Thrombopoietin receptor

Last updated
MPL
Identifiers
Aliases MPL , C-CD110, MPLV, THCYT2, TPOR, MPL proto-oncogene, thrombopoietin receptor
External IDs MGI: 97076 HomoloGene: 7845 GeneCards: MPL
Gene location (Human)
Ideogram human chromosome 1.svg
Chr. Chromosome 1 (human) [1]
Human chromosome 1 ideogram.svg
HSR 1996 II 3.5e.svg
Red rectangle 2x18.png
Band 1p34.2Start43,337,849 bp [1]
End43,352,772 bp [1]
RNA expression pattern
PBB GE MPL 207550 at fs.png

PBB GE MPL 211903 s at fs.png

PBB GE MPL 216825 s at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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: 118.44 – 118.46 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5]

Protein biological molecule consisting of chains of amino acid residues

Proteins are large biomolecules, or macromolecules, consisting of one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, providing structure to cells and organisms, and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the nucleotide sequence of their genes, and which usually results in protein folding into a specific three-dimensional structure that determines its activity.

Oncogene gene that has the potential to cause cancer

An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.

Contents

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.

Thrombopoietin protein-coding gene in the species Homo sapiens

Thrombopoietin (THPO) also known as megakaryocyte growth and development factor (MGDF) is a protein that in humans is encoded by the THPO gene.

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. [5]

Interactions

Myeloproliferative leukemia virus oncogene has been shown to interact with:

Clinical relevance

Inactivating mutations in this gene have been shown to cause familial aplastic anemia. [9]

Aplastic anaemia is a rare disease in which the bone marrow and the hematopoietic stem cells that reside there are damaged. This causes a deficiency of all three blood cell types (pancytopenia): red blood cells (anemia), white blood cells (leukopenia), and platelets (thrombocytopenia). Aplastic refers to the inability of stem cells to generate mature blood cells.

Specific mutations to this gene are associated with myelofibrosis and essential thrombocythemia. [10] 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. [11]

Primary myelofibrosis is a relatively rare bone marrow cancer. It is currently classified as a myeloproliferative neoplasm, in which the proliferation of an abnormal clone of hematopoietic stem cells in the bone marrow and other sites results in fibrosis, or the replacement of the marrow with scar tissue.

Essential thrombocythemia Human disease

Essential thrombocythemia (ET) is a rare chronic blood condition characterised by the overproduction of platelets (thrombocytes) by megakaryocytes in the bone marrow. It may, albeit rarely, develop into acute myeloid leukemia or myelofibrosis. It is one of four myeloproliferative neoplasms.

See also

Related Research Articles

Megakaryocyte

A megakaryocyte is a large bone marrow cell with a lobated nucleus responsible for the production of blood thrombocytes (platelets), which are necessary for normal blood clotting. Megakaryocytes usually account for 1 out of 10,000 bone marrow cells in normal people, but can increase in number nearly 10-fold during the course of certain diseases. Owing to variations in combining forms and spelling, synonyms include megalokaryocyte and megacaryocyte.

Philadelphia chromosome Philadelphia chromosome or Philadelphia translocation is a specific chromosomal abnormality that is associated with chronic myelogenous leukemia (CML).

The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells. This chromosome is defective and unusually short because of reciprocal translocation, t(9;22)(q34;q11), of genetic material between chromosome 9 and chromosome 22, and contains a fusion gene called BCR-ABL1. This gene is the ABL1 gene of chromosome 9 juxtaposed onto the breakpoint cluster region BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signalling protein that is "always on", causing the cell to divide uncontrollably by interrupting the stability of the genome and impairing various signaling pathways governing the cell cycle.

The myeloproliferative neoplasms (MPNs), previously myeloproliferative diseases (MPDs), are a group of diseases of the bone marrow in which excess cells are produced. They are related to, and may evolve into, myelodysplastic syndrome and acute myeloid leukemia, although the myeloproliferative diseases on the whole have a much better prognosis than these conditions. The concept of myeloproliferative disease was first proposed in 1951 by the hematologist William Dameshek. In the most recent World Health Organization classification of hematologic malignancies, this group of diseases was renamed from "myeloproliferative diseases" to "myeloproliferative neoplasms". This reflects the underlying clonal genetic changes that are a salient feature of this group of disease.

Mean platelet volume (MPV) is a machine-calculated measurement of the average size of platelets found in blood and is typically included in blood tests as part of the CBC. Since the average platelet size is larger when the body is producing increased numbers of platelets, the MPV test results can be used to make inferences about platelet production in bone marrow or platelet destruction problems.

GATA1 protein-coding gene in the species Homo sapiens

GATA-binding factor 1 or GATA-1 is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded by the GATA1 and Gata1 genes, respectively. These genes are located on the X chromosome in both species.

STAT5

Signal transducer and activator of transcription 5 (STAT5) refers to two highly related proteins, STAT5A and STAT5B, which are part of the seven-membered STAT family of proteins. Though STAT5A and STAT5B are encoded by separate genes, the proteins are 90% identical at the amino acid level. STAT5 proteins are involved in cytosolic signalling and in mediating the expression of specific genes. Aberrant STAT5 activity has been shown to be closely connected to a wide range of human cancers, and silencing this aberrant activity is an area of active research in medicinal chemistry.

Tyrosine kinase 2 protein-coding gene in the species Homo sapiens

Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the TYK2 gene.

Janus kinase 2 protein-coding gene in the species Homo sapiens

Janus kinase 2 is a non-receptor tyrosine kinase. It is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptor family, the GM-CSF receptor family, the gp130 receptor family, and the single chain receptors.

ETV6 protein-coding gene in the species Homo sapiens

ETV6 protein is a transcription factor that in humans is encoded by the ETV6 gene. The ETV6 protein regulates the development and growth of diverse cell types, particularly those of hematological tissues. However, its gene, ETV6 frequently suffers various mutations that lead to an array of potentially lethal cancers, i.e., ETV6 is a clinically significant proto-oncogene in that it can fuse with other genes to drive the development and/or progression of certain cancers. However, ETV6 is also an anti-oncogene or tumor suppressor gene in that mutations in it that encode for a truncated and therefore inactive protein are also associated with certain types of cancers.

Eltrombopag chemical compound

Eltrombopag is a medication that has been developed for certain conditions that lead to thrombocytopenia. It is a small molecule agonist of the c-mpl (TpoR) receptor, which is the physiological target of the hormone thrombopoietin. Eltrombopag was discovered as a result of research collaboration between GlaxoSmithKline and Ligand Pharmaceuticals. Designated an orphan drug in the United States and European Union, it is being manufactured and marketed by Novartis under the trade name Promacta in the USA and is marketed as Revolade in the EU. Novartis acquired the drug as a part of its asset swap deal with GlaxoSmithKline.

AXL receptor tyrosine kinase protein-coding gene in the species Homo sapiens

Tyrosine-protein kinase receptor UFO is an enzyme that in humans is encoded by the AXL gene. The gene was initially designated as UFO, in allusion to the unidentified function of this protein. However, in the years since its discovery, research into AXL's expression profile and mechanism has made it an increasingly attractive target, especially for cancer therapeutics. In recent years, AXL has emerged as a key facilitator of immune escape and drug-resistance by cancer cells, leading to aggressive and metastatic cancers.

SH2B3 protein-coding gene in the species Homo sapiens

SH2B adapter protein 3 (SH2B3), also known as lymphocyte adapter protein (LNK), is a protein that in humans is encoded by the SH2B3 gene on chromosome 12.

Congenital amegakaryocytic thrombocytopenia thrombocytopenia characterized by a severe reduction in megakaryocyte and platelet numbers that has material basis in homozygous or compound heterozygous mutation in the MPL gene on chromosome 1p34

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited disorder.

Kenneth Kaushansky, M.D., Master of the American College of Physicians (MACP) is an American medical doctor, hematologist, former editor of the medical journal Blood, and has served as the Dean of the Stony Brook University School of Medicine since July 2010. Prior to moving to Stony Brook, he was the Helen M. Ranney Professor, and Chair of the Department of Medicine at University of California, San Diego School of Medicine.

CMPL might stand for:

Clonal hypereosinophilia, also termed primary hypereosinophilia or clonal eosinophilia, is a grouping of hematological disorders all of which are characterized by the development and growth of a pre-malignant or malignant population of eosinophils, a type of white blood cell that occupies the bone marrow, blood, and other tissues. This population consists of a clone of eosinophils, i.e. a group of genetically identical eosinophils derived from a sufficiently mutated ancestor cell.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000117400 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000006389 - Ensembl, May 2017
  3. "Human PubMed Reference:".
  4. "Mouse PubMed Reference:".
  5. 1 2 "Entrez Gene: MPL myeloproliferative leukemia virus oncogene".
  6. 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. PMID   11784712.
  7. Bellido M, Te Boekhorst PA (2012). "JAK2 Inhibition: Reviewing a New Therapeutical Option in Myeloproliferative Neoplasms". Adv Hematol. 2012: 535709. doi:10.1155/2012/535709. PMC   3286888 Lock-green.svg. PMID   22400031.
  8. Nakaya Y, Shide K, Niwa T, Homan J, Sugahara S, Horio T, Kuramoto K, Kotera T, Shibayama H, Hori K, Naito H, Shimoda K (2011). "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. doi:10.1038/bcj.2011.29. PMC   3255248 Lock-green.svg. PMID   22829185.
  9. Walne AJ, Dokal A, Plagnol V, Beswick R, Kirwan M, de la Fuente J, Vulliamy T, Dokal I (December 2011). "Exome sequencing identifies MPL as a causative gene in familial aplastic anemia". Haematologica. 97 (4): 524–8. doi:10.3324/haematol.2011.052787. PMC   3347658 Lock-green.svg. PMID   22180433.
  10. 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. ISSN   0887-6924.
  11. 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. PMC   3035972 Lock-green.svg. PMID   20428194.

Further reading

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