ID PTHR_HUMAN Reviewed; 177 AA. AC P12272; Q15251; Q6FH74; DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1989, sequence version 1. DT 02-SEP-2026, entry version 241. DE RecName: Full=Parathyroid hormone-related protein {ECO:0000303|PubMed:3616618}; DE Short=PTH-rP; DE Short=PTHrP {ECO:0000303|PubMed:2744490}; DE AltName: Full=Parathyroid hormone-like protein; DE Short=PLP; DE Contains: DE RecName: Full=PTHrP[1-36]; DE Contains: DE RecName: Full=PTHrP[38-94]; DE Contains: DE RecName: Full=Osteostatin; DE AltName: Full=PTHrP[107-139]; DE Flags: Precursor; GN Name=PTHLH {ECO:0000303|PubMed:20170896, ECO:0000312|HGNC:HGNC:9607}; GN Synonyms=PTHRP {ECO:0000303|PubMed:2744490}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], PARTIAL PROTEIN SEQUENCE, FUNCTION, AND RP SUBCELLULAR LOCATION. RX PubMed=3616618; DOI=10.1126/science.3616618; RA Suva L.J., Winslow G.A., Wettenhall R.E.H., Hammonds R.G., Moseley J.M., RA Diefenbach-Jagger H., Rodda C.P., Kemp B.E., Rodriguez H., Chen E.Y., RA Hudson P.J., Martin T.J., Wood W.I.; RT "A parathyroid hormone-related protein implicated in malignant RT hypercalcemia: cloning and expression."; RL Science 237:893-896(1987). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=2829195; DOI=10.1073/pnas.85.2.597; RA Mangin M., Webb A.C., Dreyer B.E., Posillico J.T., Ikeda K., Weir E.C., RA Stewart A.F., Bander N.H., Milstone L., Barton D.E., Francke U., RA Broadus A.E.; RT "Identification of a cDNA encoding a parathyroid hormone-like peptide from RT a human tumor associated with humoral hypercalcemia of malignancy."; RL Proc. Natl. Acad. Sci. U.S.A. 85:597-601(1988). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=2708388; DOI=10.1016/s0021-9258(18)83294-x; RA Yasuda T., Banville D., Hendy G.N., Goltzman D.; RT "Characterization of the human parathyroid hormone-like peptide gene. RT Functional and evolutionary aspects."; RL J. Biol. Chem. 264:7720-7725(1989). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RX PubMed=3290897; DOI=10.1073/pnas.85.13.4605; RA Thiede M.A., Strewler G.J., Nissenson R.A., Rosenblatt M., Rodan G.A.; RT "Human renal carcinoma expresses two messages encoding a parathyroid RT hormone-like peptide: evidence for the alternative splicing of a single- RT copy gene."; RL Proc. Natl. Acad. Sci. U.S.A. 85:4605-4609(1988). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP NUCLEOTIDE SEQUENCE OF 1-33. RC TISSUE=Liver; RX PubMed=2744490; DOI=10.1016/0378-1119(89)90363-6; RA Suva L.J., Mather K.A., Gillespie M.T., Webb G.C., Ng K.W., Winslow G.A., RA Wood W.I., Martin T.J., Hudson P.J.; RT "Structure of the 5' flanking region of the gene encoding human RT parathyroid-hormone-related protein (PTHrP)."; RL Gene 77:95-105(1989). RN [9] RP PROTEIN SEQUENCE OF 37-52. RX PubMed=2885845; DOI=10.1073/pnas.84.14.5048; RA Moseley J.M., Kubota M., Diefenbach-Jagger H., Wettenhall R.E.H., RA Kemp B.E., Suva L.J., Rodda C.P., Ebeling P.R., Hudson P.J., Zajac J.D., RA Martin T.J.; RT "Parathyroid hormone-related protein purified from a human lung cancer cell RT line."; RL Proc. Natl. Acad. Sci. U.S.A. 84:5048-5052(1987). RN [10] RP ALTERNATIVE SPLICING (ISOFORM 3). RX PubMed=2928340; DOI=10.1073/pnas.86.7.2408; RA Mangin M., Ikeda K., Dreyer B.E., Broadus A.E.; RT "Isolation and characterization of the human parathyroid hormone-like RT peptide gene."; RL Proc. Natl. Acad. Sci. U.S.A. 86:2408-2412(1989). RN [11] RP CHARACTERIZATION OF OSTEOSTATIN ACTIVITY. RX PubMed=1915066; DOI=10.1210/endo-129-4-1762; RA Fenton A.J., Kemp B.E., Kent G.N., Moseley J.M., Zheng M.H., Rowe D.J., RA Britto J.M., Martin T.J., Nicholson G.C.; RT "A carboxyl-terminal peptide from the parathyroid hormone-related protein RT inhibits bone resorption by osteoclasts."; RL Endocrinology 129:1762-1768(1991). RN [12] RP CHARACTERIZATION OF OSTEOSTATIN ACTIVITY. RX PubMed=1954916; DOI=10.1210/endo-129-6-3424; RA Fenton A.J., Kemp B.E., Hammonds R.G., Mitchelhill K., Moseley J.M., RA Martin T.J., Nicholson G.C.; RT "A potent inhibitor of osteoclastic bone resorption within a highly RT conserved pentapeptide region of parathyroid hormone-related protein; RT PTHrP107-111."; RL Endocrinology 129:3424-3426(1991). RN [13] RP CHARACTERIZATION OF OSTEOSTATIN ACTIVITY. RX PubMed=9144344; DOI=10.1359/jbmr.1997.12.5.778; RA Martinez M.E., Garcia-Ocana A., Sanchez M., Medina S., del Campo T., RA Valin A., Sanchez-Cabezudo M.J., Esbrit P.; RT "C-terminal parathyroid hormone-related protein inhibits proliferation and RT differentiation of human osteoblast-like cells."; RL J. Bone Miner. Res. 12:778-785(1997). RN [14] RP CHARACTERIZATION OF OSTEOSTATIN ACTIVITY. RX PubMed=9048639; DOI=10.1210/endo.138.3.4990; RA Cornish J., Callon K.E., Nicholson G.C., Reid I.R.; RT "Parathyroid hormone-related protein-(107-139) inhibits bone resorption in RT vivo."; RL Endocrinology 138:1299-1304(1997). RN [15] RP SUBCELLULAR LOCATION, AND NUCLEOCYTOPLASMIC SHUTTLING. RX PubMed=12852260; DOI=10.1016/s0083-6729(03)01010-0; RA Jans D.A., Thomas R.J., Gillespie M.T.; RT "Parathyroid hormone-related protein (PTHrP): a nucleocytoplasmic shuttling RT protein with distinct paracrine and intracrine roles."; RL Vitam. Horm. 66:345-384(2003). RN [16] RP NUCLEAR LOCALIZATION SIGNAL. RX PubMed=11401507; DOI=10.1006/bbrc.2001.4607; RA Lam M.H., Hu W., Xiao C.Y., Gillespie M.T., Jans D.A.; RT "Molecular dissection of the importin beta1-recognized nuclear targeting RT signal of parathyroid hormone-related protein."; RL Biochem. Biophys. Res. Commun. 282:629-634(2001). RN [17] RP REVIEW. RX PubMed=12538599; DOI=10.1210/en.2002-220818; RA Fiaschi-Taesch N.M., Stewart A.F.; RT "Minireview: parathyroid hormone-related protein as an intracrine factor RT -- trafficking mechanisms and functional consequences."; RL Endocrinology 144:407-411(2003). RN [18] RP FUNCTION. RX PubMed=20637541; DOI=10.1016/j.canlet.2010.06.009; RA Mula R.V., Bhatia V., Falzon M.; RT "PTHrP promotes colon cancer cell migration and invasion in an integrin RT alpha6beta4-dependent manner through activation of Rac1."; RL Cancer Lett. 298:119-127(2010). RN [19] RP STRUCTURE BY NMR OF 37-70. RX PubMed=10050767; DOI=10.1016/s0014-5793(98)01658-5; RA Weidler M., Marx U.C., Seidel G., Schafer W., Hoffmann E., Esswein A., RA Rosch P.; RT "The structure of human parathyroid hormone-related protein(1-34) in near- RT physiological solution."; RL FEBS Lett. 444:239-244(1999). RN [20] RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 103-130. RX PubMed=12504010; DOI=10.1016/s1097-2765(02)00727-x; RA Cingolani G., Bednenko J., Gillespie M.T., Gerace L.; RT "Molecular basis for the recognition of a nonclassical nuclear localization RT signal by importin beta."; RL Mol. Cell 10:1345-1353(2002). RN [21] RP X-RAY CRYSTALLOGRAPHY (1.94 ANGSTROMS) OF 48-70 IN COMPLEX WITH PTH1R, RP FUNCTION, INTERACTION WITH PTH1R, AND MUTAGENESIS OF ARG-57; PHE-59; RP LEU-60; LEU-63; ILE-64 AND HIS-68. RX PubMed=19674967; DOI=10.1074/jbc.m109.022905; RA Pioszak A.A., Parker N.R., Gardella T.J., Xu H.E.; RT "Structural basis for parathyroid hormone-related protein binding to the RT parathyroid hormone receptor and design of conformation-selective RT peptides."; RL J. Biol. Chem. 284:28382-28391(2009). RN [22] {ECO:0007744|PDB:7VVJ} RP STRUCTURE BY ELECTRON MICROSCOPY (3.2 ANGSTROMS) OF 37-72 IN COMPLEX WITH RP PTH1R; GNAS; GNB1 AND GNG2, FUNCTION, AND INTERACTION WITH PTH1R. RX PubMed=35932760; DOI=10.1016/j.molcel.2022.07.003; RA Kobayashi K., Kawakami K., Kusakizako T., Miyauchi H., Tomita A., RA Kobayashi K., Shihoya W., Yamashita K., Nishizawa T., Kato H.E., Inoue A., RA Nureki O.; RT "Endogenous ligand recognition and structural transition of a human PTH RT receptor."; RL Mol. Cell 82:3468-3483(2022). RN [23] RP VARIANT [LARGE SCALE ANALYSIS] THR-169. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). RN [24] RP VARIANTS BDE2 PRO-44 AND PRO-60. RX PubMed=20170896; DOI=10.1016/j.ajhg.2010.01.023; RA Klopocki E., Hennig B.P., Dathe K., Koll R., de Ravel T., Baten E., RA Blom E., Gillerot Y., Weigel J.F., Krueger G., Hiort O., Seemann P., RA Mundlos S.; RT "Deletion and point mutations of PTHLH cause brachydactyly type E."; RL Am. J. Hum. Genet. 86:434-439(2010). CC -!- FUNCTION: Neuroendocrine peptide which is a critical regulator of CC cellular and organ growth, development, migration, differentiation and CC survival and of epithelial calcium ion transport (PubMed:12538599, CC PubMed:35932760, PubMed:3616618). Acts by binding to its receptor, CC PTH1R, activating G protein-coupled receptor signaling CC (PubMed:19674967, PubMed:35932760). Regulates endochondral bone CC development and epithelial-mesenchymal interactions during the CC formation of the mammary glands and teeth (By similarity). Required for CC skeletal homeostasis (PubMed:12538599). Promotes mammary mesenchyme CC differentiation and bud outgrowth by modulating mesenchymal cell CC responsiveness to BMPs (PubMed:12538599). Up-regulates BMPR1A CC expression in the mammary mesenchyme and this increases the sensitivity CC of these cells to BMPs and allows them to respond to BMP4 in a CC paracrine and/or autocrine fashion (By similarity). BMP4 signaling in CC the mesenchyme, in turn, triggers epithelial outgrowth and augments CC MSX2 expression, which causes the mammary mesenchyme to inhibit hair CC follicle formation within the nipple sheath (By similarity). Promotes CC colon cancer cell migration and invasion in an integrin alpha-6/beta-1- CC dependent manner through activation of Rac1 (PubMed:20637541). CC {ECO:0000250|UniProtKB:P22858, ECO:0000269|PubMed:19674967, CC ECO:0000269|PubMed:20637541, ECO:0000269|PubMed:35932760, CC ECO:0000269|PubMed:3616618, ECO:0000303|PubMed:12538599}. CC -!- FUNCTION: [Osteostatin]: Potent inhibitor of osteoclastic bone CC resorption. {ECO:0000269|PubMed:1915066, ECO:0000269|PubMed:1954916, CC ECO:0000269|PubMed:20637541, ECO:0000269|PubMed:9048639, CC ECO:0000269|PubMed:9144344}. CC -!- SUBUNIT: Interacts with PTH1R (via N-terminal extracellular domain). CC {ECO:0000269|PubMed:19674967, ECO:0000269|PubMed:35932760}. CC -!- INTERACTION: CC P12272; Q03431: PTH1R; NbExp=4; IntAct=EBI-2372758, EBI-2860297; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:3616618}. Cytoplasm CC {ECO:0000269|PubMed:12852260}. Nucleus {ECO:0000269|PubMed:12852260}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Comment=Additional isoforms seem to exist.; CC Name=1; CC IsoId=P12272-1; Sequence=Displayed; CC Name=2; CC IsoId=P12272-2; Sequence=VSP_004534; CC Name=3; CC IsoId=P12272-3; Sequence=VSP_004535; CC -!- TISSUE SPECIFICITY: Ubiquitous. Also expressed in the mammary gland. CC -!- PTM: There are 3 principal secretory forms, called PTHrP[1-36], CC PTHrP[38-94], and osteostatin (PTHrP[107-139]) arising from CC endoproteolytic cleavage of the initial translation product. Each of CC these secretory forms is believed to have one or more of its own CC receptors that mediates the normal paracrine, autocrine and endocrine CC actions. {ECO:0000303|PubMed:12538599}. CC -!- DISEASE: Brachydactyly E2 (BDE2) [MIM:613382]: A form of brachydactyly. CC Brachydactyly defines a group of inherited malformations characterized CC by shortening of the digits due to abnormal development of the CC phalanges and/or the metacarpals. Brachydactyly type E is characterized CC by shortening of the fingers mainly in the metacarpals and metatarsals. CC Wide variability in the number of digits affected occurs from person to CC person, even in the same family. Some individuals are moderately short CC of stature. In brachydactyly type E2 variable combinations of CC metacarpals are involved, with shortening also of the first and third CC distal and the second and fifth middle phalanges. CC {ECO:0000269|PubMed:20170896}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the parathyroid hormone family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/41897/PTHLH"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M17183; AAA60221.1; -; Genomic_DNA. DR EMBL; X14304; CAA32480.1; -; Genomic_DNA. DR EMBL; J03580; AAA60216.1; ALT_SEQ; mRNA. DR EMBL; M24349; AAA60358.1; -; Genomic_DNA. DR EMBL; M24348; AAA60358.1; JOINED; Genomic_DNA. DR EMBL; M24350; AAA60359.1; -; Genomic_DNA. DR EMBL; M24348; AAA60359.1; JOINED; Genomic_DNA. DR EMBL; M24349; AAA60359.1; JOINED; Genomic_DNA. DR EMBL; M24351; AAA60360.1; -; Genomic_DNA. DR EMBL; M24348; AAA60360.1; JOINED; Genomic_DNA. DR EMBL; M24349; AAA60360.1; JOINED; Genomic_DNA. DR EMBL; CR541882; CAG46680.1; -; mRNA. DR EMBL; CH471094; EAW96573.1; -; Genomic_DNA. DR EMBL; BC005961; AAH05961.1; -; mRNA. DR EMBL; J03802; AAA60218.1; -; mRNA. DR EMBL; M34071; AAA60217.1; -; mRNA. DR CCDS; CCDS44853.1; -. [P12272-1] DR CCDS; CCDS8715.1; -. [P12272-2] DR PIR; A33360; PTHU2L. DR PIR; C33360; PTHU3L. DR RefSeq; NP_001432348.1; NM_001445419.1. [P12272-1] DR RefSeq; NP_002811.1; NM_002820.3. [P12272-2] DR RefSeq; NP_945315.1; NM_198964.2. [P12272-2] DR RefSeq; NP_945316.1; NM_198965.2. [P12272-1] DR RefSeq; NP_945317.1; NM_198966.2. [P12272-1] DR RefSeq; XP_016875164.1; XM_017019675.2. [P12272-1] DR RefSeq; XP_047285135.1; XM_047429179.1. [P12272-1] DR RefSeq; XP_054228585.1; XM_054372610.1. [P12272-1] DR RefSeq; XP_054228586.1; XM_054372611.1. [P12272-1] DR RefSeq; XP_054228587.1; XM_054372612.1. [P12272-1] DR PDB; 1BZG; NMR; -; A=37-70. DR PDB; 1M5N; X-ray; 2.90 A; Q=103-130. DR PDB; 3FFD; X-ray; 2.00 A; P=37-144. DR PDB; 3H3G; X-ray; 1.94 A; B=48-70. DR PDB; 7UZO; X-ray; 1.30 A; B=51-72. DR PDB; 7UZP; X-ray; 2.29 A; B/D/F=52-72. DR PDB; 7VVJ; EM; 3.20 A; P=37-72. DR PDB; 8D51; X-ray; 2.00 A; B=51-72. DR PDB; 8D52; X-ray; 2.02 A; B=51-72. DR PDB; 8FLR; EM; 2.94 A; P=37-72. DR PDB; 8HAF; EM; 3.25 A; P=37-72. DR AlphaFoldDB; P12272; -. DR BMRB; P12272; -. DR EMDB; EMD-29284; -. DR EMDB; EMD-32141; -. DR EMDB; EMD-34587; -. DR SMR; P12272; -. DR BioGRID; 111716; 18. DR FunCoup; P12272; 911. DR IntAct; P12272; 3. DR MINT; P12272; -. DR NDEx; IQUERY-CP-PTHLH; 5 NDEx IQuery Curated Pathways. DR STRING; 9606.ENSP00000441765; -. DR ChEMBL; CHEMBL3712869; -. DR GlyCosmos; P12272; 1 site, 1 glycan. DR GlyGen; P12272; 3 sites, 2 O-linked glycans (3 sites). DR iPTMnet; P12272; -. DR PhosphoSitePlus; P12272; -. DR BioMuta; PTHLH; -. DR DMDM; 131542; -. DR MassIVE; P12272; -. DR PaxDb; 9606-ENSP00000441765; -. DR PeptideAtlas; P12272; -. DR ProteomicsDB; 52842; -. [P12272-1] DR ProteomicsDB; 52843; -. [P12272-2] DR ProteomicsDB; 52844; -. [P12272-3] DR ABCD; P12272; 4 sequenced antibodies. DR Antibodypedia; 3662; 465 antibodies from 39 providers. DR CPTC; P12272; 2 antibodies. DR DNASU; 5744; -. DR Ensembl; ENST00000201015.8; ENSP00000201015.4; ENSG00000087494.17. [P12272-2] DR Ensembl; ENST00000395868.7; ENSP00000379209.3; ENSG00000087494.17. [P12272-2] DR Ensembl; ENST00000395872.5; ENSP00000379213.1; ENSG00000087494.17. [P12272-1] DR Ensembl; ENST00000535992.5; ENSP00000440613.1; ENSG00000087494.17. [P12272-2] DR Ensembl; ENST00000538310.1; ENSP00000441890.1; ENSG00000087494.17. [P12272-3] DR Ensembl; ENST00000539239.5; ENSP00000441571.1; ENSG00000087494.17. [P12272-1] DR Ensembl; ENST00000545234.6; ENSP00000441765.1; ENSG00000087494.17. [P12272-1] DR Ensembl; ENST00000851935.1; ENSP00000521994.1; ENSG00000087494.17. [P12272-1] DR Ensembl; ENST00000963668.1; ENSP00000633727.1; ENSG00000087494.17. [P12272-1] DR Ensembl; ENST00000963669.1; ENSP00000633728.1; ENSG00000087494.17. [P12272-1] DR Ensembl; ENST00000963670.1; ENSP00000633729.1; ENSG00000087494.17. [P12272-1] DR GeneID; 5744; -. DR KEGG; hsa:5744; -. DR MANE-Select; ENST00000545234.6; ENSP00000441765.1; NM_198965.2; NP_945316.1. DR UCSC; uc001ril.4; human. [P12272-1] DR AGR; HGNC:9607; -. DR ClinPGx; PA33952; -. DR CTD; 5744; -. DR DisGeNET; 5744; -. DR GeneCards; PTHLH; -. DR HGNC; HGNC:9607; PTHLH. DR HPA; ENSG00000087494; Tissue enhanced (parathyroid). DR MalaCards; PTHLH; -. DR MIM; 168470; gene. DR MIM; 613382; phenotype. DR OpenTargets; ENSG00000087494; -. DR Orphanet; 93387; Brachydactyly type E. DR VEuPathDB; HostDB:ENSG00000087494; -. DR eggNOG; ENOG502S3J9; Eukaryota. DR GeneTree; ENSGT00390000004933; -. DR InParanoid; P12272; -. DR OMA; TTHDHNL; -. DR OrthoDB; 9892514at2759; -. DR PAN-GO; P12272; 5 GO annotations based on evolutionary models. DR PhylomeDB; P12272; -. DR PathwayCommons; P12272; -. DR Reactome; R-HSA-373080; Class B/2 (Secretin family receptors). DR Reactome; R-HSA-418555; G alpha (s) signalling events. DR SignaLink; P12272; -. DR SIGNOR; P12272; -. DR Agora; ENSG00000087494; -. DR BioGRID-ORCS; 5744; 8 hits in 1156 CRISPR screens. DR EvolutionaryTrace; P12272; -. DR GeneWiki; Parathyroid_hormone-related_protein; -. DR GenomeRNAi; 5744; -. DR Pharos; P12272; Tbio. DR PRO; PR:P12272; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; P12272; protein. DR Bgee; ENSG00000087494; Expressed in periodontal ligament and 140 other cell types or tissues. DR ExpressionAtlas; P12272; baseline and differential. DR GO; GO:0005737; C:cytoplasm; EXP:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005576; C:extracellular region; EXP:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; EXP:UniProtKB. DR GO; GO:0005179; F:hormone activity; IDA:UniProtKB. DR GO; GO:0051428; F:peptide hormone receptor binding; IDA:UniProtKB. DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; IDA:MGI. DR GO; GO:0030282; P:bone mineralization; IEA:InterPro. DR GO; GO:0046058; P:cAMP metabolic process; TAS:ProtInc. DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc. DR GO; GO:0008544; P:epidermis development; TAS:ProtInc. DR GO; GO:0007565; P:female pregnancy; TAS:ProtInc. DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IDA:UniProt. DR GO; GO:0008285; P:negative regulation of cell population proliferation; TAS:ProtInc. DR GO; GO:0061182; P:negative regulation of chondrocyte development; IDA:MGI. DR GO; GO:0032331; P:negative regulation of chondrocyte differentiation; IDA:MGI. DR GO; GO:0002076; P:osteoblast development; IBA:GO_Central. DR GO; GO:0008284; P:positive regulation of cell population proliferation; TAS:ProtInc. DR GO; GO:0032330; P:regulation of chondrocyte differentiation; IBA:GO_Central. DR GO; GO:0010468; P:regulation of gene expression; IDA:MGI. DR GO; GO:0001501; P:skeletal system development; IDA:MGI. DR DisProt; DP00138; -. DR IDEAL; IID00194; -. DR InterPro; IPR003626; PTH-rel. DR InterPro; IPR001415; PTH/PTH-rel. DR PANTHER; PTHR17223; PARATHYROID HORMONE-RELATED; 1. DR PANTHER; PTHR17223:SF0; PARATHYROID HORMONE-RELATED PROTEIN; 1. DR Pfam; PF01279; Parathyroid; 1. DR SMART; SM00087; PTH; 1. DR PROSITE; PS00335; PARATHYROID; 1. DR PDBsum; 1BZG; -. DR PDBsum; 1M5N; -. DR PDBsum; 3FFD; -. DR PDBsum; 3H3G; -. DR PDBsum; 7UZO; -. DR PDBsum; 7UZP; -. DR PDBsum; 7VVJ; -. DR PDBsum; 8D51; -. DR PDBsum; 8D52; -. DR PDBsum; 8FLR; -. DR PDBsum; 8HAF; -. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Calcium; KW Cleavage on pair of basic residues; Cytoplasm; Direct protein sequencing; KW Disease variant; Hormone; Nucleus; Proteomics identification; KW Reference proteome; Secreted; Signal. FT SIGNAL 1..24 FT /evidence="ECO:0000255" FT PROPEP 25..34 FT /evidence="ECO:0000269|PubMed:2885845" FT /id="PRO_0000023224" FT CHAIN 37..177 FT /note="Parathyroid hormone-related protein" FT /id="PRO_0000023225" FT PEPTIDE 37..72 FT /note="PTHrP[1-36]" FT /evidence="ECO:0000303|PubMed:12538599" FT /id="PRO_0000023226" FT PEPTIDE 74..130 FT /note="PTHrP[38-94]" FT /evidence="ECO:0000303|PubMed:12538599" FT /id="PRO_0000023227" FT PEPTIDE 143..175 FT /note="Osteostatin" FT /evidence="ECO:0000303|PubMed:12538599" FT /id="PRO_0000023228" FT REGION 57..68 FT /note="Important for receptor binding" FT /evidence="ECO:0000269|PubMed:19674967" FT REGION 74..177 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 108..129 FT /note="Nuclear localization signal" FT /evidence="ECO:0000269|PubMed:11401507" FT COMPBIAS 76..90 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 109..118 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 122..132 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT VAR_SEQ 176..177 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:3290897" FT /id="VSP_004534" FT VAR_SEQ 176..177 FT /note="RH -> TALLWGLKKKKENNRRTHHMQLMISLFKSPLLLL (in isoform FT 3)" FT /evidence="ECO:0000305" FT /id="VSP_004535" FT VARIANT 44 FT /note="L -> P (in BDE2; dbSNP:rs267606986)" FT /evidence="ECO:0000269|PubMed:20170896" FT /id="VAR_063711" FT VARIANT 60 FT /note="L -> P (in BDE2; dbSNP:rs267606985)" FT /evidence="ECO:0000269|PubMed:20170896" FT /id="VAR_063712" FT VARIANT 169 FT /note="S -> T (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036433" FT MUTAGEN 57 FT /note="R->A: Strongly reduced affinity for PTH1R." FT /evidence="ECO:0000269|PubMed:19674967" FT MUTAGEN 59 FT /note="F->A: Reduced affinity for PTH1R." FT /evidence="ECO:0000269|PubMed:19674967" FT MUTAGEN 60 FT /note="L->A,K: Strongly reduced affinity for PTH1R." FT /evidence="ECO:0000269|PubMed:19674967" FT MUTAGEN 63 FT /note="L->A: Reduced affinity for PTH1R." FT /evidence="ECO:0000269|PubMed:19674967" FT MUTAGEN 64 FT /note="I->A: Reduced affinity for PTH1R." FT /evidence="ECO:0000269|PubMed:19674967" FT MUTAGEN 68 FT /note="H->A: Reduced affinity for PTH1R." FT /evidence="ECO:0000269|PubMed:19674967" FT STRAND 39..41 FT /evidence="ECO:0007829|PDB:8HAF" FT HELIX 52..67 FT /evidence="ECO:0007829|PDB:7UZO" FT HELIX 69..71 FT /evidence="ECO:0007829|PDB:8HAF" FT STRAND 114..116 FT /evidence="ECO:0007829|PDB:1M5N" FT HELIX 117..119 FT /evidence="ECO:0007829|PDB:1M5N" SQ SEQUENCE 177 AA; 20194 MW; 449FDFEE954C51DB CRC64; MQRRLVQQWS VAVFLLSYAV PSCGRSVEGL SRRLKRAVSE HQLLHDKGKS IQDLRRRFFL HHLIAEIHTA EIRATSEVSP NSKPSPNTKN HPVRFGSDDE GRYLTQETNK VETYKEQPLK TPGKKKKGKP GKRKEQEKKK RRTRSAWLDS GVTGSGLEGD HLSDTSTTSL ELDSRRH //