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Protein

Parathyroid hormone-related protein

Gene

PTHLH

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

Functioni

Neuroendocrine peptide which is a critical regulator of cellular and organ growth, development, migration, differentiation and survival and of epithelial calcium ion transport. Regulates endochondral bone development and epithelial-mesenchymal interactions during the formation of the mammary glands and teeth. Required for skeletal homeostasis. Promotes mammary mesenchyme differentiation and bud outgrowth by modulating mesenchymal cell responsiveness to BMPs. Upregulates BMPR1A expression in the mammary mesenchyme and this increases the sensitivity of these cells to BMPs and allows them to respond to BMP4 in a paracrine and/or autocrine fashion. BMP4 signaling in the mesenchyme, in turn, triggers epithelial outgrowth and augments MSX2 expression, which causes the mammary mesenchyme to inhibit hair follicle formation within the nipple sheath (By similarity). Promotes colon cancer cell migration and invasion in an integrin alpha-6/beta-1-dependent manner through activation of Rac1.By similarity1 Publication
Osteostatin is a potent inhibitor of osteoclastic bone resorption.1 Publication

GO - Molecular functioni

  • hormone activity Source: GO_Central
  • peptide hormone receptor binding Source: UniProtKB

GO - Biological processi

  • adenylate cyclase-activating G-protein coupled receptor signaling pathway Source: MGI
  • bone mineralization Source: InterPro
  • cAMP metabolic process Source: ProtInc
  • cell-cell signaling Source: ProtInc
  • epidermis development Source: ProtInc
  • female pregnancy Source: ProtInc
  • G-protein coupled receptor signaling pathway Source: Reactome
  • negative regulation of cell proliferation Source: ProtInc
  • negative regulation of chondrocyte differentiation Source: MGI
  • osteoblast development Source: GO_Central
  • positive regulation of cAMP biosynthetic process Source: MGI
  • positive regulation of cell proliferation Source: ProtInc
  • regulation of gene expression Source: MGI
  • skeletal system development Source: MGI

Keywordsi

Molecular functionHormone
LigandCalcium

Enzyme and pathway databases

ReactomeiR-HSA-373080 Class B/2 (Secretin family receptors)
R-HSA-418555 G alpha (s) signalling events
SIGNORiP12272

Names & Taxonomyi

Protein namesi
Recommended name:
Parathyroid hormone-related protein
Short name:
PTH-rP
Short name:
PTHrP
Alternative name(s):
Parathyroid hormone-like protein
Short name:
PLP
Cleaved into the following 3 chains:
Alternative name(s):
PTHrP[107-139]
Gene namesi
Name:PTHLH
Synonyms:PTHRP
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

EuPathDBiHostDB:ENSG00000087494.15
HGNCiHGNC:9607 PTHLH
MIMi168470 gene
neXtProtiNX_P12272

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus, Secreted

Pathology & Biotechi

Involvement in diseasei

Brachydactyly E2 (BDE2)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. Brachydactyly type E is characterized by shortening of the fingers mainly in the metacarpals and metatarsals. Wide variability in the number of digits affected occurs from person to person, even in the same family. Some individuals are moderately short of stature. In brachydactyly type E2 variable combinations of metacarpals are involved, with shortening also of the first and third distal and the second and fifth middle phalanges.
See also OMIM:613382
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06371144L → P in BDE2. 1 PublicationCorresponds to variant dbSNP:rs267606986EnsemblClinVar.1
Natural variantiVAR_06371260L → P in BDE2. 1 PublicationCorresponds to variant dbSNP:rs267606985EnsemblClinVar.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi57R → A: Strongly reduced affinity for PTH1R. 1 Publication1
Mutagenesisi59F → A: Reduced affinity for PTH1R. 1 Publication1
Mutagenesisi60L → A or K: Strongly reduced affinity for PTH1R. 1 Publication1
Mutagenesisi63L → A: Reduced affinity for PTH1R. 1 Publication1
Mutagenesisi64I → A: Reduced affinity for PTH1R. 1 Publication1
Mutagenesisi68H → A: Reduced affinity for PTH1R. 1 Publication1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi5744
MalaCardsiPTHLH
MIMi613382 phenotype
OpenTargetsiENSG00000087494
Orphaneti93387 Brachydactyly type E
PharmGKBiPA33952

Chemistry databases

ChEMBLiCHEMBL3712869

Polymorphism and mutation databases

BioMutaiPTHLH
DMDMi131542

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 24Sequence analysisAdd BLAST24
PropeptideiPRO_000002322425 – 3410
ChainiPRO_000002322537 – 177Parathyroid hormone-related proteinAdd BLAST141
PeptideiPRO_000002322637 – 72PTHrP[1-36]Add BLAST36
PeptideiPRO_000002322774 – 130PTHrP[38-94]Add BLAST57
PeptideiPRO_0000023228143 – 175OsteostatinAdd BLAST33

Post-translational modificationi

There are 3 principal secretory forms, called PTHrP[1-36], PTHrP[38-94], and osteostatin (PTHrP[107-139]) arising from endoproteolytic cleavage of the initial translation product. Each of these secretory forms is believed to have one or more of its own receptors that mediates the normal paracrine, autocrine and endocrine actions.

Keywords - PTMi

Cleavage on pair of basic residues

Proteomic databases

PaxDbiP12272
PeptideAtlasiP12272
PRIDEiP12272
ProteomicsDBi52842
52843 [P12272-2]
52844 [P12272-3]

PTM databases

iPTMnetiP12272
PhosphoSitePlusiP12272

Miscellaneous databases

PMAP-CutDBiP12272

Expressioni

Tissue specificityi

Ubiquitous. Also expressed in the mammary gland.

Gene expression databases

BgeeiENSG00000087494
CleanExiHS_PTHLH
ExpressionAtlasiP12272 baseline and differential
GenevisibleiP12272 HS

Organism-specific databases

HPAiHPA035982

Interactioni

Subunit structurei

PTHrP interacts with PTH1R (via N-terminal extracellular domain).1 Publication

GO - Molecular functioni

  • hormone activity Source: GO_Central
  • peptide hormone receptor binding Source: UniProtKB

Protein-protein interaction databases

BioGridi111716, 5 interactors
IntActiP12272, 1 interactor
STRINGi9606.ENSP00000379213

Structurei

Secondary structure

1177
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi41 – 44Combined sources4
Helixi51 – 67Combined sources17
Beta strandi114 – 116Combined sources3
Helixi117 – 119Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1BZGNMR-A37-70[»]
1ET3model-A37-70[»]
1M5NX-ray2.90Q103-130[»]
3FFDX-ray2.00P37-144[»]
3H3GX-ray1.94B48-70[»]
DisProtiDP00138
ProteinModelPortaliP12272
SMRiP12272
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP12272

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni57 – 68Important for receptor bindingAdd BLAST12

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi108 – 129Nuclear localization signal1 PublicationAdd BLAST22

Sequence similaritiesi

Belongs to the parathyroid hormone family.Curated

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiENOG410IW2I Eukaryota
ENOG41126XH LUCA
GeneTreeiENSGT00390000004933
HOGENOMiHOG000115765
HOVERGENiHBG003236
InParanoidiP12272
KOiK22608
OMAiTQETNKV
OrthoDBiEOG091G0SNZ
PhylomeDBiP12272
TreeFamiTF332953

Family and domain databases

InterProiView protein in InterPro
IPR003626 PTH-rel
IPR001415 PTH/PTH-rel
PANTHERiPTHR17223 PTHR17223, 1 hit
PfamiView protein in Pfam
PF01279 Parathyroid, 1 hit
SMARTiView protein in SMART
SM00087 PTH, 1 hit
PROSITEiView protein in PROSITE
PS00335 PARATHYROID, 1 hit

Sequences (3)i

Sequence statusi: Complete.

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

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Note: Additional isoforms seem to exist.
Isoform 1 (identifier: P12272-1) [UniParc]FASTAAdd to basket

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
MQRRLVQQWS VAVFLLSYAV PSCGRSVEGL SRRLKRAVSE HQLLHDKGKS
60 70 80 90 100
IQDLRRRFFL HHLIAEIHTA EIRATSEVSP NSKPSPNTKN HPVRFGSDDE
110 120 130 140 150
GRYLTQETNK VETYKEQPLK TPGKKKKGKP GKRKEQEKKK RRTRSAWLDS
160 170
GVTGSGLEGD HLSDTSTTSL ELDSRRH
Length:177
Mass (Da):20,194
Last modified:October 1, 1989 - v1
Checksum:i449FDFEE954C51DB
GO
Isoform 2 (identifier: P12272-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     176-177: Missing.

Show »
Length:175
Mass (Da):19,901
Checksum:i4FEE954C51DB3E7D
GO
Isoform 3 (identifier: P12272-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     176-177: RH → TALLWGLKKKKENNRRTHHMQLMISLFKSPLLLL

Show »
Length:209
Mass (Da):23,942
Checksum:iA994463A90B8EA0F
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06371144L → P in BDE2. 1 PublicationCorresponds to variant dbSNP:rs267606986EnsemblClinVar.1
Natural variantiVAR_06371260L → P in BDE2. 1 PublicationCorresponds to variant dbSNP:rs267606985EnsemblClinVar.1
Natural variantiVAR_036433169S → T in a breast cancer sample; somatic mutation. 1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_004534176 – 177Missing in isoform 2. 2 Publications2
Alternative sequenceiVSP_004535176 – 177RH → TALLWGLKKKKENNRRTHHM QLMISLFKSPLLLL in isoform 3. Curated2

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M17183 Genomic DNA Translation: AAA60221.1
X14304 Genomic DNA Translation: CAA32480.1
J03580 mRNA Translation: AAA60216.1 Sequence problems.
M24349, M24348 Genomic DNA Translation: AAA60358.1
M24350, M24348, M24349 Genomic DNA Translation: AAA60359.1
M24351, M24348, M24349 Genomic DNA Translation: AAA60360.1
CR541882 mRNA Translation: CAG46680.1
CH471094 Genomic DNA Translation: EAW96573.1
BC005961 mRNA Translation: AAH05961.1
J03802 mRNA Translation: AAA60218.1
M34071 mRNA Translation: AAA60217.1
CCDSiCCDS44853.1 [P12272-1]
CCDS8715.1 [P12272-2]
PIRiA33360 PTHU2L
C33360 PTHU3L
RefSeqiNP_002811.1, NM_002820.2 [P12272-2]
NP_945315.1, NM_198964.1 [P12272-2]
NP_945316.1, NM_198965.1 [P12272-1]
NP_945317.1, NM_198966.1 [P12272-1]
XP_011519076.1, XM_011520774.2 [P12272-1]
XP_011519077.1, XM_011520775.2 [P12272-1]
XP_016875163.1, XM_017019674.1 [P12272-1]
XP_016875164.1, XM_017019675.1 [P12272-1]
UniGeneiHs.591159

Genome annotation databases

EnsembliENST00000201015; ENSP00000201015; ENSG00000087494 [P12272-2]
ENST00000395868; ENSP00000379209; ENSG00000087494 [P12272-2]
ENST00000395872; ENSP00000379213; ENSG00000087494 [P12272-1]
ENST00000535992; ENSP00000440613; ENSG00000087494 [P12272-2]
ENST00000538310; ENSP00000441890; ENSG00000087494 [P12272-3]
ENST00000539239; ENSP00000441571; ENSG00000087494 [P12272-1]
ENST00000545234; ENSP00000441765; ENSG00000087494 [P12272-1]
GeneIDi5744
KEGGihsa:5744
UCSCiuc001ril.4 human [P12272-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiPTHR_HUMAN
AccessioniPrimary (citable) accession number: P12272
Secondary accession number(s): Q15251, Q6FH74
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1989
Last sequence update: October 1, 1989
Last modified: June 20, 2018
This is version 196 of the entry and version 1 of the sequence. See 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

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 12
    Human chromosome 12: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

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