P12644 (BMP4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Bone morphogenetic protein 4
Short name=BMP-4

Alternative name(s):
Bone morphogenetic protein 2B
Short name=BMP-2B

Gene names

Name:	BMP4
Synonyms:	BMP2B, DVR4

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	408 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	Induces cartilage and bone formation. Also act in mesoderm induction, tooth development, limb formation and fracture repair. Acts in concert with PTHLH/PTHRP to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction By similarity.
Subunit structure	Homodimer; disulfide-linked By similarity. Interacts with GREM2 By similarity and SOSTDC1. Part of a complex consisting of TWSG1 and CHRD By similarity. Ref.5
Subcellular location	Secreted › extracellular space › extracellular matrix.
Tissue specificity	Expressed in the lung and lower levels seen in the kidney. Present also in normal and neoplastic prostate tissues, and prostate cancer cell lines.
Involvement in disease	Defects in BMP4 are the cause of microphthalmia syndromic type 6 (MCOPS6) [MIM:607932]; also known as microphthalmia and pituitary anomalies or microphthalmia with brain and digit developmental anomalies. Microphthalmia is a clinically heterogeneous disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues (anophthalmia). In many cases, microphthalmia/anophthalmia occurs in association with syndromes that include non-ocular abnormalities. MCOPS6 is characterized by microphthalmia/anophthalmia associated with facial, genital, skeletal, neurologic and endocrine anomalies. Ref.7 Defects in BMP4 are the cause of non-syndromic orofacial cleft type 11 (OFC11) [MIM:600625]. Non-syndromic orofacial cleft is a common birth defect consisting of cleft lips with or without cleft palate. Cleft lips are associated with cleft palate in two-third of cases. A cleft lip can occur on one or both sides and range in severity from a simple notch in the upper lip to a complete opening in the lip extending into the floor of the nostril and involving the upper gum. OFC11 is an unusual anomaly consisting of a paramedian scar of the upper lip with an appearance suggesting that a typical cleft lip was corrected in utero. Ref.9
Sequence similarities	Belongs to the TGF-beta family.

Ontologies

Keywords
Biological process	Chondrogenesis Differentiation Osteogenesis
Cellular component	Extracellular matrix Secreted
Coding sequence diversity	Polymorphism
Disease	Disease mutation Microphthalmia
Domain	Signal
Molecular function	Cytokine Developmental protein Growth factor
PTM	Cleavage on pair of basic residues Disulfide bond Glycoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	BMP signaling pathway involved in heart induction Inferred from mutant phenotype. Source: BHF-UCL BMP signaling pathway involved in nephric duct formation Inferred from direct assay. Source: UniProtKB BMP signaling pathway involved in renal system segmentation Inferred from sequence or structural similarity. Source: UniProtKB BMP signaling pathway involved in ureter morphogenesis Inferred from sequence or structural similarity. Source: UniProtKB SMAD protein signal transduction Inferred from direct assay. Source: UniProtKB activation of MAPKK activity Inferred from direct assay. Source: UniProtKB blood vessel endothelial cell proliferation involved in sprouting angiogenesis Inferred from direct assay. Source: BHF-UCL branching involved in ureteric bud morphogenesis Inferred from direct assay. Source: UniProtKB bronchus development Inferred from direct assay. Source: MGI bud dilation involved in lung branching Inferred from direct assay. Source: MGI cardiac septum development Traceable author statement. Source: BHF-UCL chondrocyte differentiation Inferred from sequence or structural similarity. Source: UniProtKB deltoid tuberosity development Inferred from sequence or structural similarity. Source: UniProtKB endocardial cushion development Traceable author statement. Source: BHF-UCL endochondral ossification Inferred from sequence or structural similarity. Source: UniProtKB epithelial cell proliferation involved in lung morphogenesis Inferred from direct assay. Source: MGI glomerular capillary formation Inferred from sequence or structural similarity. Source: UniProtKB intermediate mesodermal cell differentiation Inferred from direct assay. Source: UniProtKB lung alveolus development Inferred from direct assay. Source: MGI lymphoid progenitor cell differentiation Inferred from mutant phenotype. Source: BHF-UCL macrophage differentiation Inferred from direct assay. Source: DFLAT mesenchymal to epithelial transition involved in metanephros morphogenesis Inferred from direct assay. Source: UniProtKB mesonephros development Inferred from expression pattern. Source: UniProtKB metanephric collecting duct development Inferred from sequence or structural similarity. Source: UniProtKB monocyte differentiation Inferred from direct assay. Source: DFLAT negative regulation of MAP kinase activity Inferred from direct assay. Source: UniProtKB negative regulation of T cell differentiation in thymus Inferred from mutant phenotype. Source: BHF-UCL negative regulation of branch elongation involved in ureteric bud branching by BMP signaling pathway Inferred from direct assay. Source: UniProtKB negative regulation of branching involved in ureteric bud morphogenesis Inferred from direct assay. Source: UniProtKB negative regulation of cell proliferation involved in heart morphogenesis Inferred from mutant phenotype. Source: BHF-UCL negative regulation of glomerular mesangial cell proliferation Inferred from direct assay. Source: UniProtKB negative regulation of glomerulus development Inferred from direct assay. Source: UniProtKB negative regulation of immature T cell proliferation in thymus Inferred from mutant phenotype. Source: BHF-UCL negative regulation of mesenchymal cell proliferation involved in ureter development Inferred from direct assay. Source: UniProtKB negative regulation of metanephric S-shaped body morphogenesis Inferred from direct assay. Source: UniProtKB negative regulation of metanephric comma-shaped body morphogenesis Inferred from direct assay. Source: UniProtKB negative regulation of mitosis Inferred from direct assay. Source: UniProtKB negative regulation of myoblast differentiation Inferred from direct assay. Source: MGI negative regulation of phosphorylation Inferred from direct assay. Source: UniProtKB negative regulation of striated muscle tissue development Inferred from direct assay. Source: MGI negative regulation of thymocyte apoptosis Inferred from mutant phenotype. Source: BHF-UCL negative regulation of transcription from RNA polymerase II promoter Inferred from direct assay. Source: MGI osteoblast differentiation Inferred from direct assay. Source: BHF-UCL positive regulation of BMP signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of SMAD protein import into nucleus Inferred from direct assay. Source: BHF-UCL positive regulation of apoptotic process Inferred from direct assay. Source: UniProtKB positive regulation of bone mineralization Inferred from direct assay. Source: UniProtKB positive regulation of branching involved in lung morphogenesis Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of cardiac muscle fiber development Inferred from mutant phenotype. Source: BHF-UCL positive regulation of cartilage development Inferred from direct assay Ref.1. Source: MGI positive regulation of collagen biosynthetic process Inferred from direct assay. Source: BHF-UCL positive regulation of endothelial cell migration Inferred from direct assay. Source: UniProtKB positive regulation of endothelial cell proliferation Inferred from direct assay. Source: UniProtKB positive regulation of kidney development Inferred from direct assay. Source: UniProtKB positive regulation of osteoblast differentiation Inferred from direct assay. Source: BHF-UCL positive regulation of pathway-restricted SMAD protein phosphorylation Inferred from direct assay. Source: UniProtKB positive regulation of smooth muscle cell proliferation Inferred from direct assay. Source: UniProtKB positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay. Source: MGI post-embryonic development Inferred from direct assay. Source: MGI protein localization to nucleus Inferred from direct assay. Source: UniProtKB pulmonary artery endothelial tube morphogenesis Inferred from direct assay. Source: UniProtKB secondary heart field specification Inferred from mutant phenotype. Source: BHF-UCL smoothened signaling pathway Inferred from expression pattern. Source: UniProtKB specification of ureteric bud anterior/posterior symmetry by BMP signaling pathway Inferred from direct assay. Source: UniProtKB steroid hormone mediated signaling pathway Inferred from mutant phenotype. Source: UniProtKB tendon cell differentiation Inferred from sequence or structural similarity. Source: UniProtKB ureter epithelial cell differentiation Inferred from sequence or structural similarity. Source: UniProtKB ureter smooth muscle cell differentiation Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	extracellular space Inferred from sequence or structural similarity. Source: UniProtKB proteinaceous extracellular matrix Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	BMP receptor binding Inferred from direct assay. Source: MGI chemoattractant activity Inferred from direct assay. Source: UniProtKB cytokine activity Inferred from direct assay. Source: MGI growth factor activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 19	19	Potential
	Propeptide	20 – 292	273			PRO_0000033856
	Chain	293 – 408	116	Bone morphogenetic protein 4		PRO_0000033857
Amino acid modifications
	Glycosylation	143	1	N-linked (GlcNAc...) Potential
	Glycosylation	208	1	N-linked (GlcNAc...) Potential
	Glycosylation	350	1	N-linked (GlcNAc...) Potential
	Glycosylation	365	1	N-linked (GlcNAc...) Potential
	Disulfide bond	308 ↔ 373		By similarity
	Disulfide bond	337 ↔ 405		By similarity
	Disulfide bond	341 ↔ 407		By similarity
	Disulfide bond	372		Interchain By similarity
Natural variations
	Natural variant	91	1	S → C in OFC11; also found in renal hypodysplasia patients. Ref.6 Ref.8 Ref.9		VAR_043531
	Natural variant	93	1	E → G in MCOPS6. Ref.7		VAR_043532
	Natural variant	102	1	T → A. Ref.9		VAR_058314
	Natural variant	116	1	T → S in a renal hypodysplasia patient. Ref.8		VAR_043533
	Natural variant	150	1	N → K in a renal hypodysplasia patient. Ref.8		VAR_043534
	Natural variant	152	1	V → A. Ref.2 Ref.3 Ref.6 Ref.9 Corresponds to variant rs17563 [ dbSNP | Ensembl ].		VAR_016174
	Natural variant	162	1	R → Q in OFC11. Ref.9		VAR_058315
	Natural variant	168	1	G → A. Ref.9		VAR_058316
	Natural variant	225	1	T → A. Ref.6		VAR_043535
	Natural variant	226	1	R → W. Ref.6		VAR_043536
	Natural variant	287	1	R → H in OFC11. Ref.9		VAR_058317
	Natural variant	346	1	A → V in OFC11. Ref.9		VAR_058318
	Natural variant	367	1	S → T. Ref.6		VAR_043537

Sequences

	Sequence		Length	Mass (Da)
	P12644 [UniParc]. Last modified October 1, 1989. Version 1. Checksum: 79B01179DBB98204	FASTA	408	46,555
	10 20 30 40 50 60 MIPGNRMLMV VLLCQVLLGG ASHASLIPET GKKKVAEIQG HAGGRRSGQS HELLRDFEAT 70 80 90 100 110 120 LLQMFGLRRR PQPSKSAVIP DYMRDLYRLQ SGEEEEEQIH STGLEYPERP ASRANTVRSF 130 140 150 160 170 180 HHEEHLENIP GTSENSAFRF LFNLSSIPEN EVISSAELRL FREQVDQGPD WERGFHRINI 190 200 210 220 230 240 YEVMKPPAEV VPGHLITRLL DTRLVHHNVT RWETFDVSPA VLRWTREKQP NYGLAIEVTH 250 260 270 280 290 300 LHQTRTHQGQ HVRISRSLPQ GSGNWAQLRP LLVTFGHDGR GHALTRRRRA KRSPKHHSQR 310 320 330 340 350 360 ARKKNKNCRR HSLYVDFSDV GWNDWIVAPP GYQAFYCHGD CPFPLADHLN STNHAIVQTL 370 380 390 400 VNSVNSSIPK ACCVPTELSA ISMLYLDEYD KVVLKNYQEM VVEGCGCR

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Novel regulators of bone formation: molecular clones and activities." Wozney J.M., Rosen V., Celeste A.J., Mitsock L.M., Whitters M.J., Kriz R.W., Hewick R.M., Wang E.A. Science 242:1528-1534(1988) [PubMed: 3201241] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"The human bone morphogenetic protein 4 (BMP-4) gene: molecular structure and transcriptional regulation." Shore E.M., Xu M., Shah P.B., Janoff H.B., Hahn G.V., Deardorff M.A., Sovinsky L., Spinner N.B., Zasloff M.A., Wozney J.M., Kaplan F.S. Calcif. Tissue Int. 63:221-229(1998) [PubMed: 9701626] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT ALA-152.
[3]	"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], VARIANT ALA-152. Tissue: Duodenum.
[4]	"Cloning and sequence of bone morphogenetic protein 4 (BMP-4) from a human placental cDNA library." Oida S., Iimura T., Maruoka Y., Takeda K., Sasaki S. DNA Seq. 5:273-275(1995) [PubMed: 7579580] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 7-408. Tissue: Placenta.
[5]	"USAG-1: a bone morphogenetic protein antagonist abundantly expressed in the kidney." Yanagita M., Oka M., Watabe T., Iguchi H., Niida A., Takahashi S., Akiyama T., Miyazono K., Yanagisawa M., Sakurai T. Biochem. Biophys. Res. Commun. 316:490-500(2004) [PubMed: 15020244] [Abstract] Cited for: INTERACTION WITH SOSTDC1.
[6]	"Evaluation of BMP4 and its specific inhibitor NOG as candidates in human neural tube defects (NTDs)." Felder B., Stegmann K., Schultealbert A., Geller F., Strehl E., Ermert A., Koch M.C. Eur. J. Hum. Genet. 10:753-756(2002) [PubMed: 12404109] [Abstract] Cited for: VARIANTS CYS-91; ALA-152; ALA-225; TRP-226 AND THR-367.
[7]	"Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways." Bakrania P., Efthymiou M., Klein J.C., Salt A., Bunyan D.J., Wyatt A., Ponting C.P., Martin A., Williams S., Lindley V., Gilmore J., Restori M., Robson A.G., Neveu M.M., Holder G.E., Collin J.R.O., Robinson D.O., Farndon P. , Johansen-Berg H., Gerrelli D., Ragge N.K. Am. J. Hum. Genet. 82d:304-319(2008) [PubMed: 18252212] [Abstract] Cited for: VARIANT MCOPS6 GLY-93.
[8]	"SIX2 and BMP4 mutations associate with anomalous kidney development." Weber S., Taylor J.C., Winyard P., Baker K.F., Sullivan-Brown J., Schild R., Knueppel T., Zurowska A.M., Caldas-Alfonso A., Litwin M., Emre S., Ghiggeri G.M., Bakkaloglu A., Mehls O., Antignac C., Schaefer F., Burdine R.D. J. Am. Soc. Nephrol. 19:891-903(2008) [PubMed: 18305125] [Abstract] Cited for: VARIANTS CYS-91; SER-116 AND LYS-150.
[9]	"Mutations in BMP4 are associated with subepithelial, microform, and overt cleft lip." Suzuki S., Marazita M.L., Cooper M.E., Miwa N., Hing A., Jugessur A., Natsume N., Shimozato K., Ohbayashi N., Suzuki Y., Niimi T., Minami K., Yamamoto M., Altannamar T.J., Erkhembaatar T., Furukawa H., Daack-Hirsch S., L'heureux J. , Brandon C.A., Weinberg S.M., Neiswanger K., Deleyiannis F.W., de Salamanca J.E., Vieira A.R., Lidral A.C., Martin J.F., Murray J.C. Am. J. Hum. Genet. 84:406-411(2009) [PubMed: 19249007] [Abstract] Cited for: VARIANTS OFC11 CYS-91; GLN-162; HIS-287 AND VAL-346, VARIANTS ALA-102; ALA-152 AND ALA-168.
+	Additional computationally mapped references.

Web resources

Wikipedia

Bone morphogenetic protein 4 entry

Cross-references

Sequence databases
EMBL GenBank DDBJ	M22490 mRNA. Translation: AAA51835.1. U43842 Genomic DNA. Translation: AAC72278.1. BC020546 mRNA. Translation: AAH20546.1. D30751 mRNA. Translation: BAA06410.1.
IPI	IPI00292640.
PIR	BMHU4. C37278.
RefSeq	NP_001193.2. NM_001202.3. NP_570911.2. NM_130850.2. NP_570912.2. NM_130851.2.
UniGene	Hs.68879.
3D structure databases
ProteinModelPortal	P12644.
SMR	P12644. Positions 307-408.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-5795N.
IntAct	P12644. 2 interactions.
MINT	MINT-1184353.
STRING	P12644.
Polymorphism databases
DMDM	115073.
Proteomic databases
PRIDE	P12644.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000245451; ENSP00000245451; ENSG00000125378. ENST00000395600; ENSP00000378964; ENSG00000125378. ENST00000417573; ENSP00000394165; ENSG00000125378.
GeneID	652.
KEGG	hsa:652.
UCSC	uc001xal.2. human.
Organism-specific databases
CTD	652.
GeneCards	GC14M054416.
H-InvDB	HIX0011668.
HGNC	HGNC:1071. BMP4.
HPA	CAB006863.
MIM	112262. gene. 600625. phenotype. 607932. phenotype.
neXtProt	NX_P12644.
Orphanet	264200. 14q22q23 microdeletion syndrome. 1991. Cleft lip with or without cleft palate. 139471. Microphthalmia with brain and digit anomalies.
PharmGKB	PA25381.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG16268.
HOGENOM	HBG717159.
HOVERGEN	HBG004860.
InParanoid	P12644.
OMA	RMLMVIL.
OrthoDB	EOG4JT05K.
PhylomeDB	P12644.
Enzyme and pathway databases
Pathway_Interaction_DB	bmppathway. BMP receptor signaling. glypican_3pathway. Glypican 3 network.
Gene expression databases
ArrayExpress	P12644.
Bgee	P12644.
CleanEx	HS_BMP4.
Genevestigator	P12644.
GermOnline	ENSG00000125378. Homo sapiens.
Family and domain databases
InterPro	IPR001839. TGF-b_C. IPR001111. TGF-b_N. IPR015615. TGF-beta-rel. IPR017948. TGFb_CS. [Graphical view]
KO	K04662.
PANTHER	PTHR11848. TGFbeta. 1 hit.
Pfam	PF00019. TGF_beta. 1 hit. PF00688. TGFb_propeptide. 1 hit. [Graphical view]
SMART	SM00204. TGFB. 1 hit. [Graphical view]
PROSITE	PS00250. TGF_BETA_1. 1 hit. PS51362. TGF_BETA_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	2648.
SOURCE	Search...

Entry information

Entry name

BMP4_HUMAN

Accession

Primary (citable) accession number: P12644
Secondary accession number(s): Q9UM80

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1989
Last sequence update:	October 1, 1989
Last modified:	January 25, 2012
This is version 141 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.