Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1993 Jul;12(7):2645–2653. doi: 10.1002/j.1460-2075.1993.tb05925.x

Murine c-mpl: a member of the hematopoietic growth factor receptor superfamily that transduces a proliferative signal.

R C Skoda 1, D C Seldin 1, M K Chiang 1, C L Peichel 1, T F Vogt 1, P Leder 1
PMCID: PMC413511  PMID: 8334987

Abstract

The murine myeloproliferative leukemia virus has previously been shown to contain a fragment of the coding region of the c-mpl gene, a member of the cytokine receptor superfamily. We have isolated cDNA and genomic clones encoding murine c-mpl and localized the c-mpl gene to mouse chromosome 4. Since some members of this superfamily function by transducing a proliferative signal and since the putative ligand of mpl is unknown, we have generated a chimeric receptor to test the functional potential of mpl. The chimera consists of the extracellular domain of the human interleukin-4 receptor and the cytoplasmic domain of mpl. A mouse hematopoietic cell line transfected with this construct proliferates in response to human interleukin-4, thereby demonstrating that the cytoplasmic domain of mpl contains all elements necessary to transmit a growth stimulatory signal. In addition, we show that 25-40% of mpl mRNA found in the spleen corresponds to a novel truncated and potentially soluble isoform of mpl and that both full-length and truncated forms of mpl protein can be immunoprecipitated from lysates of transfected COS cells. Interestingly, however, although the truncated form of the receptor possesses a functional signal sequence and lacks a transmembrane domain, it is not detected in the culture media of transfected cells.

Full text

PDF
2648

Images in this article

2648Image
on p.2648
2649Image
on p.2649

Selected References

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

  1. Bazan J. F. Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci U S A. 1990 Sep;87(18):6934–6938. doi: 10.1073/pnas.87.18.6934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  3. Chung S. W., Wolff L., Ruscetti S. K. Transmembrane domain of the envelope gene of a polycythemia-inducing retrovirus determines erythropoietin-independent growth. Proc Natl Acad Sci U S A. 1989 Oct;86(20):7957–7960. doi: 10.1073/pnas.86.20.7957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Crosier K. E., Wong G. G., Mathey-Prevot B., Nathan D. G., Sieff C. A. A functional isoform of the human granulocyte/macrophage colony-stimulating factor receptor has an unusual cytoplasmic domain. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7744–7748. doi: 10.1073/pnas.88.17.7744. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Daley G. Q., Van Etten R. A., Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990 Feb 16;247(4944):824–830. doi: 10.1126/science.2406902. [DOI] [PubMed] [Google Scholar]
  6. Davis S., Aldrich T. H., Valenzuela D. M., Wong V. V., Furth M. E., Squinto S. P., Yancopoulos G. D. The receptor for ciliary neurotrophic factor. Science. 1991 Jul 5;253(5015):59–63. doi: 10.1126/science.1648265. [DOI] [PubMed] [Google Scholar]
  7. Dietrich W., Katz H., Lincoln S. E., Shin H. S., Friedman J., Dracopoli N. C., Lander E. S. A genetic map of the mouse suitable for typing intraspecific crosses. Genetics. 1992 Jun;131(2):423–447. doi: 10.1093/genetics/131.2.423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fernandez-Botran R. Soluble cytokine receptors: their role in immunoregulation. FASEB J. 1991 Aug;5(11):2567–2574. doi: 10.1096/fasebj.5.11.1868981. [DOI] [PubMed] [Google Scholar]
  9. Flanagan J. G., Leder P. The kit ligand: a cell surface molecule altered in steel mutant fibroblasts. Cell. 1990 Oct 5;63(1):185–194. doi: 10.1016/0092-8674(90)90299-t. [DOI] [PubMed] [Google Scholar]
  10. Fukunaga R., Ishizaka-Ikeda E., Pan C. X., Seto Y., Nagata S. Functional domains of the granulocyte colony-stimulating factor receptor. EMBO J. 1991 Oct;10(10):2855–2865. doi: 10.1002/j.1460-2075.1991.tb07835.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fukunaga R., Ishizaka-Ikeda E., Seto Y., Nagata S. Expression cloning of a receptor for murine granulocyte colony-stimulating factor. Cell. 1990 Apr 20;61(2):341–350. doi: 10.1016/0092-8674(90)90814-u. [DOI] [PubMed] [Google Scholar]
  12. Fukunaga R., Seto Y., Mizushima S., Nagata S. Three different mRNAs encoding human granulocyte colony-stimulating factor receptor. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8702–8706. doi: 10.1073/pnas.87.22.8702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Goodwin R. G., Friend D., Ziegler S. F., Jerzy R., Falk B. A., Gimpel S., Cosman D., Dower S. K., March C. J., Namen A. E. Cloning of the human and murine interleukin-7 receptors: demonstration of a soluble form and homology to a new receptor superfamily. Cell. 1990 Mar 23;60(6):941–951. doi: 10.1016/0092-8674(90)90342-c. [DOI] [PubMed] [Google Scholar]
  14. Guenet J. L., Salzgeber B., Tassin M. T. Repeated epilation: a genetic epidermal syndrome in mice. J Hered. 1979 Mar-Apr;70(2):90–94. doi: 10.1093/oxfordjournals.jhered.a109223. [DOI] [PubMed] [Google Scholar]
  15. Kozak M. The scanning model for translation: an update. J Cell Biol. 1989 Feb;108(2):229–241. doi: 10.1083/jcb.108.2.229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Krieg P. A., Melton D. A. In vitro RNA synthesis with SP6 RNA polymerase. Methods Enzymol. 1987;155:397–415. doi: 10.1016/0076-6879(87)55027-3. [DOI] [PubMed] [Google Scholar]
  17. Kuramochi S., Ikawa Y., Todokoro K. Characterization of murine erythropoietin receptor genes. J Mol Biol. 1990 Dec 5;216(3):567–575. doi: 10.1016/0022-2836(90)90384-x. [DOI] [PubMed] [Google Scholar]
  18. Le Coniat M., Souyri M., Vigon I., Wendling F., Tambourin P., Berger R. The human homolog of the myeloproliferative virus maps to chromosome band 1p34. Hum Genet. 1989 Sep;83(2):194–196. doi: 10.1007/BF00286717. [DOI] [PubMed] [Google Scholar]
  19. Li J. P., D'Andrea A. D., Lodish H. F., Baltimore D. Activation of cell growth by binding of Friend spleen focus-forming virus gp55 glycoprotein to the erythropoietin receptor. Nature. 1990 Feb 22;343(6260):762–764. doi: 10.1038/343762a0. [DOI] [PubMed] [Google Scholar]
  20. Lowenthal J. W., Castle B. E., Christiansen J., Schreurs J., Rennick D., Arai N., Hoy P., Takebe Y., Howard M. Expression of high affinity receptors for murine interleukin 4 (BSF-1) on hemopoietic and nonhemopoietic cells. J Immunol. 1988 Jan 15;140(2):456–464. [PubMed] [Google Scholar]
  21. Manly K. F., Elliott R. W. RI Manager, a microcomputer program for analysis of data from recombinant inbred strains. Mamm Genome. 1991;1(2):123–126. doi: 10.1007/BF02443789. [DOI] [PubMed] [Google Scholar]
  22. Marchalonis J. J. An enzymic method for the trace iodination of immunoglobulins and other proteins. Biochem J. 1969 Jun;113(2):299–305. doi: 10.1042/bj1130299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Miyazaki T., Maruyama M., Yamada G., Hatakeyama M., Taniguchi T. The integrity of the conserved 'WS motif' common to IL-2 and other cytokine receptors is essential for ligand binding and signal transduction. EMBO J. 1991 Nov;10(11):3191–3197. doi: 10.1002/j.1460-2075.1991.tb04881.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Morrison B. W., Leder P. A receptor binding domain of mouse interleukin-4 defined by a solid-phase binding assay and in vitro mutagenesis. J Biol Chem. 1992 Jun 15;267(17):11957–11963. [PubMed] [Google Scholar]
  25. Mosley B., Beckmann M. P., March C. J., Idzerda R. L., Gimpel S. D., VandenBos T., Friend D., Alpert A., Anderson D., Jackson J. The murine interleukin-4 receptor: molecular cloning and characterization of secreted and membrane bound forms. Cell. 1989 Oct 20;59(2):335–348. doi: 10.1016/0092-8674(89)90295-x. [DOI] [PubMed] [Google Scholar]
  26. Nadeau J. H., Bedigian H. G., Bouchard G., Denial T., Kosowsky M., Norberg R., Pugh S., Sargeant E., Turner R., Paigen B. Multilocus markers for mouse genome analysis: PCR amplification based on single primers of arbitrary nucleotide sequence. Mamm Genome. 1992;3(2):55–64. doi: 10.1007/BF00431247. [DOI] [PubMed] [Google Scholar]
  27. Nadeau J. H., Davisson M. T., Doolittle D. P., Grant P., Hillyard A. L., Kosowsky M. R., Roderick T. H. Comparative map for mice and humans. Mamm Genome. 1992;3(9):480–536. doi: 10.1007/BF00778825. [DOI] [PubMed] [Google Scholar]
  28. Nicola N. A., Metcalf D. Subunit promiscuity among hemopoietic growth factor receptors. Cell. 1991 Oct 4;67(1):1–4. doi: 10.1016/0092-8674(91)90564-f. [DOI] [PubMed] [Google Scholar]
  29. Palacios R., Steinmetz M. Il-3-dependent mouse clones that express B-220 surface antigen, contain Ig genes in germ-line configuration, and generate B lymphocytes in vivo. Cell. 1985 Jul;41(3):727–734. doi: 10.1016/s0092-8674(85)80053-2. [DOI] [PubMed] [Google Scholar]
  30. Quelle D. E., Quelle F. W., Wojchowski D. M. Mutations in the WSAWSE and cytosolic domains of the erythropoietin receptor affect signal transduction and ligand binding and internalization. Mol Cell Biol. 1992 Oct;12(10):4553–4561. doi: 10.1128/mcb.12.10.4553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Raines M. A., Liu L., Quan S. G., Joe V., DiPersio J. F., Golde D. W. Identification and molecular cloning of a soluble human granulocyte-macrophage colony-stimulating factor receptor. Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):8203–8207. doi: 10.1073/pnas.88.18.8203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Rodriguez-Tarduchy G., Collins M., López-Rivas A. Regulation of apoptosis in interleukin-3-dependent hemopoietic cells by interleukin-3 and calcium ionophores. EMBO J. 1990 Sep;9(9):2997–3002. doi: 10.1002/j.1460-2075.1990.tb07492.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Scudiero D. A., Shoemaker R. H., Paull K. D., Monks A., Tierney S., Nofziger T. H., Currens M. J., Seniff D., Boyd M. R. Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Res. 1988 Sep 1;48(17):4827–4833. [PubMed] [Google Scholar]
  35. Seed B., Aruffo A. Molecular cloning of the CD2 antigen, the T-cell erythrocyte receptor, by a rapid immunoselection procedure. Proc Natl Acad Sci U S A. 1987 May;84(10):3365–3369. doi: 10.1073/pnas.84.10.3365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Shapiro M. B., Senapathy P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 1987 Sep 11;15(17):7155–7174. doi: 10.1093/nar/15.17.7155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Showers M. O., DeMartino J. C., Saito Y., D'Andrea A. D. Fusion of the erythropoietin receptor and the Friend spleen focus-forming virus gp55 glycoprotein transforms a factor-dependent hematopoietic cell line. Mol Cell Biol. 1993 Feb;13(2):739–748. doi: 10.1128/mcb.13.2.739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Shultz L. D., Lane P. W., Coman D. R., Taylor S., Hall E., Lyons B., Wood B. G., Schlager G. Hairpatches, a single gene mutation characterized by progressive renal disease and alopecia in the mouse. A potential model for a newly described heritable human disorder. Lab Invest. 1991 Nov;65(5):588–600. [PubMed] [Google Scholar]
  39. Souyri M., Vigon I., Penciolelli J. F., Heard J. M., Tambourin P., Wendling F. A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors. Cell. 1990 Dec 21;63(6):1137–1147. doi: 10.1016/0092-8674(90)90410-g. [DOI] [PubMed] [Google Scholar]
  40. Takaki S., Tominaga A., Hitoshi Y., Mita S., Sonoda E., Yamaguchi N., Takatsu K. Molecular cloning and expression of the murine interleukin-5 receptor. EMBO J. 1990 Dec;9(13):4367–4374. doi: 10.1002/j.1460-2075.1990.tb07886.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Tavernier J., Devos R., Cornelis S., Tuypens T., Van der Heyden J., Fiers W., Plaetinck G. A human high affinity interleukin-5 receptor (IL5R) is composed of an IL5-specific alpha chain and a beta chain shared with the receptor for GM-CSF. Cell. 1991 Sep 20;66(6):1175–1184. doi: 10.1016/0092-8674(91)90040-6. [DOI] [PubMed] [Google Scholar]
  42. Tavernier J., Tuypens T., Plaetinck G., Verhee A., Fiers W., Devos R. Molecular basis of the membrane-anchored and two soluble isoforms of the human interleukin 5 receptor alpha subunit. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):7041–7045. doi: 10.1073/pnas.89.15.7041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Todokoro K., Kuramochi S., Nagasawa T., Abe T., Ikawa Y. Isolation of a cDNA encoding a potential soluble receptor for human erythropoietin. Gene. 1991 Oct 15;106(2):283–284. doi: 10.1016/0378-1119(91)90213-u. [DOI] [PubMed] [Google Scholar]
  44. Vigon I., Mornon J. P., Cocault L., Mitjavila M. T., Tambourin P., Gisselbrecht S., Souyri M. 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. 1992 Jun 15;89(12):5640–5644. doi: 10.1073/pnas.89.12.5640. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Wendling F., Penciolelli J. F., Charon M., Tambourin P. Factor-independent erythropoietic progenitor cells in leukemia induced by the myeloproliferative leukemia virus. Blood. 1989 Apr;73(5):1161–1167. [PubMed] [Google Scholar]
  46. Wendling F., Varlet P., Charon M., Tambourin P. MPLV: a retrovirus complex inducing an acute myeloproliferative leukemic disorder in adult mice. Virology. 1986 Mar;149(2):242–246. doi: 10.1016/0042-6822(86)90125-x. [DOI] [PubMed] [Google Scholar]
  47. Yoshimura A., Zimmers T., Neumann D., Longmore G., Yoshimura Y., Lodish H. F. Mutations in the Trp-Ser-X-Trp-Ser motif of the erythropoietin receptor abolish processing, ligand binding, and activation of the receptor. J Biol Chem. 1992 Jun 5;267(16):11619–11625. [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES