Thrombopoietin

THPO
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1V7M, 1V7N
Identifiers
Aliases	THPO, MGDF, MKCSF, ML, MPLLG, THCYT1, TPO, thrombopoietin
External IDs	OMIM: 600044 MGI: 101875 HomoloGene: 398 GeneCards: THPO
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3q27.1 Start 184,371,935 bp[1] End 184,381,968 bp[1]
Gene location (Mouse) Chr. Chromosome 16 (mouse)[2] Band 16 B1|16 12.51 cM Start 20,543,204 bp[2] End 20,553,261 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lobe of liver cingulate gyrus Brodmann area 9 right adrenal gland canal of the cervix left adrenal gland gastrocnemius muscle amygdala kidney prefrontal cortex Top expressed in yolk sac proximal tubule superior frontal gyrus left lobe of liver skeletal muscle tissue upper arm cerebellar cortex triceps brachii muscle kidney triceps surae More reference expression data BioGPS More reference expression data
Gene ontology Molecular function cytokine activity growth factor activity hormone activity signaling receptor binding Cellular component extracellular region extracellular space Biological process multicellular organism development positive regulation of hematopoietic stem cell proliferation cell population proliferation regulation of signaling receptor activity positive regulation of protein phosphorylation thrombopoietin-mediated signaling pathway positive regulation of megakaryocyte differentiation positive regulation of protein kinase B signaling positive regulation of ERK1 and ERK2 cascade positive regulation of cell population proliferation myeloid cell differentiation megakaryocyte development positive regulation of MAPK cascade receptor signaling pathway via STAT Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 7066 21832 Ensembl ENSG00000090534 ENSMUSG00000022847 UniProt P40225 P40226 RefSeq (mRNA) NM_000460 NM_001177597 NM_001177598 NM_001289997 NM_001289998 NM_001290003 NM_001290022 NM_001290026 NM_001290027 NM_001290028 NM_199228 NM_199356 NM_001173505 NM_009379 NM_001289894 NM_001289896 RefSeq (protein) NP_000451 NP_001171068 NP_001171069 NP_001276926 NP_001276927 NP_001276932 NP_001276951 NP_001276955 NP_001276956 NP_001276957 NP_001166976 NP_001276823 NP_001276825 NP_033405 Location (UCSC) Chr 3: 184.37 – 184.38 Mb Chr 16: 20.54 – 20.55 Mb PubMed search [3] [4]
Wikidata
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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 production of platelets. It stimulates the production and differentiation of megakaryocytes, the bone marrow cells that bud off large numbers of platelets.^[5]

Megakaryocytopoiesis is the cellular development process that leads to platelet production. The protein encoded by this gene is a humoral growth factor necessary for megakaryocyte proliferation and maturation, as well as for thrombopoiesis. This protein is the ligand for MLP/C_MPL, the product of myeloproliferative leukemia virus oncogene.^[6]

Genetics

The thrombopoietin gene is located on the long arm of chromosome 3 (q26.3-27). Abnormalities in this gene occur in some hereditary forms of thrombocytosis (high platelet count) and in some cases of leukemia. The first 155 amino acids of the protein share homology with erythropoietin.^[7]

Function and regulation

Thrombopoietin is produced in the liver by both parenchymal cells and sinusoidal endothelial cells, as well as in the kidney by proximal convoluted tubule cells. Small amounts are also made by striated muscle and bone marrow stromal cells.^[5] In the liver, its production is augmented by interleukin 6 (IL-6).^[5] However, the liver and the kidney are the primary sites of thrombopoietin production.

Thrombopoietin regulates the differentiation of megakaryocytes and platelets, but studies on the removal of the thrombopoietin receptor show that its effects on hematopoiesis are more versatile.^[5]

Its negative feedback is different from that of most hormones in endocrinology: The effector regulates the hormone directly. Thrombopoietin is bound to the surface of platelets and megakaryocytes by the mpl receptor (CD 110). Inside the platelets it gets destroyed, while inside the megakaryocytes it gives the signal of their maturation and consecutively more platelet production. The bounding of the hormone at these cells thereby reduces further megakaryocyte exposure to the hormone.^[5] Therefore, the rising and dropping platelet and megakaryocyte concentrations regulate the thrombopoietin levels. Low platelets and megakaryocytes lead a higher degree of thrombopoietin exposure to the undifferentiated bone marrow cells, leading to differentiation into megakaryocytes and further maturation of these cells. On the other hand, high platelet and megakaryocyte concentrations lead to more thrombopoetin destruction and thus less availability of thrombopoietin to bone marrow.

TPO, like EPO, plays a role in brain development. It promotes apoptosis of newly generated neurons, an effect counteracted by EPO and neurotrophins.^[8]

Therapeutic use

Despite numerous trials, thrombopoietin has not been found to be useful therapeutically. Theoretical uses include the procurement of platelets for donation,^[9] and recovery of platelet counts after myelosuppressive chemotherapy.^[5]

Trials of a modified recombinant form, megakaryocyte growth and differentiation factor (MGDF), were stopped when healthy volunteers developed autoantibodies to endogenous thrombopoietin and then developed thrombocytopenia.^[10] Romiplostim and Eltrombopag, structurally different compounds that stimulate the same pathway, are used instead.^[11]

A quadrivalent peptide analogue is being investigated, as well as several small-molecule agents,^[5] and several non-peptide ligands of c-Mpl, which act as thrombopoietin analogues.^[12][13]

Discovery

Thrombopoietin was cloned by five independent teams in 1994. Before its identification, its function has been hypothesized for as much as 30 years as being linked to the cell surface receptor c-Mpl, and in older publications thrombopoietin is described as c-Mpl ligand (the agent that binds to the c-Mpl molecule). Thrombopoietin is one of the Class I hematopoietic cytokines.^[5]

See also

• Thrombopoietic agent

References

Further reading

External links

• Longer summary on thrombopoietin