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Gene Review

BMP4  -  bone morphogenetic protein 4

Homo sapiens

Synonyms: BMP-2B, BMP-4, BMP2B, BMP2B1, Bone morphogenetic protein 2B, ...
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Disease relevance of BMP4

  • However, a strong reduction of migratory and invasive properties was observed in these cells, suggesting that BMP4 promotes melanoma cell invasion and migration and therefore has an important role in the progression of malignant melanoma [1].
  • We suggest that BMP4 is a mechanosensitive, inflammatory factor playing a critical role in early steps of atherogenesis in the lesion-prone areas [2].
  • In an analysis of normal ovarian surface epithelium (OSE) and ovarian cancer (OC) cells, we observed BMP4 mRNA expression and found that primary OC cells produce mature BMP4 [3].
  • These studies suggest that BMP4 pathway signaling can induce senescence and thus negatively regulate the growth of A549 lung cancer cells [4].
  • BMP4 signaling induces senescence and modulates the oncogenic phenotype of A549 lung adenocarcinoma cells [4].

Psychiatry related information on BMP4


High impact information on BMP4


Chemical compound and disease context of BMP4


Biological context of BMP4


Anatomical context of BMP4

  • Regulation of myogenic progenitor proliferation in human fetal skeletal muscle by BMP4 and its antagonist Gremlin [13].
  • In contrast, the BMP4 antagonist Gremlin, specifically up-regulated in MP cells, counteracts the stimulatory effects of BMP4 and inhibits proliferation of BMPR1a-positive muscle cells [13].
  • The potency of different human BMPs in stimulating hepcidin transcription by murine primary hepatocytes is BMP9 > BMP4 > BMP2 [15].
  • Studies of the pro-neurogenic effect of BMP4 indicated that it did not increase progenitor cell proliferation, but rather promoted survival of newly generated olfactory receptor neurons [16].
  • Here, we show that BMP4 and BMP7 are up-regulated in nine melanoma cell lines, whereas BMP2 is overexpressed in only two of the analyzed cell lines [1].

Associations of BMP4 with chemical compounds

  • On the other hand, cognate receptors with serine/threonine kinase intracellular signaling domains, such as the TGF-beta receptor family are inhibitory, although BMP4 and BMPR also play key inductive roles [17].
  • OS is also known to induce monocyte adhesion by producing reactive oxygen species (ROS) from reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, raising the possibility that BMP4 may stimulate the inflammatory response by ROS-dependent mechanisms [18].
  • Similar to OS, BMP4 stimulated H2O2 and O2- production in ECs [18].
  • Retinoic acid compounds and the phorbol ester, PMA were found to stimulate BMP-2 and, to a lesser degree, BMP-4 [19].
  • In addition, ARPE-19 cells cultured in high glucose (25 mM), compared to those in physiological glucose (5.5 mM) released significantly more BMP-4 into the conditioned media (CM) [20].

Physical interactions of BMP4


Enzymatic interactions of BMP4

  • Smad1 was phosphorylated and underwent nuclear translocation in normal OSE and OC cells upon treatment with BMP4 [3].
  • Pro-BMP-4 is initially cleaved at a consensus furin motif adjacent to the mature ligand domain (the S1 site), and this allows for subsequent cleavage at an upstream motif (the S2 site) [23].

Regulatory relationships of BMP4


Other interactions of BMP4


Analytical, diagnostic and therapeutic context of BMP4

  • Immunohistochemistry of primary and metastatic melanoma also shows increased BMP4 and BMP7 expression compared with nevi [1].
  • Here, through DNA microarrays, protein expression, and functional studies, we identify bone morphogenic protein 4 (BMP4) as a mechanosensitive and pro-inflammatory gene product [2].
  • In current study, we documented the expression of BMP4 in bile duct ligation (BDL) rats and HSCs in culture [32].
  • Studies on animal models have shown that BMP4 and NOG are involved in the patterning of the neural tube [33].
  • The biphasic peak of activity and expression levels of TGF-beta and BMP4 ligands and receptors, revealed by Western blots and mink lung epithelial cell (MLEC) assays, coincided with the two main periods of retinal chick and murine PCD [34].


  1. Bone morphogenic proteins are overexpressed in malignant melanoma and promote cell invasion and migration. Rothhammer, T., Poser, I., Soncin, F., Bataille, F., Moser, M., Bosserhoff, A.K. Cancer Res. (2005) [Pubmed]
  2. Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress stimulates an inflammatory response. Sorescu, G.P., Sykes, M., Weiss, D., Platt, M.O., Saha, A., Hwang, J., Boyd, N., Boo, Y.C., Vega, J.D., Taylor, W.R., Jo, H. J. Biol. Chem. (2003) [Pubmed]
  3. Identification of a putative autocrine bone morphogenetic protein-signaling pathway in human ovarian surface epithelium and ovarian cancer cells. Shepherd, T.G., Nachtigal, M.W. Endocrinology (2003) [Pubmed]
  4. BMP4 signaling induces senescence and modulates the oncogenic phenotype of A549 lung adenocarcinoma cells. Buckley, S., Shi, W., Driscoll, B., Ferrario, A., Anderson, K., Warburton, D. Am. J. Physiol. Lung Cell Mol. Physiol. (2004) [Pubmed]
  5. 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. (1998) [Pubmed]
  6. Detection of two transforming growth factor-beta-related morphogens, bone morphogenetic proteins-4 and -5, in RNA of multiple sclerosis and Creutzfeldt-Jakob disease lesions. Deininger, M., Meyermann, R., Schluesener, H. Acta Neuropathol. (1995) [Pubmed]
  7. Overexpression of an osteogenic morphogen in fibrodysplasia ossificans progressiva. Shafritz, A.B., Shore, E.M., Gannon, F.H., Zasloff, M.A., Taub, R., Muenke, M., Kaplan, F.S. N. Engl. J. Med. (1996) [Pubmed]
  8. Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm. Liem, K.F., Tremml, G., Roelink, H., Jessell, T.M. Cell (1995) [Pubmed]
  9. Inhibition of NF-kappaB activity results in disruption of the apical ectodermal ridge and aberrant limb morphogenesis. Bushdid, P.B., Brantley, D.M., Yull, F.E., Blaeuer, G.L., Hoffman, L.H., Niswander, L., Kerr, L.D. Nature (1998) [Pubmed]
  10. A human Mad protein acting as a BMP-regulated transcriptional activator. Liu, F., Hata, A., Baker, J.C., Doody, J., Cárcamo, J., Harland, R.M., Massagué, J. Nature (1996) [Pubmed]
  11. Specific induction of apoptosis in P19 embryonal carcinoma cells by retinoic acid and BMP2 or BMP4. Glozak, M.A., Rogers, M.B. Dev. Biol. (1996) [Pubmed]
  12. Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4. Peng, H., Wright, V., Usas, A., Gearhart, B., Shen, H.C., Cummins, J., Huard, J. J. Clin. Invest. (2002) [Pubmed]
  13. Regulation of myogenic progenitor proliferation in human fetal skeletal muscle by BMP4 and its antagonist Gremlin. Frank, N.Y., Kho, A.T., Schatton, T., Murphy, G.F., Molloy, M.J., Zhan, Q., Ramoni, M.F., Frank, M.H., Kohane, I.S., Gussoni, E. J. Cell Biol. (2006) [Pubmed]
  14. Human BMP sequences can confer normal dorsal-ventral patterning in the Drosophila embryo. Padgett, R.W., Wozney, J.M., Gelbart, W.M. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  15. Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6. Truksa, J., Peng, H., Lee, P., Beutler, E. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  16. Opposing effects of bone morphogenetic proteins on neuron production and survival in the olfactory receptor neuron lineage. Shou, J., Murray, R.C., Rim, P.C., Calof, A.L. Development (2000) [Pubmed]
  17. The molecular basis of lung morphogenesis. Warburton, D., Schwarz, M., Tefft, D., Flores-Delgado, G., Anderson, K.D., Cardoso, W.V. Mech. Dev. (2000) [Pubmed]
  18. Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress induces monocyte adhesion by stimulating reactive oxygen species production from a nox1-based NADPH oxidase. Sorescu, G.P., Song, H., Tressel, S.L., Hwang, J., Dikalov, S., Smith, D.A., Boyd, N.L., Platt, M.O., Lassègue, B., Griendling, K.K., Jo, H. Circ. Res. (2004) [Pubmed]
  19. Regulation of the promoters for the human bone morphogenetic protein 2 and 4 genes. Helvering, L.M., Sharp, R.L., Ou, X., Geiser, A.G. Gene (2000) [Pubmed]
  20. Bone morphogenetic protein-4 enhances vascular endothelial growth factor secretion by human retinal pigment epithelial cells. Vogt, R.R., Unda, R., Yeh, L.C., Vidro, E.K., Lee, J.C., Tsin, A.T. J. Cell. Biochem. (2006) [Pubmed]
  21. Identification of a human type II receptor for bone morphogenetic protein-4 that forms differential heteromeric complexes with bone morphogenetic protein type I receptors. Nohno, T., Ishikawa, T., Saito, T., Hosokawa, K., Noji, S., Wolsing, D.H., Rosenbaum, J.S. J. Biol. Chem. (1995) [Pubmed]
  22. Recombinant human bone morphogenetic protein 2B stimulates PC12 cell differentiation: potentiation and binding to type IV collagen. Paralkar, V.M., Weeks, B.S., Yu, Y.M., Kleinman, H.K., Reddi, A.H. J. Cell Biol. (1992) [Pubmed]
  23. Regulation of Bone Morphogenetic Protein-4 Activity by Sequence Elements within the Prodomain. Sopory, S., Nelsen, S.M., Degnin, C., Wong, C., Christian, J.L. J. Biol. Chem. (2006) [Pubmed]
  24. Vascular endothelial growth factor synergistically enhances bone morphogenetic protein-4-dependent lymphohematopoietic cell generation from embryonic stem cells in vitro. Nakayama, N., Lee, J., Chiu, L. Blood (2000) [Pubmed]
  25. Regulation of Bone Morphogenetic Protein-4 by Matrix GLA Protein in Vascular Endothelial Cells Involves Activin-like Kinase Receptor 1. Yao, Y., Zebboudj, A.F., Shao, E., Perez, M., Bostr??m, K. J. Biol. Chem. (2006) [Pubmed]
  26. BMP4 inhibits proliferation and promotes myocyte differentiation of lung fibroblasts via Smad1 and JNK pathways. Jeffery, T.K., Upton, P.D., Trembath, R.C., Morrell, N.W. Am. J. Physiol. Lung Cell Mol. Physiol. (2005) [Pubmed]
  27. The Role of BMP-6, IL-6, and BMP-4 in Mesenchymal Stem Cell-Dependent Bone Development: Effects on Osteoblastic Differentiation Induced by Parathyroid Hormone and Vitamin D(3). Sammons, J., Ahmed, N., El-Sheemy, M., Hassan, H.T. Stem cells and development. (2004) [Pubmed]
  28. Bone morphogenic protein (Smad)-mediated repression of proopiomelanocortin transcription by interference with Pitx/Tpit activity. Nudi, M., Ouimette, J.F., Drouin, J. Mol. Endocrinol. (2005) [Pubmed]
  29. Bone morphogenetic protein-5, -6 and -7 inhibit growth and induce apoptosis in human myeloma cells. Ro, T.B., Holt, R.U., Brenne, A.T., Hjorth-Hansen, H., Waage, A., Hjertner, O., Sundan, A., Borset, M. Oncogene (2004) [Pubmed]
  30. Dysregulation of the BMP-p38 MAPK signaling pathway in cells from patients with fibrodysplasia ossificans progressiva (FOP). Fiori, J.L., Billings, P.C., de la Peña, L.S., Kaplan, F.S., Shore, E.M. J. Bone Miner. Res. (2006) [Pubmed]
  31. BMP4-Smad signaling pathway mediates adriamycin-induced premature senescence in lung cancer cells. Su, D., Zhu, S., Han, X., Feng, Y., Huang, H., Ren, G., Pan, L., Zhang, Y., Lu, J., Huang, B. J. Biol. Chem. (2009) [Pubmed]
  32. Bone morphogenetic protein 4 mediates bile duct ligation induced liver fibrosis through activation of Smad1 and ERK1/2 in rat hepatic stellate cells. Fan, J., Shen, H., Sun, Y., Li, P., Burczynski, F., Namaka, M., Gong, Y. J. Cell. Physiol. (2006) [Pubmed]
  33. 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. (2002) [Pubmed]
  34. Transforming growth factor-beta and bone morphogenetic proteins: cooperative players in chick and murine programmed retinal cell death. Franke, A.G., Gubbe, C., Beier, M., Duenker, N. J. Comp. Neurol. (2006) [Pubmed]
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