ID TPO_HUMAN Reviewed; 353 AA.
AC P40225; A1L3Y0; B7ZLR8; B9EGA8; Q13020; Q15790; Q15791; Q15792;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1995, sequence version 1.
DT 01-MAY-2013, entry version 129.
DE RecName: Full=Thrombopoietin;
DE AltName: Full=C-mpl ligand;
DE Short=ML;
DE AltName: Full=Megakaryocyte colony-stimulating factor;
DE AltName: Full=Megakaryocyte growth and development factor;
DE Short=MGDF;
DE AltName: Full=Myeloproliferative leukemia virus oncogene ligand;
DE Flags: Precursor;
GN Name=THPO; Synonyms=MGDF;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Fetal liver;
RX PubMed=8202154; DOI=10.1038/369533a0;
RA de Sauvage F.J., Hass P.E., Spencer S.D., Malloy B.E., Gurney A.L.,
RA Spencer S.A., Darbonne W.C., Henzel W.J., Wong S.C., Kuang W.-J.,
RA Oles K.J., Hultgren B., Solberg L.A. Jr., Goeddel D.V., Eaton D.L.;
RT "Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl
RT ligand.";
RL Nature 369:533-538(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Fetal liver;
RX PubMed=8020099; DOI=10.1016/0092-8674(94)90450-2;
RA Bartley T.D., Bogenberger J., Hunt P., Li Y.-S., Lu H.S., Martin F.,
RA Chang M.-S., Samal B.B., Nichol J.L., Swift S., Johnson M.J.,
RA Hsu R.-Y., Parker V.P., Suggs S., Skrine J.D., Merewether L.A.,
RA Clogson C., Hsu E., Hokom M.M., Hornkohl A., Choi E., Pangelinan M.,
RA Sun Y., Mar V., McNich J., Simonet L., Jacobsen F., Xie C.,
RA Shutter J., Chute H., Basu R., Selander L., Trollinger D., Sieu L.,
RA Padilla D., Trail G., Elliott G., Izumi R., Covey T., Crouse J.,
RA Garcia A., Xu W., del Castillo J., Biron J., Cole S., Hu M.C.-T.,
RA Pacifici R., Ponting I., Saris C., Wen D., Yung Y.P., Lin H.,
RA Bosselman R.A.;
RT "Identification and cloning of a megakaryocyte growth and development
RT factor that is a ligand for the cytokine receptor Mpl.";
RL Cell 77:1117-1124(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1).
RX PubMed=7809166; DOI=10.1073/pnas.91.26.13023;
RA Foster D.C., Sprecher C.A., Grant F.J., Kramer J.M., Kuijper J.L.,
RA Holly R.D., Whitmore T.E., Heipel M.D., Bell L.A.N., Ching A.F.,
RA McGrane V., Hart C., O'Hara P.J., Lok S.;
RT "Human thrombopoietin: gene structure, cDNA sequence, expression, and
RT chromosomal localization.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:13023-13027(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RX PubMed=7926023; DOI=10.1016/0014-5793(94)01008-0;
RA Sohma Y., Akahori H., Seki N., Hori T.-A., Ogami K., Kawamura K.,
RA Miyazaki H.;
RT "Molecular cloning and chromosomal localization of the human
RT thrombopoietin gene.";
RL FEBS Lett. 353:57-61(1994).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1 AND 2).
RX PubMed=7849319;
RA Gurney A.L., Kuang W.-J., Xie M.-H., Malloy B.E., Eaton D.L.,
RA de Sauvage F.J.;
RT "Genomic structure, chromosomal localization, and conserved
RT alternative splice forms of thrombopoietin.";
RL Blood 85:981-988(1995).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=8537317;
RA Kato T., Ogami K., Shimada Y., Iwamatsu A., Sohma Y., Akahori H.,
RA Horie K., Kokubo A., Kudo Y., Maeda E., Kobayashi K., Ohashi H.,
RA Ozawa T., Inoue H., Kawamura K., Miyazaki H.;
RT "Purification and characterization of thrombopoietin.";
RL J. Biochem. 118:229-236(1995).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=7822271; DOI=10.1074/jbc.270.2.685;
RA Chang M., McNinch J., Basu R., Shutter J., Hsu R., Perkins C., Mar V.,
RA Suggs S., Welcher A., Li L., Lu H., Bartley T., Hunt P., Martin F.,
RA Samal B., Bogenberger J.;
RT "Cloning and characterization of the human megakaryocyte growth and
RT development factor (MGDF) gene.";
RL J. Biol. Chem. 270:511-514(1995).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1 AND 3).
RA Im S.H., Lee W.S., Chung K.H.;
RT "Cloning and sequencing of human thrombopoietin.";
RL Submitted (MAY-1996) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain, and Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP DISEASE.
RX PubMed=9425899; DOI=10.1038/ng0198-49;
RA Wiestner A., Schlemper R.J., van der Maas A.P.C., Skoda R.C.;
RT "An activating splice donor mutation in the thrombopoietin gene causes
RT hereditary thrombocythaemia.";
RL Nat. Genet. 18:49-52(1998).
RN [11]
RP DISULFIDE BONDS, AND GLYCOSYLATION AT SER-22; THR-58; THR-131;
RP THR-179; THR-180; SER-184; ASN-197; ASN-206; THR-213; ASN-234; ASN-255
RP AND SER-265.
RX PubMed=8942648; DOI=10.1021/bi961075b;
RA Hoffman R.C., Andersen H., Walker K., Krakover J.D., Patel S.,
RA Stamm M.R., Osborn S.G.;
RT "Peptide, disulfide, and glycosylation mapping of recombinant human
RT thrombopoietin from ser1 to Arg246.";
RL Biochemistry 35:14849-14861(1996).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (2.51 ANGSTROMS) OF 22-184 IN COMPLEX WITH
RP ANTIBODY, AND DISULFIDE BONDS.
RX PubMed=14769915; DOI=10.1073/pnas.0308530100;
RA Feese M.D., Tamada T., Kato Y., Maeda Y., Hirose M., Matsukura Y.,
RA Shigematsu H., Muto T., Matsumoto A., Watarai H., Ogami K., Tahara T.,
RA Kato T., Miyazaki H., Kuroki R.;
RT "Structure of the receptor-binding domain of human thrombopoietin
RT determined by complexation with a neutralizing antibody fragment.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:1816-1821(2004).
CC -!- FUNCTION: Lineage-specific cytokine affecting the proliferation
CC and maturation of megakaryocytes from their committed progenitor
CC cells. It acts at a late stage of megakaryocyte development. It
CC may be the major physiological regulator of circulating platelets.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P40225-1; Sequence=Displayed;
CC Name=2; Synonyms=TPO-2;
CC IsoId=P40225-2; Sequence=VSP_001450;
CC Name=3; Synonyms=Truncated;
CC IsoId=P40225-3; Sequence=VSP_001451;
CC -!- DOMAIN: Two-domain structure with an erythropoietin-like N-
CC terminal and a Ser/Pro/Thr-rich C-terminal.
CC -!- DISEASE: Thrombocythemia 1 (THCYT1) [MIM:187950]: A
CC myeloproliferative disorder characterized by excessive platelet
CC production, resulting in increased numbers of circulating
CC platelets. It can be associated with spontaneous hemorrhages and
CC thrombotic episodes. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the EPO/TPO family.
CC -!- WEB RESOURCE: Name=R&D Systems' cytokine source book:
CC Thrombopoietin;
CC URL="http://www.rndsystems.com/molecule_detail.aspx?m=2168";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/TPO";
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DR EMBL; L33410; AAA59857.1; -; mRNA.
DR EMBL; U11025; AAA50553.1; -; mRNA.
DR EMBL; L36051; AAC37568.1; -; Genomic_DNA.
DR EMBL; L36052; AAC37566.1; -; mRNA.
DR EMBL; D32046; BAA06807.1; -; Genomic_DNA.
DR EMBL; S76771; AAB33390.1; -; Genomic_DNA.
DR EMBL; D32047; BAA21930.1; -; mRNA.
DR EMBL; U59493; AAB03392.1; -; mRNA.
DR EMBL; U59494; AAB03393.1; -; mRNA.
DR EMBL; U59495; AAB03394.1; -; mRNA.
DR EMBL; U17071; AAA74083.1; -; Genomic_DNA.
DR EMBL; BC130322; AAI30323.1; -; mRNA.
DR EMBL; BC136338; AAI36339.1; -; mRNA.
DR EMBL; BC143982; AAI43983.1; -; mRNA.
DR IPI; IPI00218254; -.
DR IPI; IPI00219943; -.
DR IPI; IPI00411545; -.
DR PIR; G02729; G02729.
DR PIR; I59281; I80105.
DR RefSeq; NP_000451.1; NM_000460.2.
DR RefSeq; NP_001171068.1; NM_001177597.1.
DR RefSeq; NP_001171069.1; NM_001177598.1.
DR UniGene; Hs.1166; -.
DR UniGene; Hs.734657; -.
DR PDB; 1V7M; X-ray; 2.51 A; V/X=22-184.
DR PDB; 1V7N; X-ray; 3.30 A; V/X/Y/Z=22-184.
DR PDBsum; 1V7M; -.
DR PDBsum; 1V7N; -.
DR ProteinModelPortal; P40225; -.
DR DIP; DIP-5729N; -.
DR IntAct; P40225; 3.
DR STRING; 9606.ENSP00000204615; -.
DR PhosphoSite; P40225; -.
DR DMDM; 730982; -.
DR PaxDb; P40225; -.
DR PRIDE; P40225; -.
DR DNASU; 7066; -.
DR Ensembl; ENST00000204615; ENSP00000204615; ENSG00000090534.
DR Ensembl; ENST00000445696; ENSP00000410763; ENSG00000090534.
DR GeneID; 7066; -.
DR KEGG; hsa:7066; -.
DR UCSC; uc003fol.1; human.
DR UCSC; uc003fom.2; human.
DR CTD; 7066; -.
DR GeneCards; GC03M184089; -.
DR HGNC; HGNC:11795; THPO.
DR MIM; 187950; phenotype.
DR MIM; 600044; gene.
DR neXtProt; NX_P40225; -.
DR Orphanet; 71493; Familial thrombocytosis.
DR PharmGKB; PA36506; -.
DR eggNOG; NOG84342; -.
DR HOVERGEN; HBG002468; -.
DR InParanoid; P40225; -.
DR KO; K06854; -.
DR OMA; CPDVNPL; -.
DR OrthoDB; EOG4HT8SV; -.
DR Reactome; REACT_604; Hemostasis.
DR ChEMBL; CHEMBL1293256; -.
DR EvolutionaryTrace; P40225; -.
DR GenomeRNAi; 7066; -.
DR NextBio; 27627; -.
DR PMAP-CutDB; P40225; -.
DR ArrayExpress; P40225; -.
DR Bgee; P40225; -.
DR CleanEx; HS_THPO; -.
DR Genevestigator; P40225; -.
DR GermOnline; ENSG00000090534; Homo sapiens.
DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW.
DR GO; GO:0008083; F:growth factor activity; TAS:ProtInc.
DR GO; GO:0008283; P:cell proliferation; TAS:ProtInc.
DR GO; GO:0007275; P:multicellular organismal development; TAS:ProtInc.
DR GO; GO:0030099; P:myeloid cell differentiation; IEA:Compara.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR Gene3D; 1.20.1250.10; -; 1.
DR InterPro; IPR009079; 4_helix_cytokine-like_core.
DR InterPro; IPR012351; 4_helix_cytokine_core.
DR InterPro; IPR019767; EPO/TPO_CS.
DR InterPro; IPR001323; EPO_TPO.
DR InterPro; IPR003978; Thrombopoeitin.
DR PANTHER; PTHR10560; PTHR10560; 1.
DR Pfam; PF00758; EPO_TPO; 1.
DR PRINTS; PR01485; THROMBOPTN.
DR SUPFAM; SSF47266; 4_helix_cytokine; 1.
DR PROSITE; PS00817; EPO_TPO; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; Cytokine;
KW Disulfide bond; Glycoprotein; Hormone; Polymorphism;
KW Reference proteome; Secreted; Signal.
FT SIGNAL 1 21
FT CHAIN 22 353 Thrombopoietin.
FT /FTId=PRO_0000008411.
FT COMPBIAS 285 337 Pro-rich.
FT CARBOHYD 22 22 O-linked (GalNAc...).
FT CARBOHYD 58 58 O-linked (GalNAc...).
FT CARBOHYD 131 131 O-linked (GalNAc...).
FT CARBOHYD 179 179 O-linked (GalNAc...).
FT CARBOHYD 180 180 O-linked (GalNAc...).
FT CARBOHYD 184 184 O-linked (GalNAc...).
FT CARBOHYD 197 197 N-linked (GlcNAc...) (complex).
FT CARBOHYD 206 206 N-linked (GlcNAc...) (complex).
FT CARBOHYD 213 213 O-linked (GalNAc...).
FT CARBOHYD 234 234 N-linked (GlcNAc...) (complex).
FT CARBOHYD 255 255 N-linked (GlcNAc...) (complex).
FT CARBOHYD 265 265 O-linked (GalNAc...).
FT CARBOHYD 340 340 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 348 348 N-linked (GlcNAc...) (Potential).
FT DISULFID 28 172
FT DISULFID 50 106
FT VAR_SEQ 133 136 Missing (in isoform 2).
FT /FTId=VSP_001450.
FT VAR_SEQ 160 198 Missing (in isoform 3).
FT /FTId=VSP_001451.
FT VARIANT 14 14 L -> P (in dbSNP:rs1042346).
FT /FTId=VAR_011795.
FT VARIANT 116 116 G -> E (in dbSNP:rs1126665).
FT /FTId=VAR_011796.
FT CONFLICT 46 46 R -> K (in Ref. 8; AAB03392/AAB03393/
FT AAB03394).
FT CONFLICT 76 76 M -> MSQ (in Ref. 7; AAA74083).
FT CONFLICT 113 113 Q -> E (in Ref. 2; AAA50553).
FT CONFLICT 131 131 T -> P (in Ref. 7; AAA74083).
FT CONFLICT 277 277 G -> E (in Ref. 8; AAB03393/AAB03394).
FT CONFLICT 346 346 S -> C (in Ref. 8; AAB03393/AAB03394).
FT HELIX 32 45
FT HELIX 46 48
FT STRAND 49 52
FT STRAND 60 63
FT HELIX 70 74
FT HELIX 77 98
FT TURN 99 101
FT STRAND 104 106
FT HELIX 107 110
FT HELIX 113 129
FT STRAND 139 143
FT HELIX 145 147
FT HELIX 148 157
FT TURN 158 160
FT HELIX 161 163
FT STRAND 165 167
SQ SEQUENCE 353 AA; 37823 MW; F0AB5449B72E5526 CRC64;
MELTELLLVV MLLLTARLTL SSPAPPACDL RVLSKLLRDS HVLHSRLSQC PEVHPLPTPV
LLPAVDFSLG EWKTQMEETK AQDILGAVTL LLEGVMAARG QLGPTCLSSL LGQLSGQVRL
LLGALQSLLG TQLPPQGRTT AHKDPNAIFL SFQHLLRGKV RFLMLVGGST LCVRRAPPTT
AVPSRTSLVL TLNELPNRTS GLLETNFTAS ARTTGSGLLK WQQGFRAKIP GLLNQTSRSL
DQIPGYLNRI HELLNGTRGL FPGPSRRTLG APDISSGTSD TGSLPPNLQP GYSPSPTHPP
TGQYTLFPLP PTLPTPVVQL HPLLPDPSAP TPTPTSPLLN TSYTHSQNLS QEG
//
