ID BMPR2_HUMAN Reviewed; 1038 AA. AC Q13873; Q16569; DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2000, sequence version 2. DT 24-JUL-2007, entry version 85. DE Bone morphogenetic protein receptor type-2 precursor (EC 2.7.11.30) DE (Bone morphogenetic protein receptor type II) (BMP type II receptor) DE (BMPR-II). GN Name=BMPR2; Synonyms=PPH1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Substantia nigra; RX MEDLINE=95372334; PubMed=7644468; RA Rosenzweig B.L., Imamura T., Okadome T., Cox G.N., Yamashita H., RA ten Dijke P., Heldin C., Miyazono K.; RT "Cloning and characterization of a human type II receptor for bone RT morphogenetic proteins."; RL Proc. Natl. Acad. Sci. U.S.A. 92:7632-7636(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Skin fibroblast; RX MEDLINE=95403457; PubMed=7673243; DOI=10.1074/jbc.270.38.22522; RA Nohno T., Ishikawa T., Saito T., Hosokawa K., Noji S., Wosing D.H., RA Rosenbaum J.S.; RT "Identification of a human type II receptor for bone morphogenetic RT protein-4 that forms differential heteromeric complexes with bone RT morphogenetic protein type I receptors."; RL J. Biol. Chem. 270:22522-22526(1995). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RX MEDLINE=95197572; PubMed=7890683; DOI=10.1074/jbc.270.10.5625; RA Kawabata M., Chytil A., Moses H.L.; RT "Cloning of a novel type II serine/threonine kinase receptor through RT interaction with the type I transforming growth factor-beta RT receptor."; RL J. Biol. Chem. 270:5625-5630(1995). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Skin; 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP VARIANTS PPH1 GLN-491 AND TRP-491. RX MEDLINE=20395844; PubMed=10903931; DOI=10.1086/303059; RA Deng Z., Morse J.H., Slager S.L., Cuervo N., Moore K.J., Venetos G., RA Kalachikov S., Cayanis E., Fischer S.G., Barst R.J., Hodge S.E., RA Knowles J.A.; RT "Familial primary pulmonary hypertension (gene PPH1) is caused by RT mutations in the bone morphogenetic protein receptor-II gene."; RL Am. J. Hum. Genet. 67:737-744(2000). RN [6] RP VARIANTS PPH1 TYR-60; TYR-117 AND ARG-483. RX MEDLINE=20473811; PubMed=11015450; DOI=10.1136/jmg.37.10.741; RA Thomson J.R., Machado R.D., Pauciulo M.W., Morgan N.V., Humbert M., RA Elliott G.C., Ward K., Yacoub M., Mikhail G., Rogers P., Newman J.H., RA Wheeler L., Higenbottam T., Gibbs J.S.R., Egan J., Crozier A., RA Peacock A., Allcock R., Corris P., Loyd J.E., Trembath R.C., RA Nichols W.C.; RT "Sporadic primary pulmonary hypertension is associated with germline RT mutations of the gene encoding BMPR-II, a receptor member of the TGF- RT beta family."; RL J. Med. Genet. 37:741-745(2000). RN [7] RP VARIANTS PPH1 TRP-118; TYR-347 AND GLY-485. RX MEDLINE=20428187; PubMed=10973254; DOI=10.1038/79226; RA Lane K.B., Machado R.D., Pauciulo M.W., Thomson J.R., RA Phillips J.A. III, Loyd J.E., Nichols W.C., Trembath R.C., Aldred M., RA Brannon C.A., Conneally P.M., Foroud T., Fretwell N., Gaddipati R., RA Koller D., Loyd E.J., Morgan N.V., Newman J.H., Prince M.A., RA Vilarino Gueell C., Wheeler L.; RT "Heterozygous germline mutations in BMPR2, encoding a TGF-beta RT receptor, cause familial primary pulmonary hypertension."; RL Nat. Genet. 26:81-84(2000). RN [8] RP VARIANTS PPH1 ARG-123; SER-123; ARG-420 AND THR-512, VARIANT ASP-224, RP AND CHARACTERIZATION OF VARIANT PPH1 GLY-485. RX MEDLINE=21063176; PubMed=11115378; DOI=10.1086/316947; RA Machado R.D., Pauciulo M.W., Thomson J.R., Lane K.B., Morgan N.V., RA Wheeler L., Phillips J.A. III, Newman J.H., Williams D., Galie N., RA Manes A., McNeil K., Yacoub M., Mikhail G., Rogers P., Corris P., RA Humbert M., Donnai D., Martensson G., Tranebjaerg L., Loyd J.E., RA Trembath R.C., Nichols W.C.; RT "BMPR2 haploinsufficiency as the inherited molecular mechanism for RT primary pulmonary hypertension."; RL Am. J. Hum. Genet. 68:92-102(2001). RN [9] RP VARIANTS PPH1 HIS-82; ASP-182 AND ARG-483. RX PubMed=12358323; DOI=10.1183/09031936.02.01762002; RA Humbert M., Deng Z., Simonneau G., Barst R.J., Sitbon O., Wolf M., RA Cuervo N., Moore K.J., Hodge S.E., Knowles J.A., Morse J.H.; RT "BMPR2 germline mutations in pulmonary hypertension associated with RT fenfluramine derivatives."; RL Eur. Respir. J. 20:518-523(2002). RN [10] RP INVOLVEMENT IN PVOD. RX PubMed=12446270; RA Runo J.R., Vnencak-Jones C.L., Prince M., Loyd J.E., Wheeler L., RA Robbins I.M., Lane K.B., Newman J.H., Johnson J., Nichols W.C., RA Phillips J.A. III; RT "Pulmonary veno-occlusive disease caused by an inherited mutation in RT bone morphogenetic protein receptor II."; RL Am. J. Respir. Crit. Care Med. 167:889-894(2003). RN [11] RP VARIANT PPH1 PRO-899, AND CHARACTERIZATION OF VARIANT PPH1 PRO-899. RX PubMed=15965979; DOI=10.1002/humu.20200; RA Sankelo M., Flanagan J.A., Machado R., Harrison R., Rudarakanchana N., RA Morrell N., Dixon M., Halme M., Puolijoki H., Kere J., Elomaa O., RA Kupari M., Raeisaenen-Sokolowski A., Trembath R.C., Laitinen T.; RT "BMPR2 mutations have short lifetime expectancy in primary pulmonary RT hypertension."; RL Hum. Mutat. 26:119-124(2005). RN [12] RP INVOLVEMENT IN PVOD. RX PubMed=16429395; DOI=10.1002/humu.20285; RA Machado R.D., Aldred M.A., James V., Harrison R.E., Patel B., RA Schwalbe E.C., Gruenig E., Janssen B., Koehler R., Seeger W., RA Eickelberg O., Olschewski H., Elliott C.G., Glissmeyer E., RA Carlquist J., Kim M., Torbicki A., Fijalkowska A., Szewczyk G., RA Parma J., Abramowicz M.J., Galie N., Morisaki H., Kyotani S., RA Nakanishi N., Morisaki T., Humbert M., Simonneau G., Sitbon O., RA Soubrier F., Coulet F., Morrell N.W., Trembath R.C.; RT "Mutations of the TGF-beta type II receptor BMPR2 in pulmonary RT arterial hypertension."; RL Hum. Mutat. 27:121-132(2006). CC -!- FUNCTION: On ligand binding, forms a receptor complex consisting CC of two type II and two type I transmembrane serine/threonine CC kinases. Type II receptors phosphorylate and activate type I CC receptors which autophosphorylate, then bind and activate SMAD CC transcriptional regulators. Binds to BMP-7, BMP-2 and, less CC efficiently, BMP-4. Binding is weak but enhanced by the presence CC of type I receptors for BMPs. CC -!- CATALYTIC ACTIVITY: ATP + [receptor-protein] = ADP + [receptor- CC protein] phosphate. CC -!- COFACTOR: Magnesium or manganese (By similarity). CC -!- INTERACTION: CC Q91X48:C4bp (xeno); NbExp=1; IntAct=EBI-527196, EBI-527325; CC P68404:Prkcb1 (xeno); NbExp=2; IntAct=EBI-527196, EBI-397048; CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane CC protein. CC -!- TISSUE SPECIFICITY: Highly expressed in heart and liver. CC -!- DISEASE: Defects in BMPR2 are the cause of primary pulmonary CC hypertension (PPH1) [MIM:178600]. PPH1 is a rare autosomal CC dominant disorder characterized by plexiform lesions of CC proliferating endothelial cells in pulmonary arterioles. The CC lesions lead to elevated pulmonary arterial pression, right CC ventricular failure, and death. The disease can occur from infancy CC throughout life and it has a mean age at onset of 36 years. CC Penetrance is reduced. Although familial PPH1 is rare, cases CC secondary to known etiologies are more common and include those CC associated with the appetite-suppressant drugs. CC -!- DISEASE: Defects in BMPR2 are a cause of pulmonary venoocclusive CC disease (PVOD) [MIM:265450]. PVOD is a rare form of pulmonary CC hypertension in which the vascular changes originate in the small CC pulmonary veins and venules. The pathogenesis is unknown and any CC link with PPH1 has been speculative. The finding of PVOD CC associated with a BMPR2 mutation reveals a possible pathogenetic CC connection with PPH1. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. TKL Ser/Thr CC protein kinase family. TGFB receptor subfamily. CC -!- SIMILARITY: Contains 1 protein kinase domain. CC -!- WEB RESOURCE: NAME=GeneReviews; CC URL="http://www.genetests.org/query?gene=BMPR2". 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; Z48923; CAA88759.1; -; mRNA. DR EMBL; D50516; BAA09094.1; -; mRNA. DR EMBL; U20165; AAC50105.1; -; mRNA. DR EMBL; BC052985; AAH52985.1; -; mRNA. DR PIR; I38935; I38935. DR UniGene; Hs.471119; -. DR HSSP; P36897; 1IAS. DR DIP; DIP:5794N; -. DR DIP; DIP:5941N; -. DR DIP; DIP:5942N; -. DR IntAct; Q13873; -. DR Ensembl; ENSG00000204217; Homo sapiens. DR KEGG; hsa:659; -. DR HGNC; HGNC:1078; BMPR2. DR MIM; 178600; phenotype. DR MIM; 265450; phenotype. DR MIM; 600799; gene. DR Orphanet; 422; Pulmonary arterial hypertension. DR Orphanet; 31837; Pulmonary venoocclusive disease. DR PharmGKB; PA25388; -. DR ArrayExpress; Q13873; -. DR GermOnline; ENSG00000204217; Homo sapiens. DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc. DR GO; GO:0005515; F:protein binding; IPI:IntAct. DR GO; GO:0042127; P:regulation of cell proliferation; IMP:HGNC. DR GO; GO:0000074; P:regulation of progression through cell cycle; IMP:HGNC. DR GO; GO:0007178; P:transmembrane receptor protein serine/threo...; TAS:ProtInc. DR InterPro; IPR000472; Activin_rcpt. DR InterPro; IPR015770; BMPRII. DR InterPro; IPR000719; Prot_kinase. DR InterPro; IPR008271; Ser_thr_pkin_AS. DR PANTHER; PTHR23255:SF12; BMPRII; 1. DR Pfam; PF01064; Activin_recp; 1. DR Pfam; PF00069; Pkinase; 1. DR ProDom; PD000001; Prot_kinase; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; FALSE_NEG. PE 1: Evidence at protein level; KW ATP-binding; Disease mutation; Glycoprotein; Kinase; Magnesium; KW Manganese; Membrane; Metal-binding; Nucleotide-binding; Polymorphism; KW Receptor; Serine/threonine-protein kinase; Signal; Transferase; KW Transmembrane. FT SIGNAL 1 26 Potential. FT CHAIN 27 1038 Bone morphogenetic protein receptor type- FT 2. FT /FTId=PRO_0000024415. FT TOPO_DOM 27 150 Extracellular (Potential). FT TRANSMEM 151 171 Potential. FT TOPO_DOM 172 1038 Cytoplasmic (Potential). FT DOMAIN 203 504 Protein kinase. FT NP_BIND 209 217 ATP (By similarity). FT COMPBIAS 547 550 Poly-Ser. FT COMPBIAS 610 618 Poly-Thr. FT COMPBIAS 901 908 Poly-Asn. FT ACT_SITE 333 333 Proton acceptor (By similarity). FT BINDING 230 230 ATP (By similarity). FT CARBOHYD 55 55 N-linked (GlcNAc...) (Potential). FT CARBOHYD 110 110 N-linked (GlcNAc...) (Potential). FT CARBOHYD 126 126 N-linked (GlcNAc...) (Potential). FT DISULFID 34 66 By similarity. FT DISULFID 94 117 By similarity. FT VARIANT 60 60 C -> Y (in PPH1). FT /FTId=VAR_013670. FT VARIANT 82 82 Q -> H (in PPH1). FT /FTId=VAR_033109. FT VARIANT 117 117 C -> Y (in PPH1). FT /FTId=VAR_013671. FT VARIANT 118 118 C -> W (in PPH1). FT /FTId=VAR_013672. FT VARIANT 123 123 C -> R (in PPH1). FT /FTId=VAR_013673. FT VARIANT 123 123 C -> S (in PPH1). FT /FTId=VAR_013674. FT VARIANT 182 182 G -> D (in PPH1). FT /FTId=VAR_033110. FT VARIANT 224 224 E -> D. FT /FTId=VAR_013675. FT VARIANT 347 347 C -> Y (in PPH1). FT /FTId=VAR_013676. FT VARIANT 420 420 C -> R (in PPH1). FT /FTId=VAR_013677. FT VARIANT 483 483 C -> R (in PPH1; sporadic). FT /FTId=VAR_013678. FT VARIANT 485 485 D -> G (in PPH1; complete loss of FT function). FT /FTId=VAR_013679. FT VARIANT 491 491 R -> Q (in PPH1; sporadic). FT /FTId=VAR_013680. FT VARIANT 491 491 R -> W (in PPH1). FT /FTId=VAR_013681. FT VARIANT 512 512 K -> T (in PPH1). FT /FTId=VAR_013682. FT VARIANT 519 519 N -> K (in PPH1). FT /FTId=VAR_013683. FT VARIANT 775 775 S -> N (in dbSNP:rs2228545). FT /FTId=VAR_019996. FT VARIANT 899 899 R -> P (in PPH1; leads to constitutive FT activation of the MAPK14 pathway). FT /FTId=VAR_033111. FT CONFLICT 828 828 G -> R (in Ref. 1). SQ SEQUENCE 1038 AA; 115201 MW; 1389923CE574B913 CRC64; MTSSLQRPWR VPWLPWTILL VSTAAASQNQ ERLCAFKDPY QQDLGIGESR ISHENGTILC SKGSTCYGLW EKSKGDINLV KQGCWSHIGD PQECHYEECV VTTTPPSIQN GTYRFCCCST DLCNVNFTEN FPPPDTTPLS PPHSFNRDET IIIALASVSV LAVLIVALCF GYRMLTGDRK QGLHSMNMME AAASEPSLDL DNLKLLELIG RGRYGAVYKG SLDERPVAVK VFSFANRQNF INEKNIYRVP LMEHDNIARF IVGDERVTAD GRMEYLLVME YYPNGSLCKY LSLHTSDWVS SCRLAHSVTR GLAYLHTELP RGDHYKPAIS HRDLNSRNVL VKNDGTCVIS DFGLSMRLTG NRLVRPGEED NAAISEVGTI RYMAPEVLEG AVNLRDCESA LKQVDMYALG LIYWEIFMRC TDLFPGESVP EYQMAFQTEV GNHPTFEDMQ VLVSREKQRP KFPEAWKENS LAVRSLKETI EDCWDQDAEA RLTAQCAEER MAELMMIWER NKSVSPTVNP MSTAMQNERN LSHNRRVPKI GPYPDYSSSS YIEDSIHHTD SIVKNISSEH SMSSTPLTIG EKNRNSINYE RQQAQARIPS PETSVTSLST NTTTTNTTGL TPSTGMTTIS EMPYPDETNL HTTNVAQSIG PTPVCLQLTE EDLETNKLDP KEVDKNLKES SDENLMEHSL KQFSGPDPLS STSSSLLYPL IKLAVEATGQ QDFTQTANGQ ACLIPDVLPT QIYPLPKQQN LPKRPTSLPL NTKNSTKEPR LKFGSKHKSN LKQVETGVAK MNTINAAEPH VVTVTMNGVA GRNHSVNSHA ATTQYANGTV LSGQTTNIVT HRAQEMLQNQ FIGEDTRLNI NSSPDEHEPL LRREQQAGHD EGVLDRLVDR RERPLEGGRT NSNNNNSNPC SEQDVLAQGV PSTAADPGPS KPRRAQRPNS LDLSATNVLD GSSIQIGEST QDGKSGSGEK IKKRVKTPYS LKRWRPSTWV ISTESLDCEV NNNGSNRAVH SKSSTAVYLA EGGTATTMVS KDIGMNCL //