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Ligand-independent Thrombopoietin Mutant Receptor Requires Cell Surface Localization for Endogenous Activity

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Marty, Caroline Chaligne, Ronan Lacout, Catherine Constantinescu, Stefan N. [UCL] Vainchenker, William Villeval, Jean-Luc

The activating W515L mutation in the thrombopoietin receptor (MPL) has been identified in primary myelofibrosis and essential thrombocythemia. MPL belongs to a subset of the cytokine receptor superfamily that requires the JAK2 kinase for signaling. We examined whether the ligand-independent MPLW515L mutant could signal intracellularly. Addition of the endoplasmic reticulum (ER) retention KDEL sequence to the receptor C terminus efficiently locked MPLW515L within its natural ER/Golgi maturation pathway. In contrast to cells expressing the parental MPLW515L, MPLW515L-KDEL-expressing FDC-P1 cells were unable to grow autonomously and to produce tumors in nude mice. When observed, tumor nodules resulted from in vivo selection of cells leaking the receptor at their surface. JAK2 co-immunoprecipitated with MPLW515L-KDEL but was not phosphorylated. We generated disulfide-bonded MPLW515L homodimers by the S402C substitution, both in the normal and KDEL context. Unlike MPLW515L-KDEL, MPLW515L-S402C-KDEL signaled constitutively and exhibited cell surface localization. These data establish that MPLW515L with appended JAK2 matures through the ER/Golgi system in an inactive conformation and suggest that the MPLW515L/JAK2 complex requires membrane localization for JAK2 phosphorylation, resulting in autonomous receptor signaling.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2009
Language Anglais
Journal information "Journal of Biological Chemistry" - Vol. 284, no. 18, p. 11781-11791 (2009)
Peer reviewed yes
Publisher Amer Soc Biochemistry Molecular Biology Inc (Bethesda)
issn 0021-9258
e-issn 1083-351X
Publication status Publié
Affiliation UCL
Links
  1. J. Leukocyte Biol., 57, 719 (1995)
  2. Huang Lily Jun-shen, Constantinescu Stefan N., Lodish Harvey F., The N-Terminal Domain of Janus Kinase 2 Is Required for Golgi Processing and Cell Surface Expression of Erythropoietin Receptor, 10.1016/s1097-2765(01)00401-4
  3. Gent J., van Kerkhof P., Roza M., Bu G., Strous G. J., Ligand-independent growth hormone receptor dimerization occurs in the endoplasmic reticulum and is required for ubiquitin system-dependent endocytosis, 10.1073/pnas.152294299
  4. Livnah O., Stura E. A., Middleton S. A., Johnson D. L., Jolliffe L. K., Wilson I. A., Crystallographic Evidence for Preformed Dimers of Erythropoietin Receptor Before Ligand Activation, 10.1126/science.283.5404.987
  5. Kuter D. J., New thrombopoietic growth factors, 10.1182/blood-2006-10-019315
  6. Otto K. G., Membrane localization is not required for Mpl function in normal hematopoietic cells, 10.1182/blood.v98.7.2077
  7. Beer P. A., Campbell P. J., Scott L. M., Bench A. J., Erber W. N., Bareford D., Wilkins B. S., Reilly J. T., Hasselbalch H. C., Bowman R., Wheatley K., Buck G., Harrison C. N., Green A. R., MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort, 10.1182/blood-2008-01-131664
  8. Chaligne R., James C., Tonetti C., Besancenot R., Le Couedic J. P., Fava F., Mazurier F., Godin I., Maloum K., Larbret F., Lecluse Y., Vainchenker W., Giraudier S., Evidence for MPL W515L/K mutations in hematopoietic stem cells in primitive myelofibrosis, 10.1182/blood-2007-05-089003
  9. Pardanani A. D., Levine R. L., Lasho T., Pikman Y., Mesa R. A., Wadleigh M., Steensma D. P., Elliott M. A., Wolanskyj A. P., Hogan W. J., McClure R. F., Litzow M. R., Gilliland D. G., Tefferi A., MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients, 10.1182/blood-2006-04-018879
  10. Pikman Yana, Lee Benjamin H, Mercher Thomas, McDowell Elizabeth, Ebert Benjamin L, Gozo Maricel, Cuker Adam, Wernig Gerlinde, Moore Sandra, Galinsky Ilene, DeAngelo Daniel J, Clark Jennifer J, Lee Stephanie J, Golub Todd R, Wadleigh Martha, Gilliland D. Gary, Levine Ross L, MPLW515L Is a Novel Somatic Activating Mutation in Myelofibrosis with Myeloid Metaplasia, 10.1371/journal.pmed.0030270
  11. Staerk J., An amphipathic motif at the transmembrane-cytoplasmic junction prevents autonomous activation of the thrombopoietin receptor, 10.1182/blood-2005-06-2600
  12. Gurney A., Carver-Moore K, de Sauvage F., Moore M., Thrombocytopenia in c-mpl-deficient mice, 10.1126/science.8073287
  13. Bejcek B., Li D., Deuel T., Transformation by v-sis occurs by an internal autoactivation mechanism, 10.1126/science.2551043
  14. Santos S. C. R., Internal and external autocrine VEGF/KDR loops regulate survival of subsets of acute leukemia through distinct signaling pathways, 10.1182/blood-2003-05-1634
  15. Lacout C., JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis, 10.1182/blood-2006-02-002030
  16. Blood, 94, 2555 (1999)
  17. 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., 10.1073/pnas.89.12.5640
  18. EMBO J., 14, 5569 (1995)
  19. Constantinescu S. N., Keren T., Socolovsky M., Nam H.-s., Henis Y. I., Lodish H. F., Ligand-independent oligomerization of cell-surface erythropoietin receptor is mediated by the transmembrane domain, 10.1073/pnas.081069198
  20. Constantinescu Stefan N, Huang Lily Jun-shen, Nam Hyung-song, Lodish Harvey F, The Erythropoietin Receptor Cytosolic Juxtamembrane Domain Contains an Essential, Precisely Oriented, Hydrophobic Motif, 10.1016/s1097-2765(01)00185-x
  21. D'Andrea A D, Zon L I, Erythropoietin receptor. Subunit structure and activation., 10.1172/jci114763
  22. Miesenbock G., The capacity to retrieve escaped ER proteins extends to the trans-most cisterna of the Golgi stack, 10.1083/jcb.129.2.309
  23. Kaushansky Kenneth, Lok Si, Holly Richard D., Broudy Virginia C., Lin Nancy, Bailey Mason C., Forstrom John W., Buddle Michele M., Oort Pieter J., Hagen Fredrick S., Roth Gerald J., Papayannopoulou Thalia, Foster Donald C., Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin, 10.1038/369568a0
  24. Jacobson K, Sheets E., Simson R, Revisiting the fluid mosaic model of membranes, 10.1126/science.7770769
  25. Brown Deborah A., London Erwin, Structure and Function of Sphingolipid- and Cholesterol-rich Membrane Rafts, 10.1074/jbc.r000005200
  26. Watowich S. S., Yoshimura A., Longmore G. D., Hilton D. J., Yoshimura Y., Lodish H. F., Homodimerization and constitutive activation of the erythropoietin receptor., 10.1073/pnas.89.6.2140
  27. Yoshimura Akihiko, Longmore Gregory, Lodish Harvey F., Point mutation in the exoplasmic domain of the erythropoietin receptor resulting in hormone-independent activation and tumorigenicity, 10.1038/348647a0
  28. Blood, 96, 771 (2000)
  29. Thromb. Haemostasis, 74, 526 (1995)
  30. Haematologica, 84, 158 (1999)
  31. Cosman David, Lyman Stewart D., Idzerda Rejean L., Beckmann M.Patricia, Park Linda S., Goodwin Raymond G., March Carl J., A new cytokine receptor superfamily, 10.1016/0968-0004(90)90051-c
  32. Parganas Evan, Wang Demin, Stravopodis Dimitrios, Topham David J, Marine Jean-Christophe, Teglund Stephan, Vanin Elio F, Bodner Sara, Colamonici Oscar R, van Deursen Jan M, Grosveld Gerard, Ihle James N, Jak2 Is Essential for Signaling through a Variety of Cytokine Receptors, 10.1016/s0092-8674(00)81167-8
  33. Yamaoka Kunihiro, Saharinen Pipsa, Pesu Marko, Holt Vance ET, Silvennoinen Olli, O'Shea John J, 10.1186/gb-2004-5-12-253
  34. Royer Yohan, Staerk Judith, Costuleanu Marcel, Courtoy Pierre J., Constantinescu Stefan N., Janus Kinases Affect Thrombopoietin Receptor Cell Surface Localization and Stability, 10.1074/jbc.m501376200
Bibliographic reference Marty, Caroline ; Chaligne, Ronan ; Lacout, Catherine ; Constantinescu, Stefan N. ; Vainchenker, William ; et. al. Ligand-independent Thrombopoietin Mutant Receptor Requires Cell Surface Localization for Endogenous Activity. In: Journal of Biological Chemistry, Vol. 284, no. 18, p. 11781-11791 (2009)
Permanent URL http://hdl.handle.net/2078.1/35639