Skip Header

You are using a version of Internet Explorer that may not display all features of this website. Please upgrade to a modern browser.
Contribute Send feedback
Read comments (?) or add your own

P40238 (TPOR_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 145. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Thrombopoietin receptor

Short name=TPO-R
Alternative name(s):
Myeloproliferative leukemia protein
Proto-oncogene c-Mpl
CD_antigen=CD110
Gene names
Name:MPL
Synonyms:TPOR
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length635 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Receptor for thrombopoietin. May represent a regulatory molecule specific for TPO-R-dependent immune responses.

Subunit structure

Interacts with ATXN2L. Ref.8

Subcellular location

Membrane; Single-pass type I membrane protein.

Tissue specificity

Expressed at a low level in a large number of cells of hematopoietic origin. Isoform 1 and isoform 2 are always found to be coexpressed.

Domain

The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.

The box 1 motif is required for JAK interaction and/or activation.

Post-translational modification

Ubiquitination at Lys-553 and Lys-573 targets MPL for degradation by both the lysosomal and proteasomal pathways. The E3 ubiquitin-protein ligase CBL significantly contributes to this ubiquitination.

Involvement in disease

Congenital amegakaryocytic thrombocytopenia (CAMT) [MIM:604498]: Disease characterized by isolated thrombocytopenia and megakaryocytopenia with no physical anomalies.
Note: The disease is caused by mutations affecting the gene represented in this entry.

Thrombocythemia 2 (THCYT2) [MIM:601977]: A myeloproliferative disorder characterized by excessive platelet production, resulting in increased numbers of circulating platelets. It can be associated with spontaneous hemorrhages and thrombotic episodes.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.9 Ref.13 Ref.14

Myelofibrosis with myeloid metaplasia (MMM) [MIM:254450]: A chronic myeloproliferative disorder characterized by replacement of the bone marrow by fibrous tissue, extramedullary hematopoiesis, anemia, leukoerythroblastosis and hepatosplenomegaly.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.11 Ref.12

Sequence similarities

Belongs to the type I cytokine receptor family. Type 1 subfamily.

Contains 2 fibronectin type-III domains.

Caution

It is uncertain whether Met-1 or Met-8 is the initiator.

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P40238-1)

Also known as: C-mpl-P;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: P40238-2)

Also known as: C-mpl-K;

The sequence of this isoform differs from the canonical sequence as follows:
     523-579: RLRHALWPSL...ILPKSSERTP → YRPRQAGDWR...LWDSPRLLTL
     580-635: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2525 Potential
Chain26 – 635610Thrombopoietin receptor
PRO_0000010987

Regions

Topological domain26 – 491466Extracellular Potential
Transmembrane492 – 51322Helical; Potential
Topological domain514 – 635122Cytoplasmic Potential
Domain172 – 281110Fibronectin type-III 1
Domain392 – 48695Fibronectin type-III 2
Motif474 – 4785WSXWS motif
Motif528 – 5369Box 1 motif
Compositional bias335 – 3384Poly-Glu
Compositional bias508 – 5136Poly-Leu

Amino acid modifications

Glycosylation1171N-linked (GlcNAc...) Potential
Glycosylation1781N-linked (GlcNAc...) Potential
Glycosylation2981N-linked (GlcNAc...) Potential
Glycosylation3581N-linked (GlcNAc...) Potential
Disulfide bond40 ↔ 50 By similarity
Disulfide bond77 ↔ 93 By similarity
Disulfide bond291 ↔ 301 By similarity
Disulfide bond323 ↔ 334 By similarity
Cross-link553Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.5
Cross-link573Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)

Natural variations

Alternative sequence523 – 57957RLRHA…SERTP → YRPRQAGDWRWTRWSRTCKQ AFLVRSVTPDLRPPPVRTYG FALPARHLWDSPRLLTL in isoform 2.
VSP_001734
Alternative sequence580 – 63556Missing in isoform 2.
VSP_001735
Natural variant391K → N Functional polymorphism associated with thrombocytosis; results in altered MPL expression. Ref.10
Corresponds to variant rs17292650 [ dbSNP | Ensembl ].
VAR_049173
Natural variant581A → V. Ref.6
Corresponds to variant rs6087 [ dbSNP | Ensembl ].
VAR_011988
Natural variant1141V → M.
Corresponds to variant rs12731981 [ dbSNP | Ensembl ].
VAR_049174
Natural variant1681E → K. Ref.6
Corresponds to variant rs6088 [ dbSNP | Ensembl ].
VAR_011989
Natural variant5051S → N in THCYT2; activating mutation; induces MPL autonomous dimerization and signal activation in the absence of the ligand. Ref.9 Ref.13
Corresponds to variant rs121913614 [ dbSNP | Ensembl ].
VAR_067559
Natural variant5151W → K in MMM; somatic mutation; requires 2 nucleotide substitutions. Ref.11
VAR_067560
Natural variant5151W → L in THCYT2 and MMM; somatic mutation in myelofibrosis with myeloid metaplasia; results in cytokine-independent growth and thrombopoietin hypersensitivity; results in constitutive activation of JAK-STAT signaling pathway. Ref.12 Ref.14
Corresponds to variant rs121913615 [ dbSNP | Ensembl ].
VAR_067561

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (C-mpl-P) [UniParc].

Last modified February 1, 1995. Version 1.
Checksum: D25D8D8959359DDC

FASTA63571,245
        10         20         30         40         50         60 
MPSWALFMVT SCLLLAPQNL AQVSSQDVSL LASDSEPLKC FSRTFEDLTC FWDEEEAAPS 

        70         80         90        100        110        120 
GTYQLLYAYP REKPRACPLS SQSMPHFGTR YVCQFPDQEE VRLFFPLHLW VKNVFLNQTR 

       130        140        150        160        170        180 
TQRVLFVDSV GLPAPPSIIK AMGGSQPGEL QISWEEPAPE ISDFLRYELR YGPRDPKNST 

       190        200        210        220        230        240 
GPTVIQLIAT ETCCPALQRP HSASALDQSP CAQPTMPWQD GPKQTSPSRE ASALTAEGGS 

       250        260        270        280        290        300 
CLISGLQPGN SYWLQLRSEP DGISLGGSWG SWSLPVTVDL PGDAVALGLQ CFTLDLKNVT 

       310        320        330        340        350        360 
CQWQQQDHAS SQGFFYHSRA RCCPRDRYPI WENCEEEEKT NPGLQTPQFS RCHFKSRNDS 

       370        380        390        400        410        420 
IIHILVEVTT APGTVHSYLG SPFWIHQAVR LPTPNLHWRE ISSGHLELEW QHPSSWAAQE 

       430        440        450        460        470        480 
TCYQLRYTGE GHQDWKVLEP PLGARGGTLE LRPRSRYRLQ LRARLNGPTY QGPWSSWSDP 

       490        500        510        520        530        540 
TRVETATETA WISLVTALHL VLGLSAVLGL LLLRWQFPAH YRRLRHALWP SLPDLHRVLG 

       550        560        570        580        590        600 
QYLRDTAALS PPKATVSDTC EEVEPSLLEI LPKSSERTPL PLCSSQAQMD YRRLQPSCLG 

       610        620        630 
TMPLSVCPPM AESGSCCTTH IANHSYLPLS YWQQP 

« Hide

Isoform 2 (C-mpl-K) [UniParc].

Checksum: 7A1431E9F64E21D4
Show »

FASTA57965,521

References

« Hide 'large scale' references
[1]"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."
Vigon I., Mornon J.-P., Cocault L., Mitjavila M.-T., Tambourin P., Gisselbrecht S., Souyri M.
Proc. Natl. Acad. Sci. U.S.A. 89:5640-5644(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
[2]"Structure and transcription of the human c-mpl gene (MPL)."
Mignotte V., Vigon I., Boucher de Crevecoeur E., Romeo P.-H., Lemarchandel V., Chretien S.
Genomics 20:5-12(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE (ISOFORMS 1 AND 2).
[3]"The DNA sequence and biological annotation of human chromosome 1."
Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. expand/collapse author list , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.
Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]"Ubiquitination and degradation of the thrombopoietin receptor c-Mpl."
Saur S.J., Sangkhae V., Geddis A.E., Kaushansky K., Hitchcock I.S.
Blood 115:1254-1263(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION AT LYS-553 AND LYS573.
[6]"Characterization of single-nucleotide polymorphisms in coding regions of human genes."
Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., Lander E.S.
Nat. Genet. 22:231-238(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS VAL-58 AND LYS-168.
[7]Erratum
Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., Lander E.S.
Nat. Genet. 23:373-373(1999)
[8]"Cloning and characterization of a family of proteins associated with Mpl."
Meunier C.F., Bordereaux D., Porteu F., Gisselbrecht S., Chretien S., Courtois G.
J. Biol. Chem. 277:9139-9147(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ATXN2L.
[9]"Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin."
Ding J., Komatsu H., Wakita A., Kato-Uranishi M., Ito M., Satoh A., Tsuboi K., Nitta M., Miyazaki H., Iida S., Ueda R.
Blood 103:4198-4200(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT THCYT2 ASN-505.
[10]"Mpl Baltimore: a thrombopoietin receptor polymorphism associated with thrombocytosis."
Moliterno A.R., Williams D.M., Gutierrez-Alamillo L.I., Salvatori R., Ingersoll R.G., Spivak J.L.
Proc. Natl. Acad. Sci. U.S.A. 101:11444-11447(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT ASN-39, CHARACTERIZATION OF VARIANT ASN-39.
[11]"MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients."
Pardanani A.D., Levine R.L., Lasho T., Pikman Y., Mesa R.A., Wadleigh M., Steensma D.P., Elliott M.A., Wolanskyj A.P., Hogan W.J., McClure R.F., Litzow M.R., Gilliland D.G., Tefferi A.
Blood 108:3472-3476(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT MMM LYS-515.
[12]"MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia."
Pikman Y., Lee B.H., Mercher T., McDowell E., Ebert B.L., Gozo M., Cuker A., Wernig G., Moore S., Galinsky I., DeAngelo D.J., Clark J.J., Lee S.J., Golub T.R., Wadleigh M., Gilliland D.G., Levine R.L.
PLoS Med. 3:E270-E270(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT MMM LEU-515, CHARACTERIZATION OF VARIANT MMM LEU-515.
[13]"The Asn505 mutation of the c-MPL gene, which causes familial essential thrombocythemia, induces autonomous homodimerization of the c-Mpl protein due to strong amino acid polarity."
Ding J., Komatsu H., Iida S., Yano H., Kusumoto S., Inagaki A., Mori F., Ri M., Ito A., Wakita A., Ishida T., Nitta M., Ueda R.
Blood 114:3325-3328(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION OF VARIANT THCYT2 ASN-505.
[14]"MPL W515L mutation in pediatric essential thrombocythemia."
Farruggia P., D'Angelo P., La Rosa M., Scibetta N., Santangelo G., Lo Bello A., Duner E., Randi M.L., Putti M.C., Santoro A.
Pediatr. Blood Cancer 60:E52-E54(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT THCYT2 LEU-515.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M90102 mRNA. Translation: AAA69971.1.
M90103 mRNA. Translation: AAA69972.1.
U68162 expand/collapse EMBL AC list , U68159, U68160, U68161 Genomic DNA. Translation: AAB08424.1.
U68162 expand/collapse EMBL AC list , U68159, U68160, U68161 Genomic DNA. Translation: AAB08425.1.
AL139289 Genomic DNA. Translation: CAI23380.1.
CH471059 Genomic DNA. Translation: EAX07103.1.
PIRA45266.
B45266.
RefSeqNP_005364.1. NM_005373.2.
UniGeneHs.82906.

3D structure databases

ProteinModelPortalP40238.
SMRP40238. Positions 21-283, 285-486.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid110492. 6 interactions.
DIPDIP-5730N.
IntActP40238. 1 interaction.
STRING9606.ENSP00000361548.

Chemistry

BindingDBP40238.
ChEMBLCHEMBL1864.
GuidetoPHARMACOLOGY1722.

PTM databases

PhosphoSiteP40238.

Polymorphism databases

DMDM730980.

Proteomic databases

PaxDbP40238.
PRIDEP40238.

Protocols and materials databases

DNASU4352.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000372470; ENSP00000361548; ENSG00000117400. [P40238-1]
GeneID4352.
KEGGhsa:4352.
UCSCuc001ciw.3. human. [P40238-1]

Organism-specific databases

CTD4352.
GeneCardsGC01P043803.
HGNCHGNC:7217. MPL.
HPACAB002011.
HPA007619.
MIM159530. gene.
254450. phenotype.
601977. phenotype.
604498. phenotype.
neXtProtNX_P40238.
Orphanet3319. Congenital amegakaryocytic thrombocytopenia.
3318. Essential thrombocythemia.
71493. Familial thrombocytosis.
824. Myelofibrosis with myeloid metaplasia.
729. Polycythemia vera.
PharmGKBPA30923.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG39882.
HOGENOMHOG000138191.
HOVERGENHBG000085.
InParanoidP40238.
KOK05082.
OMAQETCYQL.
PhylomeDBP40238.
TreeFamTF336573.

Enzyme and pathway databases

ReactomeREACT_604. Hemostasis.
SignaLinkP40238.

Gene expression databases

ArrayExpressP40238.
BgeeP40238.
CleanExHS_MPL.
GenevestigatorP40238.

Family and domain databases

Gene3D2.60.40.10. 4 hits.
InterProIPR003961. Fibronectin_type3.
IPR015152. Growth/epo_recpt_lig-bind.
IPR013783. Ig-like_fold.
IPR003528. Long_hematopoietin_rcpt_CS.
[Graphical view]
PfamPF09067. EpoR_lig-bind. 1 hit.
PF00041. fn3. 1 hit.
[Graphical view]
SMARTSM00060. FN3. 2 hits.
[Graphical view]
SUPFAMSSF49265. SSF49265. 4 hits.
PROSITEPS50853. FN3. 2 hits.
PS01352. HEMATOPO_REC_L_F1. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiThrombopoietin_receptor.
GenomeRNAi4352.
NextBio17122.
PROP40238.
SOURCESearch...

Entry information

Entry nameTPOR_HUMAN
AccessionPrimary (citable) accession number: P40238
Secondary accession number(s): Q5JUZ0
Entry history
Integrated into UniProtKB/Swiss-Prot: February 1, 1995
Last sequence update: February 1, 1995
Last modified: April 16, 2014
This is version 145 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 1

Human chromosome 1: entries, gene names and cross-references to MIM

Human cell differentiation molecules

CD nomenclature of surface proteins of human leucocytes and list of entries