Reviewed, UniProtKB/Swiss-Prot P12272 (PTHR_HUMAN)

Names and origin

Protein names

Recommended name:
    Parathyroid hormone-related protein
      Short name=PTH-rP
      Short name=PTHrP
Cleaved into the following 3 chains:
    1- Recommended name:
            PTHrP[1-36]
    2- Recommended name:
            PTHrP[38-94]
    3- Recommended name:
            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. Osteostatin is a potent inhibitor of osteoclastic bone resorption.
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	Produced by many tumors from patients with HHM (humoral hypercalcemia of malignancy).
Sequence similarities	Belongs to the parathyroid hormone family.

Ontologies

Keywords
Cellular component	Cytoplasm Nucleus Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Signal
Ligand	Calcium
Molecular function	Hormone
PTM	Cleavage on pair of basic residues
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	G-protein signaling, adenylate cyclase activating 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 lactation Inferred from electronic annotation. Source: InterPro negative regulation of cell proliferation Traceable author statement. Source: ProtInc positive regulation of cell proliferation Traceable author statement. Source: ProtInc skeletal system development Inferred from direct assay. Source: MGI
Cellular component	cytoplasm Traceable author statement. Source: ProtInc extracellular space Traceable author statement. Source: ProtInc nucleus Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	calcium ion binding Inferred from electronic annotation. Source: UniProtKB-KW hormone activity Ref.3 Traceable author statement. Source: ProtInc
Complete GO annotation...

Alternative products

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

Notes: 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

Motif

108 – 129

22

Nuclear localization signal

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

169

1

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

VAR_036433

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		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		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.
[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]	"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.
[6]	"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.
[7]	"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.
[8]	"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).
[9]	"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.
[10]	"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.
[11]	"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.
[12]	"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.
[13]	"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.
[14]	"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.
[15]	"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.
[16]	"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.
[17]	"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.
[18]	"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.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

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.
BC005961 mRNA. Translation: AAH05961.1.
J03802 mRNA. Translation: AAA60218.1.
M34071 mRNA. Translation: AAA60217.1.

PIR

PTHU2L. A33360.
PTHU3L. C33360.

RefSeq

NP_002811.1.
NP_945315.1.
NP_945316.1.
NP_945317.1.

UniGene

Hs.591159

3D structure databases

PDBMSD

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	[»]

DisProt

DP00138.

ModBase

Search...

Genome annotation databases

Ensembl

ENSG00000087494. Homo sapiens. [Contig view]

GeneID

5744.

KEGG

hsa:5744.

Organism-specific databases

H-InvDB

HIX0010511.

HGNC

HGNC:9607. PTHLH.

HPA

CAB000072.

MIM

168470. gene+phenotype.

PharmGKB

PA33952.

GenAtlas

Search...

GeneCards

Search...

Phylogenomic databases

HOGENOM

P12272.

HOVERGEN

P12272.

Gene expression databases

ArrayExpress

P12272.

CleanEx

HS_PTHLH.

GermOnline

ENSG00000087494. Homo sapiens.

Family and domain databases

InterPro

IPR001415. Parathyrd_hrm.
IPR003626. PTH_related.
[Graphical view]

PANTHER

PTHR17223. PTH_related. 1 hit.

Pfam

PF01279. Parathyroid. 1 hit.
[Graphical view]

ProDom

PD013225. PTH_related. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00087. PTH. 1 hit.
[Graphical view]

PROSITE

PS00335. PARATHYROID. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

22362.

SOURCE

Search...

Entry information

Entry name

PTHR_HUMAN

Accession

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

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1989
Last sequence update:	October 1, 1989
Last modified:	November 25, 2008
This is version 101 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)