Thrombopoietin receptor

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.

MPL
Identifiers
Aliases	MPL, C-CD110, MPLV, THCYT2, TPOR, MPL proto-oncogene, thrombopoietin receptor, THPOR
External IDs	OMIM: 159530; MGI: 97076; HomoloGene: 7845; GeneCards: MPL; OMA:MPL - orthologs
Gene location (Human) Chr. Chromosome 1 (human) Band 1p34.2 Start 43,337,818 bp End 43,354,466 bp
Gene location (Mouse) Chr. Chromosome 4 (mouse) Band 4 D2.1|4 54.61 cM Start 118,299,612 bp End 118,314,710 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in testicle mononuclear cell monocyte right frontal lobe bone marrow cells bronchial epithelial cell sural nerve left ovary Brodmann area 9 prefrontal cortex Top expressed in blood gastrula vasculature of trunk tibiofemoral joint embryo dorsal aorta morula yolk sac embryo spleen More reference expression data BioGPS More reference expression data
Gene ontology Molecular function cytokine receptor activity protein binding transmembrane signaling receptor activity thrombopoietin receptor activity Cellular component integral component of membrane cell surface Golgi apparatus integral component of plasma membrane membrane plasma membrane neuron projection soma Biological process cell surface receptor signaling pathway cell population proliferation cytokine-mediated signaling pathway thrombopoietin-mediated signaling pathway neutrophil homeostasis monocyte homeostasis positive regulation of lymphocyte proliferation platelet aggregation cellular response to hypoxia positive regulation of platelet formation eosinophil homeostasis basophil homeostasis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4352 17480 Ensembl ENSG00000117400 ENSMUSG00000006389 UniProt P40238 Q08351 RefSeq (mRNA) NM_005373 NM_001122949 NM_001285496 NM_001285497 NM_010823 RefSeq (protein) NP_005364 NP_001116421 NP_001272425 NP_001272426 NP_034953 Location (UCSC) Chr 1: 43.34 – 43.35 Mb Chr 4: 118.3 – 118.31 Mb PubMed search
Wikidata
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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.

Interactions

Myeloproliferative leukemia virus oncogene has been shown to interact with:

• ATXN2L
• JAK2
• thrombopoietin

Clinical relevance

Inactivating mutations in this gene have been shown to cause familial aplastic anemia.

Specific mutations to this gene are associated with myelofibrosis and essential thrombocythemia. 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.

See also

• Cluster of differentiation
• Congenital amegakaryocytic thrombocytopenia

Further reading

• Kato T, Matsumoto A, Ogami K, Tahara T, Morita H, Miyazaki H (1999). "Native thrombopoietin: structure and function". Stem Cells. 16 (5): 322–328. doi:10.1002/stem.160322. PMID 9766811. S2CID 25655839.
• Vigon I, Mornon JP, Cocault L, Mitjavila MT, Tambourin P, Gisselbrecht S, et al. (June 1992). "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. Bibcode:1992PNAS...89.5640V. doi:10.1073/pnas.89.12.5640. PMC 49348. PMID 1608974.
• Souyri M, Vigon I, Penciolelli JF, Heard JM, Tambourin P, Wendling F (December 1990). "A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors". Cell. 63 (6): 1137–1147. doi:10.1016/0092-8674(90)90410-G. PMID 2175677. S2CID 7946220.
• Le Coniat M, Souyri M, Vigon I, Wendling F, Tambourin P, Berger R (September 1989). "The human homolog of the myeloproliferative virus maps to chromosome band 1p34". Human Genetics. 83 (2): 194–196. doi:10.1007/BF00286717. PMID 2550356. S2CID 20970372.
• Drachman JG, Griffin JD, Kaushansky K (March 1995). "The c-Mpl ligand (thrombopoietin) stimulates tyrosine phosphorylation of Jak2, Shc, and c-Mpl". The Journal of Biological Chemistry. 270 (10): 4979–4982. doi:10.1074/jbc.270.10.4979. PMID 7534285.
• Mignotte V, Vigon I, Boucher de Crèvecoeur E, Roméo PH, Lemarchandel V, Chrétien S (March 1994). "Structure and transcription of the human c-mpl gene (MPL)". Genomics. 20 (1): 5–12. doi:10.1006/geno.1994.1120. PMID 8020956.
• Mu SX, Xia M, Elliott G, Bogenberger J, Swift S, Bennett L, et al. (December 1995). "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. doi:10.1182/blood.V86.12.4532.bloodjournal86124532. PMID 8541543.
• Deveaux S, Filipe A, Lemarchandel V, Ghysdael J, Roméo PH, Mignotte V (June 1996). "Analysis of the thrombopoietin receptor (MPL) promoter implicates GATA and Ets proteins in the coregulation of megakaryocyte-specific genes". Blood. 87 (11): 4678–4685. doi:10.1182/blood.V87.11.4678.bloodjournal87114678. PMID 8639837.
• Drachman JG, Kaushansky K (March 1997). "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. Bibcode:1997PNAS...94.2350D. doi:10.1073/pnas.94.6.2350. PMC 20091. PMID 9122198.
• Ihara K, Ishii E, Eguchi M, Takada H, Suminoe A, Good RA, et al. (March 1999). "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. Bibcode:1999PNAS...96.3132I. doi:10.1073/pnas.96.6.3132. PMC 15907. PMID 10077649.
• Drachman JG, Millett KM, Kaushansky K (May 1999). "Thrombopoietin signal transduction requires functional JAK2, not TYK2". The Journal of Biological Chemistry. 274 (19): 13480–13484. doi:10.1074/jbc.274.19.13480. PMID 10224114.
• Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, et al. (July 1999). "Characterization of single-nucleotide polymorphisms in coding regions of human genes". Nature Genetics. 22 (3): 231–238. doi:10.1038/10290. PMID 10391209. S2CID 195213008.
• Okabe S, Tauchi T, Morita H, Ohashi H, Yoshimura A, Ohyashiki K (October 1999). "Thrombopoietin induces an SH2-containing protein, CIS1, which binds to Mpl: involvement of the ubiquitin proteosome pathway". Experimental Hematology. 27 (10): 1542–1547. doi:10.1016/S0301-472X(99)00094-6. PMID 10517496.
• Miyakawa Y, Drachman JG, Gallis B, Kaushansky A, Kaushansky K (October 2000). "A structure-function analysis of serine/threonine phosphorylation of the thrombopoietin receptor, c-Mpl". The Journal of Biological Chemistry. 275 (41): 32214–32219. doi:10.1074/jbc.M005080200. PMID 10918061.
• van den Oudenrijn S, Bruin M, Folman CC, Peters M, Faulkner LB, de Haas M, et al. (August 2000). "Mutations in the thrombopoietin receptor, Mpl, in children with congenital amegakaryocytic thrombocytopenia". British Journal of Haematology. 110 (2): 441–448. doi:10.1046/j.1365-2141.2000.02175.x. PMID 10971406. S2CID 41534975.
• Wang Q, Miyakawa Y, Fox N, Kaushansky K (September 2000). "Interferon-alpha directly represses megakaryopoiesis by inhibiting thrombopoietin-induced signaling through induction of SOCS-1". Blood. 96 (6): 2093–2099. doi:10.1182/blood.V96.6.2093. PMID 10979953.
• Miyakawa Y, Rojnuckarin P, Habib T, Kaushansky K (January 2001). "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. doi:10.1074/jbc.M002633200. PMID 11054408.
• Tonelli R, Scardovi AL, Pession A, Strippoli P, Bonsi L, Vitale L, et al. (September 2000). "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. doi:10.1007/s004390000357. PMID 11071383. S2CID 10211260.
• Ballmaier M, Germeshausen M, Schulze H, Cherkaoui K, Lang S, Gaudig A, et al. (January 2001). "c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia". Blood. 97 (1): 139–146. doi:10.1182/blood.V97.1.139. PMID 11133753.

External links

• MPL+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.