Thrombopoietin receptor explained

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]

Discovery

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:

• ATXN2L^[2]
• JAK2^[3]
• thrombopoietin^[4]

Clinical relevance

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]

See also

• Cluster of differentiation
• Congenital amegakaryocytic thrombocytopenia

Further reading

• Kato T, Matsumoto A, Ogami K, Tahara T, Morita H, Miyazaki H . Native thrombopoietin: structure and function . Stem Cells . 16 . 5 . 322–328 . 1999 . 9766811 . 10.1002/stem.160322 . 25655839 . free .
• Vigon I, Mornon JP, Cocault L, Mitjavila MT, 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 . Proceedings of the National Academy of Sciences of the United States of America . 89 . 12 . 5640–5644 . June 1992 . 1608974 . 49348 . 10.1073/pnas.89.12.5640 . free . 1992PNAS...89.5640V .
• 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 . 63 . 6 . 1137–1147 . December 1990 . 2175677 . 10.1016/0092-8674(90)90410-G . 7946220 .
• 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 . Human Genetics . 83 . 2 . 194–196 . September 1989 . 2550356 . 10.1007/BF00286717 . 20970372 .
• Drachman JG, Griffin JD, Kaushansky K . The c-Mpl ligand (thrombopoietin) stimulates tyrosine phosphorylation of Jak2, Shc, and c-Mpl . The Journal of Biological Chemistry . 270 . 10 . 4979–4982 . March 1995 . 7534285 . 10.1074/jbc.270.10.4979 . free .
• Mignotte V, Vigon I, Boucher de Crèvecoeur E, Roméo PH, Lemarchandel V, Chrétien S . Structure and transcription of the human c-mpl gene (MPL) . Genomics . 20 . 1 . 5–12 . March 1994 . 8020956 . 10.1006/geno.1994.1120 .
• Mu SX, Xia M, Elliott G, Bogenberger J, Swift S, Bennett L, Lappinga DL, Hecht R, Lee R, Saris CJ . 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 . 4532–4543 . December 1995 . 8541543 . 10.1182/blood.V86.12.4532.bloodjournal86124532 . free .
• Deveaux S, Filipe A, Lemarchandel V, Ghysdael J, Roméo PH, Mignotte V . Analysis of the thrombopoietin receptor (MPL) promoter implicates GATA and Ets proteins in the coregulation of megakaryocyte-specific genes . Blood . 87 . 11 . 4678–4685 . June 1996 . 8639837 . 10.1182/blood.V87.11.4678.bloodjournal87114678 . free .
• Drachman JG, Kaushansky K . Dissecting the thrombopoietin receptor: functional elements of the Mpl cytoplasmic domain . Proceedings of the National Academy of Sciences of the United States of America . 94 . 6 . 2350–2355 . March 1997 . 9122198 . 20091 . 10.1073/pnas.94.6.2350 . free . 1997PNAS...94.2350D .
• Ihara K, Ishii E, Eguchi M, Takada H, Suminoe A, Good RA, Hara T . Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia . Proceedings of the National Academy of Sciences of the United States of America . 96 . 6 . 3132–3136 . March 1999 . 10077649 . 15907 . 10.1073/pnas.96.6.3132 . free . 1999PNAS...96.3132I .
• Drachman JG, Millett KM, Kaushansky K . Thrombopoietin signal transduction requires functional JAK2, not TYK2 . The Journal of Biological Chemistry . 274 . 19 . 13480–13484 . May 1999 . 10224114 . 10.1074/jbc.274.19.13480 . free .
• 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 . Characterization of single-nucleotide polymorphisms in coding regions of human genes . Nature Genetics . 22 . 3 . 231–238 . July 1999 . 10391209 . 10.1038/10290 . 195213008 .
• Okabe S, Tauchi T, Morita H, Ohashi H, Yoshimura A, Ohyashiki K . Thrombopoietin induces an SH2-containing protein, CIS1, which binds to Mpl: involvement of the ubiquitin proteosome pathway . Experimental Hematology . 27 . 10 . 1542–1547 . October 1999 . 10517496 . 10.1016/S0301-472X(99)00094-6 . free .
• Miyakawa Y, Drachman JG, Gallis B, Kaushansky A, Kaushansky K . A structure-function analysis of serine/threonine phosphorylation of the thrombopoietin receptor, c-Mpl . The Journal of Biological Chemistry . 275 . 41 . 32214–32219 . October 2000 . 10918061 . 10.1074/jbc.M005080200 . free .
• van den Oudenrijn S, Bruin M, Folman CC, Peters M, Faulkner LB, de Haas M, von dem Borne AE . Mutations in the thrombopoietin receptor, Mpl, in children with congenital amegakaryocytic thrombocytopenia . British Journal of Haematology . 110 . 2 . 441–448 . August 2000 . 10971406 . 10.1046/j.1365-2141.2000.02175.x . 41534975 . free .
• Wang Q, Miyakawa Y, Fox N, Kaushansky K . Interferon-alpha directly represses megakaryopoiesis by inhibiting thrombopoietin-induced signaling through induction of SOCS-1 . Blood . 96 . 6 . 2093–2099 . September 2000 . 10979953 . 10.1182/blood.V96.6.2093 .
• Miyakawa Y, Rojnuckarin P, Habib T, Kaushansky K . Thrombopoietin induces phosphoinositol 3-kinase activation through SHP2, Gab, and insulin receptor substrate proteins in BAF3 cells and primary murine megakaryocytes . The Journal of Biological Chemistry . 276 . 4 . 2494–2502 . January 2001 . 11054408 . 10.1074/jbc.M002633200 . free .
• Tonelli R, Scardovi AL, Pession A, Strippoli P, Bonsi L, Vitale L, Prete A, Locatelli F, Bagnara GP, Paolucci G . Compound heterozygosity for two different amino-acid substitution mutations in the thrombopoietin receptor (c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT) . Human Genetics . 107 . 3 . 225–233 . September 2000 . 11071383 . 10.1007/s004390000357 . 10211260 .
• Ballmaier M, Germeshausen M, Schulze H, Cherkaoui K, Lang S, Gaudig A, Krukemeier S, Eilers M, Strauss G, Welte K . c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia . Blood . 97 . 1 . 139–146 . January 2001 . 11133753 . 10.1182/blood.V97.1.139 . free .

Notes and References

1. Web site: Entrez Gene: MPL myeloproliferative leukemia virus oncogene.
2. Meunier C, Bordereaux D, Porteu F, Gisselbrecht S, Chrétien S, Courtois G . Cloning and characterization of a family of proteins associated with Mpl . The Journal of Biological Chemistry . 277 . 11 . 9139–9147 . March 2002 . 11784712 . 10.1074/jbc.M105970200 . free .
3. Bellido M, Te Boekhorst PA . JAK2 Inhibition: Reviewing a New Therapeutical Option in Myeloproliferative Neoplasms . Advances in Hematology . 2012 . 535709 . 2012 . 22400031 . 3286888 . 10.1155/2012/535709 . free .
4. Nakaya Y, Shide K, Niwa T, Homan J, Sugahara S, Horio T, Kuramoto K, Kotera T, Shibayama H, Hori K, Naito H, Shimoda K . Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasms . Blood Cancer Journal . 1 . 7 . e29 . July 2011 . 22829185 . 3255248 . 10.1038/bcj.2011.29 .
5. Walne AJ, Dokal A, Plagnol V, Beswick R, Kirwan M, de la Fuente J, Vulliamy T, Dokal I . Exome sequencing identifies MPL as a causative gene in familial aplastic anemia . Haematologica . 97 . 4 . 524–528 . April 2012 . 22180433 . 3347658 . 10.3324/haematol.2011.052787 .
6. Tefferi A, Lasho TL, Finke CM, Knudson RA, Ketterling R, Hanson CH, Maffioli M, Caramazza D, Passamonti F, Pardanani A . CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons . Leukemia . 28 . 7 . 1472–1477 . July 2014 . 24402162 . 10.1038/leu.2014.3 . 52852665 .
7. Tefferi A . Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1 . Leukemia . 24 . 6 . 1128–1138 . June 2010 . 20428194 . 3035972 . 10.1038/leu.2010.69 .