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Protein

Thrombopoietin receptor

Gene

MPL

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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

GO - Molecular functioni

  • thrombopoietin receptor activity Source: UniProtKB
  • transmembrane signaling receptor activity Source: ProtInc

GO - Biological processi

  • cell proliferation Source: ProtInc
  • cell surface receptor signaling pathway Source: ProtInc
  • cellular response to hypoxia Source: Ensembl
  • platelet aggregation Source: Ensembl
  • positive regulation of lymphocyte proliferation Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Receptor

Enzyme and pathway databases

BioCyciZFISH:ENSG00000117400-MONOMER.
ReactomeiR-HSA-76009. Platelet Aggregation (Plug Formation).
SignaLinkiP40238.
SIGNORiP40238.

Names & Taxonomyi

Protein namesi
Recommended name:
Thrombopoietin receptor
Short name:
TPO-R
Alternative name(s):
Myeloproliferative leukemia protein
Proto-oncogene c-Mpl
CD_antigen: CD110
Gene namesi
Name:MPL
Synonyms:TPOR
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

HGNCiHGNC:7217. MPL.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini26 – 491ExtracellularSequence analysisAdd BLAST466
Transmembranei492 – 513HelicalSequence analysisAdd BLAST22
Topological domaini514 – 635CytoplasmicSequence analysisAdd BLAST122

GO - Cellular componenti

  • cell surface Source: UniProtKB
  • Golgi apparatus Source: UniProtKB
  • integral component of plasma membrane Source: ProtInc
  • neuronal cell body Source: Ensembl
  • neuron projection Source: Ensembl
  • plasma membrane Source: HPA
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Golgi apparatus, Membrane

Pathology & Biotechi

Involvement in diseasei

Congenital amegakaryocytic thrombocytopenia (CAMT)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionDisease characterized by isolated thrombocytopenia and megakaryocytopenia with no physical anomalies.
See also OMIM:604498
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_073030102R → C in CAMT. 1 PublicationCorresponds to variant rs763568293dbSNPEnsembl.1
Natural variantiVAR_073031102R → P in CAMT; loss of function; loss of membrane localization, impaired glycosylation. 2 PublicationsCorresponds to variant rs28928907dbSNPEnsembl.1
Natural variantiVAR_073032104F → S in CAMT; loss of function. 2 Publications1
Natural variantiVAR_073034136P → L in CAMT. 1 Publication1
Natural variantiVAR_073035154W → R in CAMT. 1 PublicationCorresponds to variant rs758428763dbSNPEnsembl.1
Natural variantiVAR_073036257R → L in CAMT. 1 Publication1
Natural variantiVAR_073037275P → T in CAMT. 1 PublicationCorresponds to variant rs28928908dbSNPEnsembl.1
Natural variantiVAR_073038435W → C in CAMT. 1 Publication1
Natural variantiVAR_073039594L → W in CAMT. 1 Publication1
Thrombocythemia 2 (THCYT2)3 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA myeloproliferative disorder characterized by excessive platelet production, resulting in increased numbers of circulating platelets. It can be associated with spontaneous hemorrhages and thrombotic episodes.
See also OMIM:601977
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_073033106P → L in THCYT2; gain of function; loss of membrane localization, impaired glycosylation. 1 PublicationCorresponds to variant rs750046020dbSNPEnsembl.1
Natural variantiVAR_067559505S → N in THCYT2; activating mutation; induces MPL autonomous dimerization and signal activation in the absence of the ligand. 2 PublicationsCorresponds to variant rs121913614dbSNPEnsembl.1
Natural variantiVAR_067561515W → 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. 2 PublicationsCorresponds to variant rs121913615dbSNPEnsembl.1
Myelofibrosis with myeloid metaplasia (MMM)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA chronic myeloproliferative disorder characterized by replacement of the bone marrow by fibrous tissue, extramedullary hematopoiesis, anemia, leukoerythroblastosis and hepatosplenomegaly.
See also OMIM:254450
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_067560515W → K in MMM; somatic mutation; requires 2 nucleotide substitutions. 1 PublicationCorresponds to variant rs121913616dbSNPEnsembl.1
Natural variantiVAR_067561515W → 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. 2 PublicationsCorresponds to variant rs121913615dbSNPEnsembl.1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi4352.
MalaCardsiMPL.
MIMi254450. phenotype.
601977. phenotype.
604498. phenotype.
OpenTargetsiENSG00000117400.
Orphaneti3319. Congenital amegakaryocytic thrombocytopenia.
3318. Essential thrombocythemia.
71493. Familial thrombocytosis.
397692. Hereditary isolated aplastic anemia.
824. Myelofibrosis with myeloid metaplasia.
729. Polycythemia vera.
PharmGKBiPA30923.

Chemistry databases

ChEMBLiCHEMBL1864.
DrugBankiDB06210. Eltrombopag.
DB05332. Romiplostim.
GuidetoPHARMACOLOGYi1722.

Polymorphism and mutation databases

BioMutaiMPL.
DMDMi730980.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 25Sequence analysisAdd BLAST25
ChainiPRO_000001098726 – 635Thrombopoietin receptorAdd BLAST610

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi40 ↔ 50By similarity
Disulfide bondi77 ↔ 93By similarity
Glycosylationi117N-linked (GlcNAc...)Sequence analysis1
Glycosylationi178N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi291 ↔ 301By similarity
Glycosylationi298N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi323 ↔ 334By similarity
Glycosylationi358N-linked (GlcNAc...)Sequence analysis1
Cross-linki553Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Cross-linki573Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)

Post-translational modificationi

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.1 Publication

Keywords - PTMi

Disulfide bond, Glycoprotein, Isopeptide bond, Ubl conjugation

Proteomic databases

PaxDbiP40238.
PeptideAtlasiP40238.
PRIDEiP40238.

PTM databases

iPTMnetiP40238.
PhosphoSitePlusiP40238.

Expressioni

Tissue specificityi

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.

Gene expression databases

BgeeiENSG00000117400.
CleanExiHS_MPL.
ExpressionAtlasiP40238. baseline and differential.
GenevisibleiP40238. HS.

Organism-specific databases

HPAiCAB002011.
HPA007619.

Interactioni

Subunit structurei

Homodimer (PubMed:25538044). Interacts with ATXN2L.1 Publication1 Publication

Binary interactionsi

WithEntry#Exp.IntActNotes
JAK2O606746EBI-6511486,EBI-518647

Protein-protein interaction databases

BioGridi110492. 5 interactors.
DIPiDIP-5730N.
IntActiP40238. 2 interactors.
STRINGi9606.ENSP00000361548.

Chemistry databases

BindingDBiP40238.

Structurei

3D structure databases

ProteinModelPortaliP40238.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini172 – 281Fibronectin type-III 1PROSITE-ProRule annotationAdd BLAST110
Domaini392 – 486Fibronectin type-III 2PROSITE-ProRule annotationAdd BLAST95

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi474 – 478WSXWS motif5
Motifi528 – 536Box 1 motif9

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi335 – 338Poly-Glu4
Compositional biasi508 – 513Poly-Leu6

Domaini

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.

Sequence similaritiesi

Contains 2 fibronectin type-III domains.PROSITE-ProRule annotation

Keywords - Domaini

Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IFK2. Eukaryota.
ENOG410YM4I. LUCA.
GeneTreeiENSGT00840000129885.
HOGENOMiHOG000138191.
HOVERGENiHBG000085.
InParanoidiP40238.
KOiK05082.
OMAiCCTTHIA.
OrthoDBiEOG091G049O.
PhylomeDBiP40238.
TreeFamiTF336573.

Family and domain databases

CDDicd00063. FN3. 2 hits.
Gene3Di2.60.40.10. 4 hits.
InterProiIPR003961. FN3_dom.
IPR015152. Growth/epo_recpt_lig-bind.
IPR013783. Ig-like_fold.
IPR003528. Long_hematopoietin_rcpt_CS.
[Graphical view]
PfamiPF09067. EpoR_lig-bind. 1 hit.
PF00041. fn3. 1 hit.
[Graphical view]
SMARTiSM00060. FN3. 2 hits.
[Graphical view]
SUPFAMiSSF49265. SSF49265. 4 hits.
PROSITEiPS50853. FN3. 2 hits.
PS01352. HEMATOPO_REC_L_F1. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P40238-1) [UniParc]FASTAAdd to basket
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.

« Hide

        10         20         30         40         50
MPSWALFMVT SCLLLAPQNL AQVSSQDVSL LASDSEPLKC FSRTFEDLTC
60 70 80 90 100
FWDEEEAAPS GTYQLLYAYP REKPRACPLS SQSMPHFGTR YVCQFPDQEE
110 120 130 140 150
VRLFFPLHLW VKNVFLNQTR TQRVLFVDSV GLPAPPSIIK AMGGSQPGEL
160 170 180 190 200
QISWEEPAPE ISDFLRYELR YGPRDPKNST GPTVIQLIAT ETCCPALQRP
210 220 230 240 250
HSASALDQSP CAQPTMPWQD GPKQTSPSRE ASALTAEGGS CLISGLQPGN
260 270 280 290 300
SYWLQLRSEP DGISLGGSWG SWSLPVTVDL PGDAVALGLQ CFTLDLKNVT
310 320 330 340 350
CQWQQQDHAS SQGFFYHSRA RCCPRDRYPI WENCEEEEKT NPGLQTPQFS
360 370 380 390 400
RCHFKSRNDS IIHILVEVTT APGTVHSYLG SPFWIHQAVR LPTPNLHWRE
410 420 430 440 450
ISSGHLELEW QHPSSWAAQE TCYQLRYTGE GHQDWKVLEP PLGARGGTLE
460 470 480 490 500
LRPRSRYRLQ LRARLNGPTY QGPWSSWSDP TRVETATETA WISLVTALHL
510 520 530 540 550
VLGLSAVLGL LLLRWQFPAH YRRLRHALWP SLPDLHRVLG QYLRDTAALS
560 570 580 590 600
PPKATVSDTC EEVEPSLLEI LPKSSERTPL PLCSSQAQMD YRRLQPSCLG
610 620 630
TMPLSVCPPM AESGSCCTTH IANHSYLPLS YWQQP
Length:635
Mass (Da):71,245
Last modified:February 1, 1995 - v1
Checksum:iD25D8D8959359DDC
GO
Isoform 2 (identifier: P40238-2) [UniParc]FASTAAdd to basket
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.

Show »
Length:579
Mass (Da):65,521
Checksum:i7A1431E9F64E21D4
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04917339K → N Functional polymorphism associated with thrombocytosis; results in altered MPL expression. 1 PublicationCorresponds to variant rs17292650dbSNPEnsembl.1
Natural variantiVAR_01198858A → V.1 PublicationCorresponds to variant rs6087dbSNPEnsembl.1
Natural variantiVAR_073030102R → C in CAMT. 1 PublicationCorresponds to variant rs763568293dbSNPEnsembl.1
Natural variantiVAR_073031102R → P in CAMT; loss of function; loss of membrane localization, impaired glycosylation. 2 PublicationsCorresponds to variant rs28928907dbSNPEnsembl.1
Natural variantiVAR_073032104F → S in CAMT; loss of function. 2 Publications1
Natural variantiVAR_073033106P → L in THCYT2; gain of function; loss of membrane localization, impaired glycosylation. 1 PublicationCorresponds to variant rs750046020dbSNPEnsembl.1
Natural variantiVAR_049174114V → M.Corresponds to variant rs12731981dbSNPEnsembl.1
Natural variantiVAR_073034136P → L in CAMT. 1 Publication1
Natural variantiVAR_073035154W → R in CAMT. 1 PublicationCorresponds to variant rs758428763dbSNPEnsembl.1
Natural variantiVAR_011989168E → K.1 PublicationCorresponds to variant rs6088dbSNPEnsembl.1
Natural variantiVAR_073036257R → L in CAMT. 1 Publication1
Natural variantiVAR_073037275P → T in CAMT. 1 PublicationCorresponds to variant rs28928908dbSNPEnsembl.1
Natural variantiVAR_073038435W → C in CAMT. 1 Publication1
Natural variantiVAR_067559505S → N in THCYT2; activating mutation; induces MPL autonomous dimerization and signal activation in the absence of the ligand. 2 PublicationsCorresponds to variant rs121913614dbSNPEnsembl.1
Natural variantiVAR_067560515W → K in MMM; somatic mutation; requires 2 nucleotide substitutions. 1 PublicationCorresponds to variant rs121913616dbSNPEnsembl.1
Natural variantiVAR_067561515W → 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. 2 PublicationsCorresponds to variant rs121913615dbSNPEnsembl.1
Natural variantiVAR_073039594L → W in CAMT. 1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_001734523 – 579RLRHA…SERTP → YRPRQAGDWRWTRWSRTCKQ AFLVRSVTPDLRPPPVRTYG FALPARHLWDSPRLLTL in isoform 2. 1 PublicationAdd BLAST57
Alternative sequenceiVSP_001735580 – 635Missing in isoform 2. 1 PublicationAdd BLAST56

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M90102 mRNA. Translation: AAA69971.1.
M90103 mRNA. Translation: AAA69972.1.
U68162
, U68159, U68160, U68161 Genomic DNA. Translation: AAB08424.1.
U68162
, U68159, U68160, U68161 Genomic DNA. Translation: AAB08425.1.
AL139289 Genomic DNA. Translation: CAI23380.1.
CH471059 Genomic DNA. Translation: EAX07103.1.
CCDSiCCDS483.1. [P40238-1]
PIRiA45266.
B45266.
RefSeqiNP_005364.1. NM_005373.2. [P40238-1]
UniGeneiHs.82906.

Genome annotation databases

EnsembliENST00000372470; ENSP00000361548; ENSG00000117400. [P40238-1]
GeneIDi4352.
KEGGihsa:4352.
UCSCiuc001ciw.4. human. [P40238-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M90102 mRNA. Translation: AAA69971.1.
M90103 mRNA. Translation: AAA69972.1.
U68162
, U68159, U68160, U68161 Genomic DNA. Translation: AAB08424.1.
U68162
, U68159, U68160, U68161 Genomic DNA. Translation: AAB08425.1.
AL139289 Genomic DNA. Translation: CAI23380.1.
CH471059 Genomic DNA. Translation: EAX07103.1.
CCDSiCCDS483.1. [P40238-1]
PIRiA45266.
B45266.
RefSeqiNP_005364.1. NM_005373.2. [P40238-1]
UniGeneiHs.82906.

3D structure databases

ProteinModelPortaliP40238.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi110492. 5 interactors.
DIPiDIP-5730N.
IntActiP40238. 2 interactors.
STRINGi9606.ENSP00000361548.

Chemistry databases

BindingDBiP40238.
ChEMBLiCHEMBL1864.
DrugBankiDB06210. Eltrombopag.
DB05332. Romiplostim.
GuidetoPHARMACOLOGYi1722.

PTM databases

iPTMnetiP40238.
PhosphoSitePlusiP40238.

Polymorphism and mutation databases

BioMutaiMPL.
DMDMi730980.

Proteomic databases

PaxDbiP40238.
PeptideAtlasiP40238.
PRIDEiP40238.

Protocols and materials databases

DNASUi4352.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000372470; ENSP00000361548; ENSG00000117400. [P40238-1]
GeneIDi4352.
KEGGihsa:4352.
UCSCiuc001ciw.4. human. [P40238-1]

Organism-specific databases

CTDi4352.
DisGeNETi4352.
GeneCardsiMPL.
HGNCiHGNC:7217. MPL.
HPAiCAB002011.
HPA007619.
MalaCardsiMPL.
MIMi159530. gene.
254450. phenotype.
601977. phenotype.
604498. phenotype.
neXtProtiNX_P40238.
OpenTargetsiENSG00000117400.
Orphaneti3319. Congenital amegakaryocytic thrombocytopenia.
3318. Essential thrombocythemia.
71493. Familial thrombocytosis.
397692. Hereditary isolated aplastic anemia.
824. Myelofibrosis with myeloid metaplasia.
729. Polycythemia vera.
PharmGKBiPA30923.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IFK2. Eukaryota.
ENOG410YM4I. LUCA.
GeneTreeiENSGT00840000129885.
HOGENOMiHOG000138191.
HOVERGENiHBG000085.
InParanoidiP40238.
KOiK05082.
OMAiCCTTHIA.
OrthoDBiEOG091G049O.
PhylomeDBiP40238.
TreeFamiTF336573.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000117400-MONOMER.
ReactomeiR-HSA-76009. Platelet Aggregation (Plug Formation).
SignaLinkiP40238.
SIGNORiP40238.

Miscellaneous databases

GeneWikiiThrombopoietin_receptor.
GenomeRNAii4352.
PROiP40238.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000117400.
CleanExiHS_MPL.
ExpressionAtlasiP40238. baseline and differential.
GenevisibleiP40238. HS.

Family and domain databases

CDDicd00063. FN3. 2 hits.
Gene3Di2.60.40.10. 4 hits.
InterProiIPR003961. FN3_dom.
IPR015152. Growth/epo_recpt_lig-bind.
IPR013783. Ig-like_fold.
IPR003528. Long_hematopoietin_rcpt_CS.
[Graphical view]
PfamiPF09067. EpoR_lig-bind. 1 hit.
PF00041. fn3. 1 hit.
[Graphical view]
SMARTiSM00060. FN3. 2 hits.
[Graphical view]
SUPFAMiSSF49265. SSF49265. 4 hits.
PROSITEiPS50853. FN3. 2 hits.
PS01352. HEMATOPO_REC_L_F1. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiTPOR_HUMAN
AccessioniPrimary (citable) accession number: P40238
Secondary accession number(s): Q5JUZ0
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 1, 1995
Last sequence update: February 1, 1995
Last modified: November 30, 2016
This is version 171 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Caution

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

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human cell differentiation molecules
    CD nomenclature of surface proteins of human leucocytes and list of entries
  2. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.