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FLASH GENE
Symbol BMP4 contributors: shn/mct - updated : 26-05-2015
HGNC name bone morphogenetic protein 4
HGNC id 1071
Corresponding disease
DEL14Q22 chromosome 14q deletion, encompassing band q22
MCOPS6 microphthalmia syndromic 6
Location 14q22.2      Physical location : 54.416.456 - 54.423.554
Synonym name bone morphogenetic protein 2B
Synonym symbol(s) BMP2B, ZYME, BMP2B1, OFC11, MCOPS6, DVR4
DNA
TYPE functioning gene
STRUCTURE 7.10 kb     4 Exon(s)
10 Kb 5' upstream gene genomic sequence study
regulatory sequence Promoter
Binding site   transcription factor
text structure
  • E-box motif recognized by osteogenic cells specific nuclear factor
  • specific cis-active elements that bind to and mediate transcriptional regulation by TITF1
  • MAPPING cloned Y linked N status confirmed
    Map cen - D15S658 - D14S587 - BMP4 - D14S747 - D14S281 - qter
    Physical map
    KIAA1344 14q22.1 KIAA1344 DKFZp762F0713 14q22.1 hypothetical protein DKFZp762F0713 ERO1L 14q22.1 ERO1-like (S. cerevisiae) PSMC6 12q15 proteasome (prosome, macropain) 26S subunit, ATPase, 6 STYX  serine/threonine/tyrosine interacting protein GNPNAT1 14q22.1 glucosamine-phosphate N-acetyltransferase 1 PLEKHC1 14q22.1 pleckstrin homology domain containing, family C (with FERM domain) member 1 NDUFB3P3 14q22.3-q23.1 NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 3, 12kDa pseudogene 3 DDHD1 14q21 DDHD domain containing 1 BMP4 14q22-q23 bone morphogenetic protein 4 LOC341862 14q22.1 similar to ATP synthase gamma chain, mitochondrial precursor CDKN3 14q22 cyclin-dependent kinase inhibitor 3 (CDK2-associated dual specificity phosphatase) CNIH 14q22.1 cornichon homolog (Drosophila) GMFB 14q22.1 glia maturation factor, beta CGRRF1 14q22.1 cell growth regulator with ring finger domain 1 SAMD4 14q22.2 sterile alpha motif domain containing 4 GCH1 14q22.1-q22.2 GTP cyclohydrolase 1 (dopa-responsive dystonia) WDHD1 14q22.2 WD repeat and HMG-box DNA binding protein 1 SOCS7 14q22.2 suppressor of cytokine signaling 7 C14orf32 14q22.1 chromosome 14 open reading frame 32 LGALS3 14q21-q22 lectin, galactoside-binding, soluble, 3 (galectin 3) GALIG 14q21-q22 lectin, galactoside-binding, soluble, 3 (galectin 3) DLG7 14q22.1-q22.3 discs, large homolog 7 (Drosophila) UBE2L7 5p14.1 ubiquitin-conjugating enzyme E2L 7 pseudogene COX5AP1 14q22 cytochrome c oxidase subunit Va pseudogene 1 FBXO34 14q22.1 F-box only protein 34 KIAA0831 14q22.2 KIAA0831 HMGN1P1 14 high-mobility group nucleosome binding domain 1 pseudogene 1 LOC390477 14 similar to 60S ribosomal protein L7a (Surfeit locus protein 3) (PLA-X polypeptide)
    RNA
    TRANSCRIPTS type messenger
    text transcripts from two promoters, one upstream exon 1, the other in intron 2, acting in a cell-type and differentiation manner. Promoter region is GC-rich and contains no obvious TATA or CAAT consensus sequences (PMID: 10457277)
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    4 - 1957 - 408 - 1999
    4 splicing 1802 - 408 - 1999
    4 - 1748 - 408 - 1999
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly Homo sapiensAdult
    Nervousbrain     Homo sapiens
    Reproductivemale systemtestis    Homo sapiens
    Visualeyeretinamacula highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialbarrier liningretinal pigment epithelium (RPE) highly
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousastrocyte Homo sapiens
    ReproductiveSertoli cell Homo sapiens
    Skeletonosteoclast Homo sapiens
    cell lineage
    cell lines prostate cancer cell lines
    fluid/secretion
    at STAGE
    physiological period fetal
    Text tooth, developing skeletal structures, trabecular meshwork, in optic vesicle, developing retina and lens, pituitary region, and digits
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • TGFB-like domain
  • mono polymer homomer , dimer
    isoforms Precursor cleaved at a consensus Arg-X-X-Arg to yield C terminus mature dimer
    HOMOLOGY
    interspecies ortholog to bmp4, Danio rerio
    ortholog to Bmp4, Mus musculus
    ortholog to Bmp4, Rattus norvegicus
    ortholog to BMP4, Pan troglodytes
    Homologene
    FAMILY
  • bone morphogenetic protein family (part of the transforming growth factor-beta superfamily)
  • CATEGORY structural protein , signaling cytokine growth factor
    SUBCELLULAR LOCALIZATION extracellular
    text secreted into the extracellular matrix
    basic FUNCTION
  • play a role in the onset of endochondral bone formation in humans
  • essential for proper development and regionalization of telencephalic forebrain structures and induce differentiation of telencephalic neural stem cells into a variety of cellular fates, including astrocytic, neuronal, and mesenchymal cells
  • inducing ventralizing signals inhibited by noggin
  • inducing apoptosis and chondrogenesis in the chick limb bud
  • involved in the pathobiology of cartilaginous and osteogenic metaplasia observed in synovial chondromatosis
  • regulating myogenesis through dosage-dependent PAX3 expression in pre-myogenic cells
  • inhibiting HOTT (human-ovarian-theca-like tumor) cell expression of CYP17 leading to alteration of the steroidogenic pathway
  • potently enhancing growth factor-induced cell proliferation when added in combination with suboptimal concentrations of FGF-2, FGF-7, FGF-10, EGF or HGF
  • periodic expression BMP4 in the dermis regulates the process of hair follicle regeneration
  • may be playing a role in wound healing
  • acts as a mediator in oxidative stress-induced senescence and this mediator function is via Smad and the p38 signaling pathway
  • BMP4/Smad5 dependent stress erythropoiesis is required for the expansion of erythroid progenitors during fetal development
  • both BMP2 and BMP4 can suppress the expression of DPYSL2 in primary cortical cells at the transcriptional level
  • role of BMP4-mediated osteogenesis in the progression of prostate cancer in bone
  • BMP4 signaling suppresses tooth developmental inhibitors in the tooth mesenchyme, including DKK2 and OSR2, and synergizes with MSX1 to activate mesenchymal odontogenic potential for tooth morphogenesis and sequential tooth formation
  • endogenous BMP4 in preadipocytes is indispensable for the onset of the adipogenic program, and may help to maintain the preadipocytic state during adipocyte differentiation
  • BMP4 and BMP7 induce the white-to-brown transition of primary human adipose stem cells
  • promotes vascularization of human adipose stromal cells and endothelial cells
  • plays an important anti-inflammatory role, controlling the strength and facilitating the resolution of acute lung inflammation, and also contributes to lung function impairment during chronic lung inflammation
  • CELLULAR PROCESS cell life, differentiation
    cell life, proliferation/growth
    cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS development
    text dorsoventral polarity
    PATHWAY
    metabolism
    signaling signal transduction
  • BMP4 signaling pathway may play a crucial role in the development of diabetic glomerulosclerosis
  • a component
  • forming a ternary complex with TSG and CHRD
  • homodimer, disulfide-linked
  • potential novel regulatory loop of BMP4-SMAD1-WIF1-Wnt/beta-catenin in coordinating BMP and Wnt pathways to control fetal lung development
  • INTERACTION
    DNA
    RNA
  • CXXC5
  • small molecule
    protein
  • BMPER (bone morphogenetic protein [BMP]-binding endothelial cell precursor-derived regulator)
  • BMP8B, BMPR1A, BMPR1B, BMPR2
  • USAG-1
  • osteogenic protein (OP)-1
  • activin receptor-like kinase 3(ALK-3) and ALK-6
  • TWSG1 twisted gastrulation homolog 1
  • COL4A1
  • interacting with GREM1 (BMP4 and GREM1, which are highly expressed by fetal skeletal muscle side population and main population cells, respectively, are regulators of myogenic progenitor proliferation)
  • GREM2 might serve as a mediator to antagonize BMP4 signaling by WNT
  • harmonious interactions between NOGGIN and BMP4 in periodontal ligament-forming cells, which show higher cell proliferation than neighboring cells, might be important for proper periodontium development
  • specifically interacts with BMP15 protein (blocks the epidermal-inducing activity of BMP4 protein)
  • WFIKKN1 and WFIKKN2 proteins are antagonists of MSTN and GDF11, but in the case of TGFB1, BMP2 and BMP4 they function as growth factor binding proteins
  • BMP2 and BMP4 bind to neogenin (NEO1)
  • BMP4 and SOX9 are potential candidate regulators of phenotypic change of mesangial cells in the advanced stage of diabetic nephropathy
  • regulated JUND activity at the transcriptional regulation and post-translational modification levels
  • was also able to increase ZFP423 gene activation, adding another layer of cross-talk in promoting adipogenic differentiation
  • CHRDL1 protein antagonizes BMP4 activity and induces spinal cord&
  • 8209;derived NSCs to differentiate into neurons
  • BMP4 antagonist NOG attenuates valve interstitial cells (VICs) activation and biomineralization
  • BMP4 is a mediator of WWTR1-induced cell migration (WWTR1 induces BMP4 transcription through the TEAD family of transcription factors, which mediate BMP4 promoter activation through binding to TEAD response element 1)
  • link between PTK2 and BMP4 induction of mesenchymal stem cells (MSCs) adipogenesis, and may indicate a potential therapeutic approach targeting PTK2 for dealing with obesity
  • BMP4 induces MITF expression in pluripotent stem cells and EDN3 subsequently promotes differentiation of these MITF expressing cells along the melanocyte lineage
  • ROCK1 negatively regulates BMP4-stimulated BGLAP synthesis via the MAPK14 pathway in osteoblasts
  • regulation of CHST11 expression by opposing effects of arylsulfatase B on BMP4 and WNT9A
  • BMP4-dependent transcription is negatively autoregulated in part by SIN3B alternative splicing, and RBM39 plays a role in this process
  • TBX3 represses BMP4 transcription and is required in the eye field for both neural induction and normal eye formation
  • cell & other interacting with oxidative stress may interact to promote RPE senescence
    REGULATION
    activated by MSX1
    GLI and GLI3
    cleaved by subtilisin-like convertases (furin) PACE
    NK2 HOMEOBOX 1
    inhibited by FGF4,BARX1
    exogenous noggin
    its association with TSG and CHRD,released through cleavage of CHRD by BMP1
    Gremlin
    Other BMP4 expression under MSX2 control
    Biglycan a new extracellular modulator of BMP4 signaling
    ASSOCIATED DISORDERS
    corresponding disease(s) MCOPS6 , DEL14Q22
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in patients with fibrodysplasia ossificans progressive (FOP)
    constitutional     --over  
    in a syndrome of axial skeletal malformations and heterotopic ossification of the neck and back (ASMHO), analog to the short ear mouse
    constitutional germinal mutation      
    in ASD, VSD
    constitutional     --over  
    in synovial chondromatosis
    constitutional     --over  
    in RPE cells in both the early and late form of dry Age-related Macular Degeneration
    constitutional       loss of function
    of SIX2 and BMP4, could affect kidney development at multiple stages, leading to the congenital anomalies observed in patients with renal hypodysplasia
    tumoral germinal mutation      
    in colorectal cancer (CRC)
    constitutional   deletion    
    detected in a patient affected with SHORT syndrome
    constitutional     --over  
    may be associated with Sertoli cell-only syndrome and maturation arrest in spermatogonia or spermatocytes
    constitutional     --over  
    aberrant BMP4-mediated signaling in cranial neural crest (CNC) cells leads to mis-patterned facial skeleton and congenital bony syngnathia
    Susceptibility
  • to hypospadias
  • to microform and subepithelial orbicularis oris muscle (OOM) defects
  • to congenital anomalies of the kidney and urinary tract
  • Variant & Polymorphism SNP , other
  • polymorphism increasing the risk of hypospadias
  • SNP modulating hemochromatosis penetrance
  • amino acid variations in BMP4 are associated with microform and subepithelial OOM defects
  • polymorphisms of the BMP4 gene have a higher risk to develop CAKUT, especially the malformations related to nephrogenesis
  • Candidate gene
    Marker
    Therapy target
  • non-cytotoxic therapeutic effector which may be used to prevent growth and recurrence of glioblastomas
  • SystemTypeDisorderPubmed
    osteoarticularbone 
    BMP antagonists such as noggin might be useful therapeutic tools for preventing chondrogenic metaplasia occurred in synovial chondromatosis
    cancerlung 
    responsive molecular target for cancer chemotherapy in lung carcinoma
    neurosensorial  
    may represent a novel therapeutic target to inhibit the progressive effects of oxidative stress and senescence in dry age-related macular degeneration
    diabetetype 2 
    preferential inhibition of the BMP4 signaling pathway may provide a novel therapeutic approach to diabetic nephropathy without undesirable adverse effects
    cancer  
    BMP4 may become an antitumor agent and open a new field of antiangiogenic therapy
    ANIMAL & CELL MODELS
  • early lethality of Bmp4 null mouse embryos
  • development of progressive postnatal heterotopic endochondral ossification has been observed in mice overexpressing BMP4