Biology:Thrombopoietin receptor
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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
References
- ↑ 1.0 1.1 "Entrez Gene: MPL myeloproliferative leukemia virus oncogene". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4352.
- ↑ "Cloning and characterization of a family of proteins associated with Mpl". J. Biol. Chem. 277 (11): 9139–47. Mar 2002. doi:10.1074/jbc.M105970200. PMID 11784712.
- ↑ "JAK2 Inhibition: Reviewing a New Therapeutical Option in Myeloproliferative Neoplasms.". Adv Hematol 2012: 535709. 2012. doi:10.1155/2012/535709. PMID 22400031.
- ↑ "Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasms.". Blood Cancer J 1 (7): e29. 2011. doi:10.1038/bcj.2011.29. PMID 22829185.
- ↑ "Exome sequencing identifies MPL as a causative gene in familial aplastic anemia". Haematologica 97 (4): 524–8. December 2011. doi:10.3324/haematol.2011.052787. PMID 22180433.
- ↑ Tefferi, A; Lasho, T L; Finke, C M; Knudson, R A; Ketterling, R; Hanson, C H; Maffioli, M; Caramazza, D et al. (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. ISSN 0887-6924. PMID 24402162.
- ↑ Tefferi, A (2010). "Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1". Leukemia 24 (6): 1128–1138. doi:10.1038/leu.2010.69. ISSN 0887-6924. PMID 20428194.
Further reading
- "Native thrombopoietin: structure and function.". Stem Cells 16 (5): 322–8. 1999. doi:10.1002/stem.160322. PMID 9766811.
- "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. 89 (12): 5640–4. 1992. doi:10.1073/pnas.89.12.5640. PMID 1608974. Bibcode: 1992PNAS...89.5640V.
- "A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors.". Cell 63 (6): 1137–47. 1991. doi:10.1016/0092-8674(90)90410-G. PMID 2175677.
- "The human homolog of the myeloproliferative virus maps to chromosome band 1p34.". Hum. Genet. 83 (2): 194–6. 1989. doi:10.1007/BF00286717. PMID 2550356.
- "The c-Mpl ligand (thrombopoietin) stimulates tyrosine phosphorylation of Jak2, Shc, and c-Mpl.". J. Biol. Chem. 270 (10): 4979–82. 1995. doi:10.1074/jbc.270.10.4979. PMID 7534285.
- "Structure and transcription of the human c-mpl gene (MPL).". Genomics 20 (1): 5–12. 1994. doi:10.1006/geno.1994.1120. PMID 8020956.
- "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. 1996. doi:10.1182/blood.V86.12.4532.bloodjournal86124532. PMID 8541543.
- "Analysis of the thrombopoietin receptor (MPL) promoter implicates GATA and Ets proteins in the coregulation of megakaryocyte-specific genes.". Blood 87 (11): 4678–85. 1996. doi:10.1182/blood.V87.11.4678.bloodjournal87114678. PMID 8639837.
- "Dissecting the thrombopoietin receptor: functional elements of the Mpl cytoplasmic domain.". Proc. Natl. Acad. Sci. U.S.A. 94 (6): 2350–5. 1997. doi:10.1073/pnas.94.6.2350. PMID 9122198. Bibcode: 1997PNAS...94.2350D.
- "Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia.". Proc. Natl. Acad. Sci. U.S.A. 96 (6): 3132–6. 1999. doi:10.1073/pnas.96.6.3132. PMID 10077649. Bibcode: 1999PNAS...96.3132I.
- "Thrombopoietin signal transduction requires functional JAK2, not TYK2.". J. Biol. Chem. 274 (19): 13480–4. 1999. doi:10.1074/jbc.274.19.13480. PMID 10224114.
- "Characterization of single-nucleotide polymorphisms in coding regions of human genes.". Nat. Genet. 22 (3): 231–8. 1999. doi:10.1038/10290. PMID 10391209.
- "Thrombopoietin induces an SH2-containing protein, CIS1, which binds to Mpl: involvement of the ubiquitin proteosome pathway.". Exp. Hematol. 27 (10): 1542–7. 1999. doi:10.1016/S0301-472X(99)00094-6. PMID 10517496.
- "A structure-function analysis of serine/threonine phosphorylation of the thrombopoietin receptor, c-Mpl.". J. Biol. Chem. 275 (41): 32214–9. 2000. doi:10.1074/jbc.M005080200. PMID 10918061.
- "Mutations in the thrombopoietin receptor, Mpl, in children with congenital amegakaryocytic thrombocytopenia.". Br. J. Haematol. 110 (2): 441–8. 2000. doi:10.1046/j.1365-2141.2000.02175.x. PMID 10971406.
- "Interferon-alpha directly represses megakaryopoiesis by inhibiting thrombopoietin-induced signaling through induction of SOCS-1.". Blood 96 (6): 2093–9. 2000. doi:10.1182/blood.V96.6.2093. PMID 10979953.
- "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. 2001. doi:10.1074/jbc.M002633200. PMID 11054408.
- "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. 2000. doi:10.1007/s004390000357. PMID 11071383.
- "c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia.". Blood 97 (1): 139–46. 2001. doi:10.1182/blood.V97.1.139. PMID 11133753.
External links
- MPL+protein,+human at the US 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.
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