The thrombopoietin receptor also known as the myeloproliferative leukemia protein or CD110 (Cluster of Differentiation 110) is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the MPL (myeloproliferative leukemia virus)
oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. .
Discovery
In 1990 an oncogene, v-mpl, was identified from the murine myeloproliferative
leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...
virus that was capable of immortalizing bone marrow
hematopoietic cells
Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem 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
SUPERFAMILY is a database and search platform of structural and functional annotation for all proteins and genomes. It classifies amino acid sequences into known structural domains, especially into SCOP superfamilies. Domains are functional, str ...
. Presence of anti-sense oligodeoxynucleotides of c-mpl inhibited megakaryocyte colony formation.
Function
The ligand for c-mpl,
thrombopoietin
Thrombopoietin (THPO) also known as megakaryocyte growth and development factor (MGDF) is a protein that in humans is encoded by the ''THPO'' gene.
Thrombopoietin is a glycoprotein hormone produced by the liver and kidney which regulates the pro ...
, 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
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
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ATXN2L
Ataxin-2-like protein was initially identified in 1996 and designated Ataxin-2 Related protein (A2RP) as the search for the gene causing SCA2 lead to the identification of 2 cDNA clones with high similarity to ATXN2 (Pulst et al, 1996). It was lat ...
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JAK2
Janus kinase 2 (commonly called JAK2) 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 (e.g. interferon receptors), the GM-CSF rec ...
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thrombopoietin
Thrombopoietin (THPO) also known as megakaryocyte growth and development factor (MGDF) is a protein that in humans is encoded by the ''THPO'' gene.
Thrombopoietin is a glycoprotein hormone produced by the liver and kidney which regulates the pro ...
Clinical relevance
Inactivating mutations in this gene have been shown to cause familial
aplastic anemia
Aplastic anemia is a cancer in which the body fails to make blood cells in sufficient numbers. Blood cells are produced in the bone marrow by stem cells that reside there. Aplastic anemia causes a deficiency of all blood cell types: red blood ...
.
Specific mutations to this gene are associated with
myelofibrosis
Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is growth of abnormal cells in the bone marrow. ...
and
essential thrombocythemia
Essential thrombocythemia (ET) is a rare chronic blood cancer (myeloproliferative neoplasm) characterised by the overproduction of platelets (thrombocytes) by megakaryocytes in the bone marrow. It may, albeit rarely, develop into acute myeloid leuk ...
.
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
A megakaryocyte (''mega-'' + '' karyo-'' + '' -cyte'', "large-nucleus cell") 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. In hum ...
.
See also
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Cluster of differentiation
The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophen ...
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Congenital amegakaryocytic thrombocytopenia
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited disorder.
Presentation
The primary manifestations are thrombocytopenia and megakaryocytopenia, or low numbers of platelets and megakaryocytes. There is an absence of megakaryo ...
References
Further reading
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External links
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{{Cytokine receptor modulators
Clusters of differentiation