Gene spans approximately 9 kbp on the minus strand at 14q22.2.

Alternative splicing in the 5UTR gives rise to 3 transcript variants, all encoding an identical protein. Transcript variant 1 is 1917 bp in length with 4 exons (2 coding exons), transcript variant 2 is 1708 bp in length with 4 exons (2 coding exons), and transcript variant 3 is 1705 bp in length with 3 exons (2 coding exons).
In Xenopus embryos, BMP4 itself, along with the homeobox genes Vox, X-vent1, X-vent2, GATA-1, GATA-2 and AP-1 were found to induce the expression of BMP4 and control dorsoventral patterning in the mesoderm (Jones et al., 1992; Kim et al., 1998; Onichtchouk et al., 1996; Schmidt et al., 1996), whereas organizer signals, chordin and noggin, and X-lim1 negatively regulate BMP4 transcription (Kim et al., 1998). Lung specification in Xenopus depends on the suppression of BMP4 expression by zinc-finger transcriptional repressors Osr1 and Osr2 (Rankin et al., 2012).
Analysis of the mouse BMP4 gene identified 2 G-C rich Sp1 binding motifs proximal to the transcriptional start sites for exons I and II (Kurihara et al., 1993). The presence of dual promoter regions flanking exons I and II were later confirmed in human cancer cell lines (van den Wijngaard et al., 1996). Mouse BMP4 is negatively regulated by direct binding of chicken ovalbumin upstream-transcription factor I (COUP-TF1) to the proximal promoter of exon I (Feng et al., 1995). Deletion analysis of the mouse BMP4 promoter in MC3T3E1 cells identified a cis-acting E-box element proximal to the transcriptional start site that is bound by upstream regulatory factor (USF), a member of the helix-loop-helix family of regulatory proteins (Ebara et al., 1997). In mouse development, GATA-4 and -GATA-6 were found to specifically regulate BMP4 transcription to mediate endoderm-mesoderm signalling and early vasculogenesis (Nemer et al., 2003). Similarly, analysis of mouse embryonic stem cells identified the transcriptional corepressor Bcor as an important regulator of ES cell differentiation into mesoderm, ectoderm and hematopoietic lineages through regulating developmental genes including BMP4 expression (Wamstad et al., 2008). Furthermore, the transcription factor Cdx2 has been shown to directly regulate BMP4 expression in mouse trophoblast cells to promote early mouse embryogenesis (Murohashi et al., 2010), while Shox2 regulates BMP4 expression to promote pacemaker development in the murine heart (Puskaric et al., 2010).
Analysis of the human BMP4 promoter in U2OS and SaOS2 cells identified the lack of a proximal TATA box, while sharing similar transcriptional start sites and regulatory elements with the mouse BMP4 promoter (Helvering et al., 2000; Shore et al., 1998). Putative binding motifs for AP1, Sp1, CRE, Cfab1 were identified, and direct binding of Cfab1 to the BMP4 promoter was confirmed, along with transcriptional upregulation of BMP4 by osteogenic compounds such as retinoic acid and the phorbol ester PMA (Helvering et al., 2000).
Transcriptional control of BMP4 is also important in diseased states. During recovery from acute anemia, hypoxia induces BMP4 expression and subsequent erythropoiesis in the murine spleen through direct binding of HIF2alpha to the BMP4 promoter (Wu et al., 2010). In retinal pigment epithelium cells of patients suffering from the wet form, but not the dry form, of macular degeneration, TNFalpha represses BMP4 transcription through phosphorylation of the transcription factor Sp1, demonstrating a BMP4 expression-dependent molecular switch (Xu et al., 2011). In hepatocellular carcinoma cells, Ets-1 was demonstrated to directly regulate hypoxia-induced BMP4 transcription to promote tumorigenesis (Maegdefrau et al., 2009). In colorectal cancer cells, oncogenic KRAS can repress BMP4 expression through a novel ras-responsive region (Duerr et al., 2012).
In addition to many proximal regulatory sites, the BMP4 gene, along with many other BMP family genes, resides within a conserved gene desert, which contains many additional distal cis-regulatory regions (located over 30 kbp from coding sequences) that control BMP4 expression in a spatiotemporal and tissue-dependent manner (Chandler et al., 2009; Pregizer et al., 2009). For example, an evolutionarily conserved distal enhancer site, 46 kb upstream of the transcriptional start site, is bound by Pitx2 and likely participates in tooth and limb morphogenesis (Jumlongras et al., 2012). Furthermore, a common polymorphism found within the distal BMP4 promoter (17kb upstream) acts as a cis-acting enhancer of BMP4 transcription, and is significantly associated with colorectal cancer risk (Lubbe et al., 2012).

None annotated.

BMP4, a member of the TGFbeta superfamily of signalling molecules, is a 46.5 kDa, 408 aa protein that is translated as a precursor containing a signal peptide (aa 1 - 19), a prodomain (aa 20 - 292) and a mature domain (aa 293 - 408). After the BMP signal peptide has been removed, dimerization of the proproteins proceeds. Proprotein cleavage is achieved by the candidate serine endoproteases Furin, PCSK5, PCSK6, or PCSK7 at the consensus sequence RXXR, resulting in the generation and secretion of biologically active molecules (Bragdon et al., 2011; Cui et al., 1998; Goldman et al., 2006; Shimasaki et al., 2004). As with other TGFbeta family members, BMP4 is a cysteine knot-containing, disulfide-linked dimer (Jones et al., 1994; Shimasaki et al., 2004), containing a conserved TGF-beta propeptide domain (pfam00668) and transforming growth factor beta like domain (cl02510). One high-throughput study has identified a ubiquitination site at Lys-185 (Kim et al., 2011).

The amino acid sequence for BMP4 was first derived from an isolated preparation of bovine bone (Wozney et al., 1988). Human BMP4 was cloned from a placental cDNA library (Oida et al., 1995). Apart from its high expression in developing embryonic tissues (Chen et al., 2004), BMP4 was determined by microarray analysis to be highly expressed in adult tissues such as the thymus, spleen, brain, heart, muscle, kidney, lung, liver, pancreas, and prostate (Schmueli et al., 2003; Yanai et al., 2005). Immunohistochemical analysis of adult tissues shows high expression in epithelial cells of the skin, bladder and stomach (Alarmo et al., 2012). In tumors, BMP4 is expressed in melanoma, ovarian, gastric, basal cell, renal and squamous carcinomas of the head and neck (Chiu et al., 2012; Deng et al., 2007; Davies et al., 2008; Giacomini et al., 2006; Johnson et al., 2009; Kim et al., 2011; Kwak et al., 2007; Laatio et al., 2011; Lombardo et al., 2011; Sneddon et al., 2006; Rothhammer et al., 2005; Xu et al., 2011). Overexpression of BMP4 in comparison to normal tissues is observed in breast, ovarian, gastric, hepatocellular and colorectal carcinomas (Alarmo et al., 2012; Chiu et al., 2012; Deng et al., 2007; Kim et al., 2011).

BMP4 is a secreted protein localized within the extracellular milieu (Chen et al., 2004), but has also been shown to localize within the cytoplasm in vesicles directed for lysosomal degradation, in order to tightly mitigate BMP4 signalling (Kelley et al., 2009).

BMP4 is a member of the bone morphogenetic protein family, which is part of the transforming growth factor-beta superfamily of growth and differentiation factors. Bone morphogenetic proteins were originally identified by an ability of demineralized bone extract to induce endochondral osteogenesis in vivo in an extraskeletal site (Urist, 1965), but are now considered essential factors with varying roles during embryogenesis, skeletal formation, hematopoiesis and neurogenesis (Bragdon et al., 2001; Chen et al., 2004; Kallioniemi, 2012). In adult tissues, BMP4 signalling can control many cellular behaviours including differentiation, proliferation, apoptosis, and motility (Kallioniemi, 2012).
The mature BMP4 dimer binds to type I and II serine-threonine kinase receptors, and the constitutively active BMP type II receptor will phosphorylate the type I receptor upon ligand binding (Miyazono et al., 2010; Nohe et al., 2004). The activated type I BMP receptor is then able to phosphorylate the cytosolic receptor-regulated SMAD proteins (Attisano et al., 2000; Bragdon et al., 2001; Miyazono et al., 2010), which will then form a complex with the common SMAD4, translocate to the nucleus to regulate gene transcription (Feng et al., 2005; ten Dijke et al., 2003). In addition to this canonical SMAD-dependent signaling pathway, BMP4 can signal through SMAD-independent means to directly induce ERK and p38 MAPKs, JNK, NFkB, PI3K, PKA, PKC and PKD signaling pathways affecting cell survival, apoptosis, migration and differentiation (Bragdon et al., 2011). In addition to intracellular regulation, BMP4 signals can be modulated at the receptor level through interaction with three different type I (BMPR1A [ALK3], BMPR1B [ALK6], and ACVR1A [ALK2]) and type II (BMPR2, ACVR2A [Act-RII], and ACVR2B [Act-RIIB]) receptors (Kawabata et al., 1998; Miyazono et al., 2010; Nohe et al., 2004), and negatively regulated by interaction with the pseudoreceptor BAMBI (Onichtchouk et al., 1999). BMP4 signalling can also be regulated at the extracellular level through binding to the endogenous inhibitors tsg (Twisted gastrulation) and Follistatin, and those belonging to the Dan family (Dan, Gremlin, Gremlin2, Cerberus, Coco, Caronte, Ectodin, and Sclerostin), and the Chordin family (Chordin, Chordin-like-2, Noggin) of BMP antagonists (Bragdon et al., 2011).

There are BMP4 homologs in several vertebrate species, including chimpanzee, rhesus monkey, dog, cow, chicken, rat, mouse, lizard, frog (Xenopus laevis), and zebrafish (Danio rerio) and in invertebrates such as the fruit fly (Drosophila melanogaster) and the worm (Caenorhabditis elegans).

Heterozygous mutations in exons 3 and 4 of the BMP4 gene resulting in decreased expression were found in children with cleft lip and cleft palate (Suzuki et al., 2009), including: a 1037C-T transition resulting in an A346V substitution; a 271A-T transversion resulting in a S91C substitution; a 860G-A transition resulting in an R287H substitution; and a 592C-T transition resulting in an R198X substitution.
Three pathogenic germline mutations were identified in a cohort of 504 genetically enriched colorectal cancer cases. p.R286X (g.8330C>T) localizes to the N-terminal of the prodomain truncating the protein prior to the active domain; p.W325C (g.8449G>T) and p.C373S (g.8592G>C) mutations are predicted from protein homology modelling with BMP2 to impact deleteriously on BMP4 function; and p.C373S (g.8592G>C) segregates with adenoma and hyperplastic polyps in first-degree relatives, suggesting this germline mutation may confer a juvenile polyposis-type phenotype (Lubbe et al., 2011).

Four substitution missense mutations have been identified: two mutations were detected in two different single prostate tumors (c.344A>T, p.N115I (Grasso et al., 2012), c.857G>A, p.R286Q (Barbieri et al., 2012), and two in two different large intestinal carcinoma tumors (c.631C>T, p.R211W, and c.1222C>T, p.R408C)) (The Cancer Genome Atlas Network, 2012).