P40238 (TPOR_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	635 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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 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.

Ontologies

Keywords
Cellular component	Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Repeat Signal Transmembrane Transmembrane helix
Molecular function	Receptor
PTM	Disulfide bond Glycoprotein Isopeptide bond Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cell proliferation Traceable author statement Ref.2. Source: ProtInc cytokine-mediated signaling pathway Inferred from electronic annotation. Source: GOC homeostasis of number of cells Inferred from electronic annotation. Source: Compara platelet activation Traceable author statement. Source: Reactome regulation of chemokine production Inferred from electronic annotation. Source: Compara
Cellular_component	integral to plasma membrane Traceable author statement Ref.2. Source: ProtInc
Molecular_function	cytokine receptor activity Inferred from electronic annotation. Source: InterPro transmembrane signaling receptor activity Traceable author statement Ref.2. Source: ProtInc
Complete GO annotation...

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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 25	25	Potential
	Chain	26 – 635	610	Thrombopoietin receptor		PRO_0000010987
Regions
	Topological domain	26 – 491	466	Extracellular Potential
	Transmembrane	492 – 513	22	Helical; Potential
	Topological domain	514 – 635	122	Cytoplasmic Potential
	Domain	133 – 215	83	Fibronectin type-III 1
	Domain	394 – 481	88	Fibronectin type-III 2
	Motif	474 – 478	5	WSXWS motif
	Motif	528 – 536	9	Box 1 motif
	Compositional bias	335 – 338	4	Poly-Glu
	Compositional bias	508 – 513	6	Poly-Leu
Amino acid modifications
	Glycosylation	117	1	N-linked (GlcNAc...) Potential
	Glycosylation	178	1	N-linked (GlcNAc...) Potential
	Glycosylation	298	1	N-linked (GlcNAc...) Potential
	Glycosylation	358	1	N-linked (GlcNAc...) Potential
	Disulfide bond	40 ↔ 50		By similarity
	Disulfide bond	77 ↔ 93		By similarity
	Disulfide bond	291 ↔ 301		By similarity
	Disulfide bond	323 ↔ 334		By similarity
	Cross-link	553		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.5
	Cross-link	573		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)
Natural variations
	Alternative sequence	523 – 579	57	RLRHA…SERTP → YRPRQAGDWRWTRWSRTCKQ AFLVRSVTPDLRPPPVRTYG FALPARHLWDSPRLLTL in isoform 2.		VSP_001734
	Alternative sequence	580 – 635	56	Missing in isoform 2.		VSP_001735
	Natural variant	39	1	K → N Functional polymorphism associated with thrombocytosis; results in altered MPL expression. Ref.10 Corresponds to variant rs17292650 [ dbSNP | Ensembl ].		VAR_049173
	Natural variant	58	1	A → V. Ref.6 Corresponds to variant rs6087 [ dbSNP | Ensembl ].		VAR_011988
	Natural variant	114	1	V → M. Corresponds to variant rs12731981 [ dbSNP | Ensembl ].		VAR_049174
	Natural variant	168	1	E → K. Ref.6 Corresponds to variant rs6088 [ dbSNP | Ensembl ].		VAR_011989
	Natural variant	505	1	S → 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 variant	515	1	W → K in MMM; somatic mutation; requires 2 nucleotide substitutions. Ref.11		VAR_067560
	Natural variant	515	1	W → L in MMM; somatic mutation; results in cytokine-independent growth and thrombopoietin hypersensitivity; results in constitutive activation of JAK-STAT signaling pathway. Ref.12 Corresponds to variant rs121913615 [ dbSNP | Ensembl ].		VAR_067561

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (C-mpl-P) [UniParc]. Last modified February 1, 1995. Version 1. Checksum: D25D8D8959359DDC	FASTA	635	71,245
	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
	Isoform 2 (C-mpl-K) [UniParc]. Checksum: 7A1431E9F64E21D4	FASTA	579	65,521
	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 YRYRPRQAGD WRWTRWSRTC 550 560 570 KQAFLVRSVT PDLRPPPVRT YGFALPARHL WDSPRLLTL

References

	« Hide 'large scale' referencesShow '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. , 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. , 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.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	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.
IPI	IPI00027637. IPI00218148.
PIR	A45266. B45266.
RefSeq	NP_005364.1. NM_005373.2.
UniGene	Hs.82906.
3D structure databases
ProteinModelPortal	P40238.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-5730N.
STRING	9606.ENSP00000361548.
PTM databases
PhosphoSite	P40238.
Polymorphism databases
DMDM	730980.
Proteomic databases
PaxDb	P40238.
PRIDE	P40238.
Protocols and materials databases
DNASU	4352.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000372470; ENSP00000361548; ENSG00000117400.
GeneID	4352.
KEGG	hsa:4352.
UCSC	uc001ciw.3. human.
Organism-specific databases
CTD	4352.
GeneCards	GC01P043803.
HGNC	HGNC:7217. MPL.
HPA	CAB002011. HPA007619.
MIM	159530. gene. 254450. phenotype. 601977. phenotype. 604498. phenotype.
neXtProt	NX_P40238.
Orphanet	3319. Congenital amegakaryocytic thrombocytopenia. 71493. Familial thrombocytosis. 729. Polycythemia vera.
PharmGKB	PA30923.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG39882.
HOGENOM	HOG000138191.
HOVERGEN	HBG000085.
InParanoid	P40238.
KO	K05082.
OMA	CCTTHIA.
OrthoDB	EOG49P9ZF.
PhylomeDB	P40238.
Enzyme and pathway databases
Reactome	REACT_604. Hemostasis.
Gene expression databases
ArrayExpress	P40238.
Bgee	P40238.
CleanEx	HS_MPL.
Genevestigator	P40238.
GermOnline	ENSG00000117400. Homo sapiens.
Family and domain databases
Gene3D	2.60.40.10. 4 hits.
InterPro	IPR003961. Fibronectin_type3. IPR015152. Growth/epo_recpt_lig-bind. IPR013783. Ig-like_fold. IPR003528. Long_hematopoietin_rcpt_CS. [Graphical view]
Pfam	PF09067. EpoR_lig-bind. 1 hit. PF00041. fn3. 1 hit. [Graphical view]
SMART	SM00060. FN3. 2 hits. [Graphical view]
SUPFAM	SSF49265. FN_III-like. 3 hits.
PROSITE	PS50853. FN3. 2 hits. PS01352. HEMATOPO_REC_L_F1. 1 hit. [Graphical view]
ProtoNet	Search...
Other
BindingDB	P40238.
ChEMBL	CHEMBL1864.
GenomeRNAi	4352.
NextBio	17122.
SOURCE	Search...

Entry information

Entry name

TPOR_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 135 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.