A heterodimer formed by bone morphogenetic protein 9 (BMP9) and BMP10 provides most BMP biological activity in plasma

Zinski, 2017, TGF-β family signaling in early vertebrate development, Cold Spring Harbor Perspect. Biol, 2017 Hinck, 2016, Structural biology and evolution of the TGF-β family, Cold Spring Harbor Perspect. Biol, 8, a022103, 10.1101/cshperspect.a022103 Constam, 2014, Regulation of TGFβ and related signals by precursor processing, Semin. Cell Dev. Biol, 32, 85, 10.1016/j.semcdb.2014.01.008 Mueller, 2012, Promiscuity and specificity in BMP receptor activation, FEBS Lett, 586, 1846, 10.1016/j.febslet.2012.02.043 Miyazono, 2010, Bone morphogenetic protein receptors and signal transduction, J. Biochem, 147, 35, 10.1093/jb/mvp148 Garcia de Vinuesa, 2016, BMP signaling in vascular biology and dysfunction, Cytokine Growth Factor Rev, 27, 65, 10.1016/j.cytogfr.2015.12.005 David, 2007, Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells, Blood, 109, 1953, 10.1182/blood-2006-07-034124 Scharpfenecker, 2007, BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis, J. Cell Sci, 120, 964, 10.1242/jcs.002949 Johnson, 1996, Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2, Nat. Genet, 13, 189, 10.1038/ng0696-189 Oh, 2000, Activin receptor-like kinase 1 modulates transforming growth factor-β 1 signaling in the regulation of angiogenesis, Proc. Natl. Acad. Sci. U.S.A, 97, 2626, 10.1073/pnas.97.6.2626 Urness, 2000, Arteriovenous malformations in mice lacking activin receptor-like kinase-1, Nat. Genet, 26, 328, 10.1038/81634 Bidart, 2012, BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain, Cell. Mol. Life Sci, 69, 313, 10.1007/s00018-011-0751-1 Neuhaus, 1999, Heart specific expression of mouse BMP-10 a novel member of the TGF-β superfamily, Mech. Dev, 80, 181, 10.1016/S0925-4773(98)00221-4 Chen, 2004, BMP10 is essential for maintaining cardiac growth during murine cardiogenesis, Development, 131, 2219, 10.1242/dev.01094 Chen, 2013, Context-dependent signaling defines roles of BMP9 and BMP10 in embryonic and postnatal development, Proc. Natl. Acad. Sci. U.S.A, 110, 11887, 10.1073/pnas.1306074110 Laux, 2013, Circulating Bmp10 acts through endothelial Alk1 to mediate flow-dependent arterial quiescence, Development, 140, 3403, 10.1242/dev.095307 Levet, 2013, Bone morphogenetic protein 9 (BMP9) controls lymphatic vessel maturation and valve formation, Blood, 122, 598, 10.1182/blood-2012-12-472142 Levet, 2015, BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus, Proc. Natl. Acad. Sci. U.S.A, 112, E3207, 10.1073/pnas.1508386112 Ricard, 2012, BMP9 and BMP10 are critical for postnatal retinal vascular remodeling, Blood, 119, 6162, 10.1182/blood-2012-01-407593 Brown, 2005, Crystal structure of BMP-9 and functional interactions with pro-region and receptors, J. Biol. Chem, 280, 25111, 10.1074/jbc.M503328200 Mi, 2015, Structure of bone morphogenetic protein 9 procomplex, Proc. Natl. Acad. Sci. U.S.A, 112, 3710, 10.1073/pnas.1501303112 Sengle, 2011, Prodomains of transforming growth factor β (TGFβ) superfamily members specify different functions: extracellular matrix interactions and growth factor bioavailability, J. Biol. Chem, 286, 5087, 10.1074/jbc.M110.188615 Shi, 2011, Latent TGF-β structure and activation, Nature, 474, 343, 10.1038/nature10152 Wolfman, 2003, Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases, Proc. Natl. Acad. Sci. U.S.A, 100, 15842, 10.1073/pnas.2534946100 Jiang, 2016, The prodomain-bound form of bone morphogenetic protein 10 is biologically active on endothelial cells, J. Biol. Chem, 291, 2954, 10.1074/jbc.M115.683292 Guo, 2012, The signaling and functions of heterodimeric bone morphogenetic proteins, Cytokine Growth Factor Rev, 23, 61, 10.1016/j.cytogfr.2012.02.001 Hernandez, 2015, Mutations in RASA1 and GDF2 identified in patients with clinical features of hereditary hemorrhagic telangiectasia, Hum. Genome Var, 2, 15040, 10.1038/hgv.2015.40 Imayoshi, 2006, Temporal regulation of Cre recombinase activity in neural stem cells, Genesis, 44, 233, 10.1002/dvg.20212 Kienast, 2016, Rapid activation of bone morphogenic protein 9 by receptor-mediated displacement of pro-domains, J. Biol. Chem, 291, 3395, 10.1074/jbc.M115.680009 Zhao, 2018, Prodomain: growth factor swapping in the structure of pro-TGF-β1, J. Biol. Chem, 295, 1579, 10.1074/jbc.M117.809657 O'Connor, 2006, Shaping BMP morphogen gradients in the Drosophila embryo and pupal wing, Development, 133, 183, 10.1242/dev.02214 Shimmi, 2005, Facilitated transport of a Dpp/Scw heterodimer by Sog/Tsg leads to robust patterning of the Drosophila blastoderm embryo, Cell, 120, 873, 10.1016/j.cell.2005.02.009 Little, 2009, Bone morphogenetic protein heterodimers assemble heteromeric type I receptor complexes to pattern the dorsoventral axis, Nat. Cell Biol, 11, 637, 10.1038/ncb1870 Suzuki, 1997, Mesoderm induction by BMP-4 and −7 heterodimers, Biochem. Biophys. Res. Commun, 232, 153, 10.1006/bbrc.1997.6219 Butler, 2003, A role for BMP heterodimers in roof plate-mediated repulsion of commissural axons, Neuron, 38, 389, 10.1016/S0896-6273(03)00254-X Fuerer, 2014, Nodal.Gdf1 heterodimers with bound prodomains enable serum-independent nodal signaling and endoderm differentiation, J. Biol. Chem, 289, 17854, 10.1074/jbc.M114.550301 Tanaka, 2007, Long-range action of Nodal requires interaction with GDF1, Genes Dev, 21, 3272, 10.1101/gad.1623907 Mottershead, 2015, Cumulin, an oocyte-secreted heterodimer of the transforming growth factor-β family, is a potent activator of granulosa cells and improves oocyte quality, J. Biol. Chem, 290, 24007, 10.1074/jbc.M115.671487 Peng, 2013, Growth differentiation factor 9:bone morphogenetic protein 15 heterodimers are potent regulators of ovarian functions, Proc. Natl. Acad. Sci. U.S.A, 110, E776, 10.1073/pnas.1218020110 Ramirez, 2009, Extracellular microfibrils: contextual platforms for TGFβ and BMP signaling, Curr. Opin. Cell Biol, 21, 616, 10.1016/j.ceb.2009.05.005 Wohl, 2016, Extracellular regulation of bone morphogenetic protein activity by the microfibril component fibrillin-1, J. Biol. Chem, 291, 12732, 10.1074/jbc.M115.704734 Sengle, 2008, Targeting of bone morphogenetic protein growth factor complexes to fibrillin, J. Biol. Chem, 283, 13874, 10.1074/jbc.M707820200 Aono, 1995, Potent ectopic bone-inducing activity of bone morphogenetic protein-4/7 heterodimer, Biochem. Biophys. Res. Commun, 210, 670, 10.1006/bbrc.1995.1712 Isaacs, 2010, Bone morphogenetic protein-2 and -6 heterodimer illustrates the nature of ligand-receptor assembly, Mol. Endocrinol, 24, 1469, 10.1210/me.2009-0496 Israel, 1996, Heterodimeric bone morphogenetic proteins show enhanced activity in vitro and in vivo, Growth Factors, 13, 291, 10.3109/08977199609003229 Valera, 2010, BMP-2/6 heterodimer is more effective than BMP-2 or BMP-6 homodimers as inductor of differentiation of human embryonic stem cells, PloS One, 5, e11167, 10.1371/journal.pone.0011167 Sebald, 2004, Molecular recognition in bone morphogenetic protein (BMP)/receptor interaction, Biol. Chem, 385, 697, 10.1515/BC.2004.086 Allendorph, 2007, BMP-3 and BMP-6 structures illuminate the nature of binding specificity with receptors, Biochemistry, 46, 12238, 10.1021/bi700907k Mahlawat, 2012, Structure of the Alk1 extracellular domain and characterization of its bone morphogenetic protein (BMP) binding properties, Biochemistry, 51, 6328, 10.1021/bi300942x Townson, 2012, Specificity and structure of a high affinity activin receptor-like kinase 1 (ALK1) signaling complex, J. Biol. Chem, 287, 27313, 10.1074/jbc.M112.377960 Herrera, 2009, Autocrine bone morphogenetic protein-9 signals through activin receptor-like kinase-2/Smad1/Smad4 to promote ovarian cancer cell proliferation, Cancer Res, 69, 9254, 10.1158/0008-5472.CAN-09-2912 Luo, 2010, TGFβ/BMP type I receptors ALK1 and ALK2 are essential for BMP9-induced osteogenic signaling in mesenchymal stem cells, J. Biol. Chem, 285, 29588, 10.1074/jbc.M110.130518 Mazerbourg, 2005, Identification of receptors and signaling pathways for orphan bone morphogenetic protein/growth differentiation factor ligands based on genomic analyses, J. Biol. Chem, 280, 32122, 10.1074/jbc.M504629200 Shimmi, 2005, The crossveinless gene encodes a new member of the Twisted gastrulation family of BMP-binding proteins which, with short gastrulation, promotes BMP signaling in the crossveins of the Drosophila wing, Dev. Biol, 282, 70, 10.1016/j.ydbio.2005.02.029 Miller, 2000, Bone morphogenetic protein-9: an autocrine/paracrine cytokine in the liver, J. Biol. Chem, 275, 17937, 10.1074/jbc.275.24.17937 Breitkopf-Heinlein, 2017, BMP-9 interferes with liver regeneration and promotes liver fibrosis, Gut, 66, 939, 10.1136/gutjnl-2016-313314 David, 2008, Bone morphogenetic protein-9 is a circulating vascular quiescence factor, Circ. Res, 102, 914, 10.1161/CIRCRESAHA.107.165530