P12272 (PTHR_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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:

1. PTHrP[1-36]
2. PTHrP[38-94]
3. Osteostatin
   Alternative name(s):
   PTHrP[107-139]

Gene names

Name:	PTHLH
Synonyms:	PTHRP

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	177 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	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. Ref.18 Osteostatin is a potent inhibitor of osteoclastic bone resorption. Ref.18
Subunit structure	PTHrP interacts with PTH1R (via N-terminal extracellular domain). Ref.21
Subcellular location	Cytoplasm. Nucleus. Secreted.
Tissue specificity	Ubiquitous. Also expressed in the mammary gland.
Post-translational modification	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.
Involvement in disease	Defects in PTHLH are the cause of brachydactyly type E2 (BDE2) [MIM:613382]. BDE2 is a 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. Ref.23
Sequence similarities	Belongs to the parathyroid hormone family.

Ontologies

Keywords
Cellular component	Cytoplasm Nucleus Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Signal
Ligand	Calcium
Molecular function	Hormone
PTM	Cleavage on pair of basic residues
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	activation of adenylate cyclase activity by G-protein signaling pathway Inferred from direct assay. Source: MGI cAMP metabolic process Traceable author statement. Source: ProtInc cell-cell signaling Traceable author statement. Source: ProtInc epidermis development Traceable author statement. Source: ProtInc female pregnancy Traceable author statement. Source: ProtInc negative regulation of cell proliferation Traceable author statement. Source: ProtInc negative regulation of chondrocyte differentiation Inferred from direct assay. Source: MGI positive regulation of cAMP biosynthetic process Inferred from direct assay. Source: MGI positive regulation of cell proliferation Traceable author statement. Source: ProtInc
Cellular component	Golgi apparatus Inferred from direct assay. Source: HPA extracellular space Traceable author statement. Source: ProtInc nucleus Inferred from direct assay. Source: HPA
Molecular function	hormone activity Traceable author statement. Source: ProtInc peptide hormone receptor binding Inferred from direct assay Ref.21. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Note: Additional isoforms seem to exist.

Isoform 1 (identifier: P12272-1)

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: P12272-2)

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

Isoform 3 (identifier: P12272-3)

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

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 24

24

Potential

Propeptide

25 – 34

10

PRO_0000023224

Chain

37 – 177

141

Parathyroid hormone-related protein

PRO_0000023225

Peptide

37 – 72

36

PTHrP[1-36]

PRO_0000023226

Peptide

74 – 130

57

PTHrP[38-94]

PRO_0000023227

Peptide

143 – 175

33

Osteostatin

PRO_0000023228

Regions

Region

57 – 68

12

Important for receptor binding

Motif

108 – 129

22

Nuclear localization signal Ref.16

Natural variations

Alternative sequence

176 – 177

2

Missing in isoform 2.

VSP_004534

Alternative sequence

176 – 177

2

RH → TALLWGLKKKKENNRRTHHM QLMISLFKSPLLLL in isoform 3.

VSP_004535

Natural variant

44

1

L → P in BDE2. Ref.23

VAR_063711

Natural variant

60

1

L → P in BDE2. Ref.23

VAR_063712

Natural variant

169

1

S → T in a breast cancer sample; somatic mutation. Ref.22

VAR_036433

Experimental info

Mutagenesis

57

1

R → A: Strongly reduced affinity for PTH1R. Ref.21

Mutagenesis

59

1

F → A: Reduced affinity for PTH1R. Ref.21

Mutagenesis

60

1

L → A or K: Strongly reduced affinity for PTH1R. Ref.21

Mutagenesis

63

1

L → A: Reduced affinity for PTH1R. Ref.21

Mutagenesis

64

1

I → A: Reduced affinity for PTH1R. Ref.21

Mutagenesis

68

1

H → A: Reduced affinity for PTH1R. Ref.21

Secondary structure

1

.

.

.

.

.

.

.

.

177

Helix Strand Turn

Details...

Helix

41 – 44

4

Helix

52 – 63

12

Beta strand

114 – 116

3

Helix

117 – 119

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 1, 1989. Version 1. Checksum: 449FDFEE954C51DB	FASTA	177	20,194
	10 20 30 40 50 60 MQRRLVQQWS VAVFLLSYAV PSCGRSVEGL SRRLKRAVSE HQLLHDKGKS IQDLRRRFFL 70 80 90 100 110 120 HHLIAEIHTA EIRATSEVSP NSKPSPNTKN HPVRFGSDDE GRYLTQETNK VETYKEQPLK 130 140 150 160 170 TPGKKKKGKP GKRKEQEKKK RRTRSAWLDS GVTGSGLEGD HLSDTSTTSL ELDSRRH
	Isoform 2 [UniParc]. Checksum: 4FEE954C51DB3E7D	FASTA	175	19,901
	10 20 30 40 50 60 MQRRLVQQWS VAVFLLSYAV PSCGRSVEGL SRRLKRAVSE HQLLHDKGKS IQDLRRRFFL 70 80 90 100 110 120 HHLIAEIHTA EIRATSEVSP NSKPSPNTKN HPVRFGSDDE GRYLTQETNK VETYKEQPLK 130 140 150 160 170 TPGKKKKGKP GKRKEQEKKK RRTRSAWLDS GVTGSGLEGD HLSDTSTTSL ELDSR
	Isoform 3 [UniParc]. Checksum: A994463A90B8EA0F	FASTA	209	23,942
	10 20 30 40 50 60 MQRRLVQQWS VAVFLLSYAV PSCGRSVEGL SRRLKRAVSE HQLLHDKGKS IQDLRRRFFL 70 80 90 100 110 120 HHLIAEIHTA EIRATSEVSP NSKPSPNTKN HPVRFGSDDE GRYLTQETNK VETYKEQPLK 130 140 150 160 170 180 TPGKKKKGKP GKRKEQEKKK RRTRSAWLDS GVTGSGLEGD HLSDTSTTSL ELDSRTALLW 190 200 GLKKKKENNR RTHHMQLMIS LFKSPLLLL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression." Suva L.J., Winslow G.A., Wettenhall R.E.H., Hammonds R.G., Moseley J.M., Diefenbach-Jagger H., Rodda C.P., Kemp B.E., Rodriguez H., Chen E.Y., Hudson P.J., Martin T.J., Wood W.I. Science 237:893-896(1987) [PubMed: 3616618] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], PARTIAL PROTEIN SEQUENCE.
[2]	"Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy." Mangin M., Webb A.C., Dreyer B.E., Posillico J.T., Ikeda K., Weir E.C., Stewart A.F., Bander N.H., Milstone L., Barton D.E., Francke U., Broadus A.E. Proc. Natl. Acad. Sci. U.S.A. 85:597-601(1988) [PubMed: 2829195] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Characterization of the human parathyroid hormone-like peptide gene. Functional and evolutionary aspects." Yasuda T., Banville D., Hendy G.N., Goltzman D. J. Biol. Chem. 264:7720-7725(1989) [PubMed: 2708388] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Human renal carcinoma expresses two messages encoding a parathyroid hormone-like peptide: evidence for the alternative splicing of a single-copy gene." Thiede M.A., Strewler G.J., Nissenson R.A., Rosenblatt M., Rodan G.A. Proc. Natl. Acad. Sci. U.S.A. 85:4605-4609(1988) [PubMed: 3290897] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
[5]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[6]	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 (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Brain.
[8]	"Structure of the 5' flanking region of the gene encoding human parathyroid-hormone-related protein (PTHrP)." Suva L.J., Mather K.A., Gillespie M.T., Webb G.C., Ng K.W., Winslow G.A., Wood W.I., Martin T.J., Hudson P.J. Gene 77:95-105(1989) [PubMed: 2744490] [Abstract] Cited for: NUCLEOTIDE SEQUENCE OF 1-33. Tissue: Liver.
[9]	"Parathyroid hormone-related protein purified from a human lung cancer cell line." Moseley J.M., Kubota M., Diefenbach-Jagger H., Wettenhall R.E.H., Kemp B.E., Suva L.J., Rodda C.P., Ebeling P.R., Hudson P.J., Zajac J.D., Martin T.J. Proc. Natl. Acad. Sci. U.S.A. 84:5048-5052(1987) [PubMed: 2885845] [Abstract] Cited for: PROTEIN SEQUENCE OF 37-52.
[10]	"Isolation and characterization of the human parathyroid hormone-like peptide gene." Mangin M., Ikeda K., Dreyer B.E., Broadus A.E. Proc. Natl. Acad. Sci. U.S.A. 86:2408-2412(1989) [PubMed: 2928340] [Abstract] Cited for: ALTERNATIVE SPLICING (ISOFORM 3).
[11]	"A carboxyl-terminal peptide from the parathyroid hormone-related protein inhibits bone resorption by osteoclasts." Fenton A.J., Kemp B.E., Kent G.N., Moseley J.M., Zheng M.H., Rowe D.J., Britto J.M., Martin T.J., Nicholson G.C. Endocrinology 129:1762-1768(1991) [PubMed: 1915066] [Abstract] Cited for: CHARACTERIZATION OF OSTEOSTATIN ACTIVITY.
[12]	"A potent inhibitor of osteoclastic bone resorption within a highly conserved pentapeptide region of parathyroid hormone-related protein; PTHrP107-111." Fenton A.J., Kemp B.E., Hammonds R.G., Mitchelhill K., Moseley J.M., Martin T.J., Nicholson G.C. Endocrinology 129:3424-3426(1991) [PubMed: 1954916] [Abstract] Cited for: CHARACTERIZATION OF OSTEOSTATIN ACTIVITY.
[13]	"C-terminal parathyroid hormone-related protein inhibits proliferation and differentiation of human osteoblast-like cells." Martinez M.E., Garcia-Ocana A., Sanchez M., Medina S., del Campo T., Valin A., Sanchez-Cabezudo M.J., Esbrit P. J. Bone Miner. Res. 12:778-785(1997) [PubMed: 9144344] [Abstract] Cited for: CHARACTERIZATION OF OSTEOSTATIN ACTIVITY.
[14]	"Parathyroid hormone-related protein-(107-139) inhibits bone resorption in vivo." Cornish J., Callon K.E., Nicholson G.C., Reid I.R. Endocrinology 138:1299-1304(1997) [PubMed: 9048639] [Abstract] Cited for: CHARACTERIZATION OF OSTEOSTATIN ACTIVITY.
[15]	"Parathyroid hormone-related protein (PTHrP): a nucleocytoplasmic shuttling protein with distinct paracrine and intracrine roles." Jans D.A., Thomas R.J., Gillespie M.T. Vitam. Horm. 66:345-384(2003) [PubMed: 12852260] [Abstract] Cited for: NUCLEOCYTOPLASMIC SHUTTLING.
[16]	"Molecular dissection of the importin beta1-recognized nuclear targeting signal of parathyroid hormone-related protein." Lam M.H., Hu W., Xiao C.Y., Gillespie M.T., Jans D.A. Biochem. Biophys. Res. Commun. 282:629-634(2001) [PubMed: 11401507] [Abstract] Cited for: NUCLEAR LOCALIZATION SIGNAL.
[17]	"Minireview: parathyroid hormone-related protein as an intracrine factor -- trafficking mechanisms and functional consequences." Fiaschi-Taesch N.M., Stewart A.F. Endocrinology 144:407-411(2003) [PubMed: 12538599] [Abstract] Cited for: REVIEW.
[18]	"PTHrP promotes colon cancer cell migration and invasion in an integrin alpha6beta4-dependent manner through activation of Rac1." Mula R.V., Bhatia V., Falzon M. Cancer Lett. 298:119-127(2010) [PubMed: 20637541] [Abstract] Cited for: FUNCTION.
[19]	"The structure of human parathyroid hormone-related protein(1-34) in near-physiological solution." Weidler M., Marx U.C., Seidel G., Schafer W., Hoffmann E., Esswein A., Rosch P. FEBS Lett. 444:239-244(1999) [PubMed: 10050767] [Abstract] Cited for: STRUCTURE BY NMR OF 37-70.
[20]	"Molecular basis for the recognition of a nonclassical nuclear localization signal by importin beta." Cingolani G., Bednenko J., Gillespie M.T., Gerace L. Mol. Cell 10:1345-1353(2002) [PubMed: 12504010] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 103-130.
[21]	"Structural basis for parathyroid hormone-related protein binding to the parathyroid hormone receptor and design of conformation-selective peptides." Pioszak A.A., Parker N.R., Gardella T.J., Xu H.E. J. Biol. Chem. 284:28382-28391(2009) [PubMed: 19674967] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.94 ANGSTROMS) OF 48-70 IN COMPLEX WITH PTH1R, INTERACTION WITH PTH1R, MUTAGENESIS OF ARG-57; PHE-59; LEU-60; LEU-63; ILE-64 AND HIS-68.
[22]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] THR-169.
[23]	"Deletion and point mutations of PTHLH cause brachydactyly type E." Klopocki E., Hennig B.P., Dathe K., Koll R., de Ravel T., Baten E., Blom E., Gillerot Y., Weigel J.F., Krueger G., Hiort O., Seemann P., Mundlos S. Am. J. Hum. Genet. 86:434-439(2010) [PubMed: 20170896] [Abstract] Cited for: VARIANTS BDE2 PRO-44 AND PRO-60.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

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.

IPI

IPI00221080.
IPI00221081.
IPI00414875.

PIR

PTHU2L. A33360.
PTHU3L. C33360.

RefSeq

NP_002811.1. NM_002820.2.
NP_945315.1. NM_198964.1.
NP_945316.1. NM_198965.1.
NP_945317.1. NM_198966.1.

UniGene

Hs.591159.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1BZG	NMR	-	A	37-70	[»]
1ET3	model	-	A	37-70	[»]
1M5N	X-ray	2.90	Q	103-130	[»]
3FFD	X-ray	2.00	P	37-144	[»]
3H3G	X-ray	1.94	B	48-70	[»]

ProteinModelPortal

P12272.

SMR

P12272. Positions 37-70, 103-130.

DisProt

DP00138.

ModBase

Search...

Protein-protein interaction databases

IntAct

P12272. 1 interaction.

STRING

P12272.

PTM databases

PhosphoSite

P12272.

Polymorphism databases

DMDM

131542.

Proteomic databases

PRIDE

P12272.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000395872; ENSP00000379213; ENSG00000087494.

GeneID

5744.

KEGG

hsa:5744.

UCSC

uc001rik.1. human.

Organism-specific databases

CTD

5744.

GeneCards

GC12M028111.

HGNC

HGNC:9607. PTHLH.

HPA

HPA035982.

MIM

168470. gene.
613382. phenotype.

neXtProt

NX_P12272.

Orphanet

93387. Brachydactyly type E.

PharmGKB

PA33952.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG04405.

HOVERGEN

HBG003236.

InParanoid

P12272.

OMA

SPNTKNH.

OrthoDB

EOG4N8R63.

Enzyme and pathway databases

Pathway_Interaction_DB

hedgehog_2pathway. Signaling events mediated by the Hedgehog family.

Reactome

REACT_111102. Signal Transduction.

Gene expression databases

ArrayExpress

P12272.

Bgee

P12272.

CleanEx

HS_PTHLH.

Genevestigator

P12272.

GermOnline

ENSG00000087494. Homo sapiens.

Family and domain databases

InterPro

IPR003626. PTH-rel.
IPR001415. PTH/PTH-rel.
[Graphical view]

PANTHER

PTHR17223. PTH_related. 1 hit.

Pfam

PF01279. Parathyroid. 1 hit.
[Graphical view]

SMART

SM00087. PTH. 1 hit.
[Graphical view]

PROSITE

PS00335. PARATHYROID. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

22362.

PMAP-CutDB

P12272.

SOURCE

Search...

Entry information

Entry name

PTHR_HUMAN

Accession

Primary (citable) accession number: P12272
Secondary accession number(s): Q15251, Q6FH74

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1989
Last sequence update:	October 1, 1989
Last modified:	January 25, 2012
This is version 138 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.