazaki M, Hibi M, et al. Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family. Proc Natl Acad Sci USA. 1991; 88:11,349–11,353.
Sakamaki K, Miyajima I, Kitamura T, Miyajima A. Critical cytoplasmic domains of the common beta subunit of the human GM-CSF, IL-3 and IL-5 receptors for growth signal transduction and tyrosine phosphorylation. EMBO J. 1992; 11: 3541–3549.
Ihle JN, Witthuhn B, Tang B, Yi T, Quelle FW. Cytokine receptors and signal transduction. Baillieres Clin Haematol. 1994; 7: 17–48.
Ihle JN. Cytokine receptor signalling. Nature. 1995; 377: 591–594.
Gurney AL, Wong SC, Henzel WJ, de Sauvage FJ. Distinct regions of c-Mpl cytoplasmic domain are coupled to the JAK-STAT signal transduction pathway and She phosphorylation. Proc Natl Acad Sci USA. 1995; 92: 5292–5296.
Sato N, Sakamaki K, Terada N, Aral K, Miyajima A. Signal transduction by the high-affinity GM-CSF receptor: two distinct cytoplasmic regions of the common beta subunit responsible for different signaling. EMBO J. 1993; 12:4181–4189.
Inhorn RC, Carlesso N, Durstin M, Frank DA, Griffin JD. Identification of a viability domain in the granulocyte/macrophage colony-stimulating factor receptor beta-chain involving tyrosine-750. Proc Natl Acad Sci USA. 1995; 92: 8665–8669.
Fukunaga R, Ishizaka-Ikeda IE, Nagata S. Growth and differentiation signals mediated by different regions in the cytoplasmic domain of granulocyte colony-stimulating factor receptor. Cell. 1993; 74: 1079–1087.
Baumann H, Gearing D, Ziegler SF. Signaling by the cytoplasmic domain of hematopoietin receptors involves two distinguishable mechanisms in hepatic cells. J Biol Chem. 1994; 269: 16297–16304.
Baumann H, Symes AJ, Comeau MR, et al. Multiple regions within the cytoplasmic domains of the leukemia inhibitory factor receptor and gp130 cooperate in signal transduction in hepatic and neuronal cells. Mol Cell Biol. 1994; 14: 138–146.
D’Andrea AD, Yoshimura A, Youssoufian H, Zon LI, Koo JW, Lodish HF. The cytoplasmic region of the erythropoietin receptor contains nonoverlapping positive and negative growth-regulatory domains. Mol Cell Biol. 1991; 11: 1980–1987.
de la Chapelle A, Traskelin AL, Juvonen E. Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis. Proc Natl Acad Sci USA. 1993; 90: 4495–4499.
Tauchi T, Feng GS, Shen R, et al. Involvement of SH2-containing phosphotyrosine phosphatase Syp in erythropoietin receptor signal transduction pathways. J Biol Chem. 1995; 270: 5631–5635.
Klingmuller U, Lorenz U, Cantley LC, Neel BG, Lodish HF. Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell. 1995; 80: 729–738.
Miyajima A, Mui AL, Ogorochi T, Sakamaki K. Receptors for granulocyte-macrophage colony-stimulating factor, interleukin-3, and interleukin-5. Blood. 1993; 82: 1960–1974.
Drachman JG, Griffin JD, Kaushansky K. The c-Mpl ligand (thrombopoietin) stimulates tyrosine phosphorylation of Jak2, She, and c-Mpl. J Biol Chem. 1995; 270: 4979–4982.
Dorsch M, Fan PD, Bogenberger J, Goff SP. TPO and IL-3 induce overlapping but distinct protein tyrosine phosphorylation in a myeloid precursor cell line. Biochem Biophys Res Commun. 1995;214:424–431.
Mu SX, Xia M, Elliot G, et al. Megakaryocyte growth and development factor and interleukin-3 induce patterns of protein-tyrosine phosphorylation that correlate with dominant differentiation over proliferation of mpl-transfected 32D cells. Blood. 1995; 86: 4532–4543.
Pallard C, Gouilleux F, Bénit L, et al. Thrombopoietin activates a STAT5-like factor in hematopoietic cells. EMBO J. 1995; 14: 2847–2856.
Sasaki K, Odai H, Hanazono Y, et al. 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. 1995; 216: 338–347.
Ezumi Y, Takayama H, Okuma M. Thrombopoietin, c-Mpl ligand, induces tyrosine phosphorylation of Tyk2, JAK2, and STAT3, and enhances agonists-induced aggregation in platelets in vitro. FEBS Lett. 1995; 374: 48–52.
Miyakawa Y, Oda A, Druker BJ, et al. Recombinant thrombopoietin induces rapid protein tyrosine phosphorylation of Janus kinase 2 and She in human blood platelets. Blood. 1995; 86: 23–27.
Izuhara K, Harada N. Interleukin-4 (IL-4) induces protein tyrosine phosphorylation of the IL-4 receptor and association of phosphatidylinositol 3-kinase to the IL-4 receptor in a mouse T cell line, HT2. J Biol Chem. 1993; 268: 13097–13102.
Miyakawa Y, Oda A, Druker BJ, et al. Thrombopoietin induces tyrosine phosphorylation of Stat3 and Stat5 in human blood platelets. Blood. 1996; 87: 439–446.
Sattler M, Durstin MA, Frank DA, et al. The thrombopoietin receptor c-MPL activates JAK2 and TYK2 tyrosine kinases. Exp Hematol. 1995; 23: 1040–1048.
Tortolani PJ, Johnston JA, Bacon CM, et al. Thrombopoietin induces tyrosine phosphorylation and activation of the Janus kinase, JAK2. Blood. 1995; 85: 3444–3451.
Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994; 264: 1415–1421.
Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D, Darnell JE Jr. Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell. 1994; 76: 821–828.
Heim MH, Kerr IM, Stark GR, Darnell JE Jr. Contribution of STAT SH2 groups to specific interferon signaling by the Jak-STAT pathway. Science. 1995; 267: 1347–1349.
Bacon CM, Tortolani PJ, Shimosaka A, Rees RC, Longo DL, O’Shea J J. Thrombopoietin (TPO) induces tyrosine phosphorylation and activation of STAT5 and STAT3. FEBS Lett. 1995; 370: 63–68.
Mui AL, Wakao H, O’Farrell AM, Harada N, Miyajima A. Interleukin-3, granulocyte-macrophage colony stimulating factor and interleukin-5 transduce signals through two STAT5 homologs. EMBO J. 1995; 14: 1166–1175.
Pallard C, Gouilleux F, Charon M, Groner B, Gisselbrecht S, Dusanter-Fourt I. Interleukin-3, erythropoietin, and prolactin activate a STAT5-like factor in lymphoid cells. J Biol Chem. 1995; 270: 15,942–15,945.
Downward J. The GRB2/Sem-5 adaptor protein. FEBS Lett. 1994; 338: 113–117.
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Kaushansky, K., Broudy, V.C., Drachman, J.G. (1997). The Thrombopoietin Receptor, Mpl, and Signal Transduction. In: Kuter, D.J., Hunt, P., Sheridan, W., Zucker-Franklin, D. (eds) Thrombopoiesis and Thrombopoietins. Humana Press. https://doi.org/10.1007/978-1-4612-3958-1_16
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DOI: https://doi.org/10.1007/978-1-4612-3958-1_16
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