The thrombopoietin receptor also known as the myeloproliferative leukemia protein or CD110 (Cluster of Differentiation 110) is a protein that in humans is encoded by the MPL (myeloproliferative leukemia virus) oncogene.[1]
In 1990 an oncogene, v-mpl, was identified from the murine myeloproliferative leukemia virus that was capable of immortalizing bone marrow hematopoietic cells from different lineages. In 1992 the human homologue, named, c-mpl, was cloned. Sequence data revealed that c-mpl encoded a protein that was homologous with members of the hematopoietic receptor superfamily. Presence of anti-sense oligodeoxynucleotides of c-mpl inhibited megakaryocyte colony formation.
Function
The ligand for c-mpl, thrombopoietin, was cloned in 1994. Thrombopoietin was shown to be the major regulator of megakaryocytopoiesis and platelet formation.
The protein encoded by the c-mpl gene, CD110, is a 635 amino acid transmembrane domain, with two extracellular cytokine receptor domains and two intracellular cytokine receptor box motifs . TPO-R deficient mice were severely thrombocytopenic, emphasizing the important role of CD110 and thrombopoietin in megakaryocyte and platelet formation. Upon binding of thrombopoietin, CD110 is dimerized and the JAK family of non-receptor tyrosine kinases, as well as the STAT family, the MAPK family, the adaptor protein Shc and the receptors themselves become tyrosine phosphorylated.[1]
Interactions
Myeloproliferative leukemia virus oncogene has been shown to interact with:
Inactivating mutations in this gene have been shown to cause familial aplastic anemia.[5]
Specific mutations to this gene are associated with myelofibrosis and essential thrombocythemia.[6] In essential thrombocythemia, mutations occur at position 505 or 515 in the protein. In myelofibrosis, a mutation occurs at position 515.
These mutations lead to the production of thrombopoietin receptors that are permanently activated, which results in the overproduction of abnormal megakaryocytes.[7]
↑Meunier C, Bordereaux D, Porteu F, Gisselbrecht S, Chrétien S, Courtois G (Mar 2002). "Cloning and characterization of a family of proteins associated with Mpl". J. Biol. Chem. 277 (11): 9139–47. doi:10.1074/jbc.M105970200. PMID11784712.
↑Tefferi, A; Lasho, T L; Finke, C M; Knudson, R A; Ketterling, R; Hanson, C H; Maffioli, M; Caramazza, D; Passamonti, F; Pardanani, A (2014). "CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons". Leukemia. 28 (7): 1472–1477. doi:10.1038/leu.2014.3. ISSN0887-6924.
Souyri M, Vigon I, Penciolelli JF, Heard JM, Tambourin P, Wendling F (1991). "A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors". Cell. 63 (6): 1137–47. doi:10.1016/0092-8674(90)90410-G. PMID2175677.
Le Coniat M, Souyri M, Vigon I, Wendling F, Tambourin P, Berger R (1989). "The human homolog of the myeloproliferative virus maps to chromosome band 1p34". Hum. Genet. 83 (2): 194–6. doi:10.1007/BF00286717. PMID2550356.
Drachman JG, Griffin JD, Kaushansky K (1995). "The c-Mpl ligand (thrombopoietin) stimulates tyrosine phosphorylation of Jak2, Shc, and c-Mpl". J. Biol. Chem. 270 (10): 4979–82. doi:10.1074/jbc.270.10.4979. PMID7534285.
Mignotte V, Vigon I, Boucher de Crèvecoeur E, Roméo PH, Lemarchandel V, Chrétien S (1994). "Structure and transcription of the human c-mpl gene (MPL)". Genomics. 20 (1): 5–12. doi:10.1006/geno.1994.1120. PMID8020956.
Mu SX, Xia M, Elliott G, Bogenberger J, Swift S, Bennett L, Lappinga DL, Hecht R, Lee R, Saris CJ (1996). "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. 86 (12): 4532–43. PMID8541543.
Deveaux S, Filipe A, Lemarchandel V, Ghysdael J, Roméo PH, Mignotte V (1996). "Analysis of the thrombopoietin receptor (MPL) promoter implicates GATA and Ets proteins in the coregulation of megakaryocyte-specific genes". Blood. 87 (11): 4678–85. PMID8639837.
Drachman JG, Millett KM, Kaushansky K (1999). "Thrombopoietin signal transduction requires functional JAK2, not TYK2". J. Biol. Chem. 274 (19): 13480–4. doi:10.1074/jbc.274.19.13480. PMID10224114.
Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, Shaw N, Lane CR, Lim EP, Kalyanaraman N, Nemesh J, Ziaugra L, Friedland L, Rolfe A, Warrington J, Lipshutz R, Daley GQ, Lander ES (1999). "Characterization of single-nucleotide polymorphisms in coding regions of human genes". Nat. Genet. 22 (3): 231–8. doi:10.1038/10290. PMID10391209.
Okabe S, Tauchi T, Morita H, Ohashi H, Yoshimura A, Ohyashiki K (1999). "Thrombopoietin induces an SH2-containing protein, CIS1, which binds to Mpl: involvement of the ubiquitin proteosome pathway". Exp. Hematol. 27 (10): 1542–7. doi:10.1016/S0301-472X(99)00094-6. PMID10517496.
Miyakawa Y, Drachman JG, Gallis B, Kaushansky A, Kaushansky K (2000). "A structure-function analysis of serine/threonine phosphorylation of the thrombopoietin receptor, c-Mpl". J. Biol. Chem. 275 (41): 32214–9. doi:10.1074/jbc.M005080200. PMID10918061.
van den Oudenrijn S, Bruin M, Folman CC, Peters M, Faulkner LB, de Haas M, von dem Borne AE (2000). "Mutations in the thrombopoietin receptor, Mpl, in children with congenital amegakaryocytic thrombocytopenia". Br. J. Haematol. 110 (2): 441–8. doi:10.1046/j.1365-2141.2000.02175.x. PMID10971406.
Wang Q, Miyakawa Y, Fox N, Kaushansky K (2000). "Interferon-alpha directly represses megakaryopoiesis by inhibiting thrombopoietin-induced signaling through induction of SOCS-1". Blood. 96 (6): 2093–9. PMID10979953.
Miyakawa Y, Rojnuckarin P, Habib T, Kaushansky K (2001). "Thrombopoietin induces phosphoinositol 3-kinase activation through SHP2, Gab, and insulin receptor substrate proteins in BAF3 cells and primary murine megakaryocytes". J. Biol. Chem. 276 (4): 2494–502. doi:10.1074/jbc.M002633200. PMID11054408.
Tonelli R, Scardovi AL, Pession A, Strippoli P, Bonsi L, Vitale L, Prete A, Locatelli F, Bagnara GP, Paolucci G (2000). "Compound heterozygosity for two different amino-acid substitution mutations in the thrombopoietin receptor (c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT)". Hum. Genet. 107 (3): 225–33. doi:10.1007/s004390000357. PMID11071383.
Ballmaier M, Germeshausen M, Schulze H, Cherkaoui K, Lang S, Gaudig A, Krukemeier S, Eilers M, Strauss G, Welte K (2001). "c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia". Blood. 97 (1): 139–46. doi:10.1182/blood.V97.1.139. PMID11133753.