Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter June 1, 2005

Molecular recognition in bone morphogenetic protein (BMP)/receptor interaction

  • Walter Sebald , Joachim Nickel , Jin-Li Zhang and Thomas D. Mueller
From the journal Biological Chemistry

Abstract

Bone morphogenetic proteins (BMPs) and other members of the TGF-β superfamily are secreted signalling proteins determining the development, maintenance and regeneration of tissues and organs. These dimeric proteins bind, via multiple epitopes, two types of signalling receptor chains and numerous extracellular modulator proteins that stringently control their activity. Crystal structures of free ligands and of complexes with type I and type II receptor extracellular domains and with the modulator protein Noggin reveal structural epitopes that determine the affinity and specificity of the interactions. Modelling of a ternary complex BMP/(BMPR-IAEC)2/(ActR-IIEC)2 suggests a mechanism of receptor activation that does not rely on direct contacts between extracellular domains of the receptors. Mutational and interaction analyses indicate that the large hydrophobic core of the interface of BMP-2 (wrist epitope) with the type I receptor does not provide a hydrophobic hot spot for binding. Instead, main chain amide and carbonyl groups that are completely buried in the contact region represent major binding determinants. The affinity between ligand and receptor chains is probably strongly increased by two-fold interactions of the dimeric ligand and receptor chains that exist as homodimers in the membrane (avidity effects). BMP muteins with disrupted epitopes for receptor chains or modulator proteins provide clues for drug design and development.

:

Corresponding author e-mail:

References

Abreu, J. G., Ketpura, N. I., Reversade, B., and De Robertis, E. M. (2002). Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-β. Nat. Cell. Biol4, 599–604.10.1038/ncb826Search in Google Scholar

Avsian-Kretchmer, O., and Hsueh, A. J. (2004). Comparative genomic analysis of the eight-membered ring cystine knot-containing bone morphogenetic protein antagonists. Mol. Endocrinol.18, 1–12.10.1210/me.2003-0227Search in Google Scholar

Balemans, W., and Van Hul, W. (2002). Extracellular regulation of BMP signaling in vertebrates: a cocktail of modulators. Dev. Biol.250, 231–250.10.1006/dbio.2002.0779Search in Google Scholar

Baur, S. T., Mai, J. J., and Dymecki, S. M. (2000). Combinatorial signaling through BMP receptor IB and GDF5: shaping of the distal mouse limb and the genetics of distal limb diversity. Development127, 605–619.10.1242/dev.127.3.605Search in Google Scholar

Bernat, B., Pal, G., Sun, M., and Kossiakoff, A. A. (2003). Determination of the energetics governing the regulatory step in growth hormone-induced receptor homodimerization. Proc. Natl. Acad. Sci. USA100, 952–957.10.1073/pnas.0235023100Search in Google Scholar

Blessing, M., Schirmacher, P., and Kaiser, S. (1996). Overexpression of bone morphogenetic protein-6 (BMP-6) in the epidermis of transgenic mice: inhibition or stimulation of proliferation depending on the pattern of transgene expression and formation of psoriatic lesions. J. Cell Biol.135, 227–239.10.1083/jcb.135.1.227Search in Google Scholar

Boesen, C. C., Radaev, S., Motyka, S. A., Patamawenu, A., and Sun, P. D. (2002). The 1.1 Å crystal structure of human TGF-β type II receptor ligand binding domain. Structure10, 913–919.Search in Google Scholar

Branton, M. H., and Kopp, J. B. (1999). TGF-β and fibrosis. Microbes Infect.1, 1349–1365.10.1016/S1286-4579(99)00250-6Search in Google Scholar

Canalis, E., Economides, A. N., and Gazzerro, E. (2003). Bone morphogenetic proteins, their antagonists, and the skeleton. Endocr. Rev.24, 218–235.10.1210/er.2002-0023Search in Google Scholar PubMed

Clackson, T., Ultsch, M. H., Wells, J. A., and de Vos, A. M. (1998). Structural and functional analysis of the 1:1 growth hormone:receptor complex reveals the molecular basis for receptor affinity. J. Mol. Biol.277, 1111–1128.10.1006/jmbi.1998.1669Search in Google Scholar PubMed

Clackson, T., and Wells, J. A. (1995). A hot spot of binding energy in a hormone-receptor interface. Science267, 383–386.10.1126/science.7529940Search in Google Scholar PubMed

Cunningham, B. C., and Wells, J. A. (1993). Comparison of a structural and a functional epitope. J. Mol. Biol.234, 554–563. [Erratum published in J. Mol. Biol. 237 (1994), p. 513]10.1006/jmbi.1993.1611Search in Google Scholar PubMed

Daopin, S., Piez, K. A., Ogawa, Y., and Davies, D. R. (1992). Crystal structure of transforming growth factor-β2: an unusual fold for the superfamily. Science257, 369–373.10.1126/science.1631557Search in Google Scholar PubMed

de Vos, A. M., Ultsch, M., and Kossiakoff, A. A. (1992). Human growth hormone and extracellular domain of its receptor: crystal structure of the complex. Science255, 306–312.10.1126/science.1549776Search in Google Scholar PubMed

Deep, S., Walker, K. P., 3rd, Shu, Z., and Hinck, A. P. (2003). Solution structure and backbone dynamics of the TGFβ type II receptor extracellular domain. Biochemistry42, 10126–10139.10.1021/bi034366aSearch in Google Scholar PubMed

DiLeone, R. J., Marcus, G. A., Johnson, M. D., and Kingsley, D. M. (2000). Efficient studies of long-distance Bmp5 gene regulation using bacterial artificial chromosomes. Proc. Natl. Acad. Sci. USA97, 1612–1617.10.1073/pnas.97.4.1612Search in Google Scholar PubMed PubMed Central

Dong, J., Albertini, D. F., Nishimori, K., Kumar, T. R., Lu, N., and Matzuk, M. M. (1996). Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature383, 531–535.10.1038/383531a0Search in Google Scholar PubMed

Duncan, M. R., Frazier, K. S., Abramson, S., Williams, S., Klapper, H., Huang, X., and Grotendorst, G. R. (1999). Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: down-regulation by cAMP. FASEB J.13, 1774–1786.10.1096/fasebj.13.13.1774Search in Google Scholar

Dunn, N. R., and Hogan, B. L. (2001). How does the mouse get its trunk? Nat. Genet.27, 351–352.Search in Google Scholar

Ebisawa, T., Tada, K., Kitajima, I., Tojo, K., Sampath, T. K., Kawabata, M., Miyazono, K., and Imamura, T. (1999). Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation. J. Cell Sci.112, 3519–3527.10.1242/jcs.112.20.3519Search in Google Scholar PubMed

Eigenbrot, C., and Gerber, N. (1997). X-ray structure of glial cell-derived neurotrophic factor at 1.9 Å resolution and implications for receptor binding. Nat. Struct. Biol.4, 435–438.Search in Google Scholar

Eketjall, S., Fainzilber, M., Murray Rust, J., and Ibanez, C. F. (1999). Distinct structural elements in GDNF mediate binding to GFRα1 and activation of the GFRα1-c-Ret receptor complex. EMBO J.18, 5901–5910.10.1093/emboj/18.21.5901Search in Google Scholar PubMed PubMed Central

Fox, K. M., Dias, J. A., and Van Roey, P. (2001). Three-dimensional structure of human follicle-stimulating hormone. Mol. Endocrinol.15, 378–389.10.1210/mend.15.3.0603Search in Google Scholar PubMed

Furthauer, M., Thisse, B., and Thisse, C. (1999). Three different noggin genes antagonize the activity of bone morphogenetic proteins in the zebrafish embryo. Dev. Biol.214, 181–196.10.1006/dbio.1999.9401Search in Google Scholar

Galloway, S. M., McNatty, K. P., Cambridge, L. M., Laitinen, M. P., Juengel, J. L., Jokiranta, T. S., McLaren, R. J., Luiro, K., Dodds, K. G., Montgomery, G. W. et al. (2000). Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation rate and infertility in a dosage-sensitive manner. Nat. Genet.25, 279–283.10.1038/77033Search in Google Scholar

Garcia Abreu, J., Coffinier, C., Larrain, J., Oelgeschlager, M., and De Robertis, E. M. (2002). Chordin-like CR domains and the regulation of evolutionarily conserved extracellular signaling systems. Gene287, 39–47.Search in Google Scholar

Gilboa, L., Wells, R. G., Lodish, H. F., and Henis, Y. I. (1998). Oligomeric structure of type I and type II transforming growth factor β receptors: homodimers form in the ER and persist at the plasma membrane. J. Cell Biol.140, 767–777.10.1083/jcb.140.4.767Search in Google Scholar

Gilboa, L., Nohe, A., Geissendorfer, T., Sebald, W., Henis, Y. I., and Knaus, P. (2000). Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors. Mol. Biol. Cell11, 1023–1035.10.1091/mbc.11.3.1023Search in Google Scholar

Gray, P. C., Bilezikjian, L. M., and Vale, W. (2002). Antagonism of activin by inhibin and inhibin receptors: a functional role for betaglycan. Mol. Cell. Endocrinol.188, 254–260.Search in Google Scholar

Greenwald, J., Fischer, W. H., Vale, W. W., and Choe, S. (1999). Three-finger toxin fold for the extracellular ligand-binding domain of the type II activin receptor serine kinase. Nat. Struct. Biol.6, 18–22.Search in Google Scholar

Greenwald, J., Groppe, J., Gray, P., Wiater, E., Kwiatkowski, W., Vale, W., and Choe, S. (2003). The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly. Mol. Cell11, 605–617.10.1016/S1097-2765(03)00094-7Search in Google Scholar

Griffith, D. L., Keck, P. C., Sampath, T. K., Rueger, D. C., and Carlson, W. D. (1996). Three-dimensional structure of recombinant human osteogenic protein 1: structural paradigm for the transforming growth factor β superfamily. Proc. Natl. Acad. Sci. USA93, 878–883.10.1073/pnas.93.2.878Search in Google Scholar

Groppe, J., Greenwald, J., Wiater, E., Rodriguez-Leon, J., Economides, A. N., Kwiatkowski, W., Affolter, M., Vale, W. W., Belmonte, J. C., and Choe, S. (2002). Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature420, 636–642.10.1038/nature01245Search in Google Scholar

Grotendorst, G. R. (1997). Connective tissue growth factor: a mediator of TGF-β action on fibroblasts. Cytokine Growth Factor Rev.8, 171–179.10.1016/S1359-6101(97)00010-5Search in Google Scholar

Hart, P. J., Deep, S., Taylor, A. B., Shu, Z., Hinck, C. S., and Hinck, A. P. (2002). Crystal structure of the human TβR2 ectodomain-TGF-β3 complex. Nat. Struct. Biol.9, 203–208.10.1038/nsb766Search in Google Scholar

Hatta, T., Konishi, H., Katoh, E., Natsume, T., Ueno, N., Kobayashi, Y., and Yamazaki, T. (2000). Identification of the ligand-binding site of the BMP type IA receptor for BMP-4. Biopolymers55, 399–406.10.1002/1097-0282(2000)55:5<399::AID-BIP1014>3.0.CO;2-9Search in Google Scholar

He, S., Jin, M. L., Worpel, V., and Hinton, D. R. (2003). A role for connective tissue growth factor in the pathogenesis of choroidal neovascularization. Arch. Ophthalmol.121, 1283–1288.10.1001/archopht.121.9.1283Search in Google Scholar

Heldin, C. H. (1995). Dimerization of cell surface receptors in signal transduction. Cell80, 213–223.10.1016/0092-8674(95)90404-2Search in Google Scholar

Heldin, C. H., and Ostman, A. (1996). Ligand-induced dimerization of growth factor receptors: variations on the theme. Cytokine Growth Factor Rev.7, 3–10.10.1016/1359-6101(96)00002-0Search in Google Scholar

Heldin, C. H., Miyazono, K., and ten Dijke, P. (1997). TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature390, 465–471.10.1038/37284Search in Google Scholar

Henis, Y. I., Moustakas, A., Lin, H. Y., and Lodish, H. F. (1994). The types II and III transforming growth factor-β receptors form homo-oligomers. J. Cell Biol.126, 139–154.10.1083/jcb.126.1.139Search in Google Scholar

Hinck, A. P., Archer, S. J., Qian, S. W., Roberts, A. B., Sporn, M. B., Weatherbee, J. A., Tsang, M. L., Lucas, R., Zhang, B. L., Wenker, J., and Torchia, D. A. (1996). Transforming growth factor β1: three-dimensional structure in solution and comparison with the X-ray structure of transforming growth factor β2. Biochemistry35, 8517–8534.10.1021/bi9604946Search in Google Scholar

Hogan, B. L. (1996). Bone morphogenetic proteins in development. Curr. Opin. Genet. Dev.6, 432–438.10.1016/S0959-437X(96)80064-5Search in Google Scholar

Huang, S. S., Liu, Q., Johnson, F. E., Konish, Y., and Huang, J. S. (1997). Transforming growth factor β peptide antagonists and their conversion to partial agonists. J. Biol. Chem.272, 27155–27159.10.1074/jbc.272.43.27155Search in Google Scholar

Huse, M., Chen, Y. G., Massague, J., and Kuriyan, J. (1999). Crystal structure of the cytoplasmic domain of the type I TGFβ receptor in complex with FKBP12. Cell96, 425–436.10.1016/S0092-8674(00)80555-3Search in Google Scholar

Katagiri, T., Boorla, S., Frendo, J. L., Hogan, B. L., and Karsenty, G. (1998). Skeletal abnormalities in doubly heterozygous Bmp4 and Bmp7 mice. Dev. Genet.22, 340–348.10.1002/(SICI)1520-6408(1998)22:4<340::AID-DVG4>3.0.CO;2-6Search in Google Scholar

Keller, S., Nickel, J., Zhang, J. L., Sebald, W., and Mueller, T. D. (2004). Molecular recognition of BMP-2 and BMP receptor IA. Nat. Struct. Mol. Biol.11, 481–488.10.1038/nsmb756Search in Google Scholar

Kim, M., Carman, C. V., and Springer, T. A. (2003). Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins. Science301, 1720–1725.10.1126/science.1084174Search in Google Scholar

Kingsley, D. M. (1994). What do BMPs do in mammals? Clues from the mouse short-ear mutation. Trends Genet.10, 16–21.10.1016/0168-9525(94)90014-0Search in Google Scholar

Kirsch, T., Nickel, J., and Sebald, W. (2000a). BMP-2 antagonists emerge from alterations in the low-affinity binding epitope for receptor BMPR-II. EMBO J.19, 3314–3324.10.1093/emboj/19.13.3314Search in Google Scholar PubMed PubMed Central

Kirsch, T., Sebald, W., and Dreyer, M. K. (2000b). Crystal structure of the BMP-2-BRIA ectodomain complex. Nat. Struct. Biol.7, 492–496.10.1038/75903Search in Google Scholar PubMed

Knaus, P., and Sebald, W. (2001). Cooperativity of binding epitopes and receptor chains in the BMP/TGFβ superfamily. Biol. Chem.382, 1189–1195.10.1515/BC.2001.149Search in Google Scholar PubMed

Koenig, B. B., Cook, J. S., Wolsing, D. H., Ting, J., Tiesman, J. P., Correa, P. E., Olson, C. A., Pecquet, A. L., Ventura, F., Grant, R. A., and et al. (1994). Characterization and cloning of a receptor for BMP-2 and BMP-4 from NIH 3T3 cells. Mol. Cell. Biol.14, 5961–5974.10.1128/MCB.14.9.5961Search in Google Scholar PubMed PubMed Central

Kusu, N., Laurikkala, J., Imanishi, M., Usui, H., Konishi, M., Miyake, A., Thesleff, I., and Itoh, N. (2003). Sclerostin is a novel secreted osteoclast-derived bone morphogenetic protein antagonist with unique ligand specificity. J. Biol. Chem.278, 24113–24117.10.1074/jbc.M301716200Search in Google Scholar PubMed

Lapthorn, A. J., Harris, D. C., Littlejohn, A., Lustbader, J. W., Canfield, R. E., Machin, K. J., Morgan, F. J., and Isaacs, N. W. (1994). Crystal structure of human chorionic gonadotropin. Nature369, 455–461.10.1038/369455a0Search in Google Scholar PubMed

Larrain, J., Bachiller, D., Lu, B., Agius, E., Piccolo, S., and De Robertis, E. M. (2000). BMP-binding modules in chordin: a model for signalling regulation in the extracellular space. Development127, 821–830.10.1242/dev.127.4.821Search in Google Scholar PubMed PubMed Central

Larrain, J., Oelgeschlager, M., Ketpura, N. I., Reversade, B., Zakin, L., and De Robertis, E. M. (2001). Proteolytic cleavage of Chordin as a switch for the dual activities of Twisted gastrulation in BMP signaling. Development128, 4439–4447.10.1242/dev.128.22.4439Search in Google Scholar PubMed PubMed Central

Lee, S. J., and McPherron, A. C. (2001). Regulation of myostatin activity and muscle growth. Proc. Natl. Acad. Sci. USA98, 9306–9311.10.1073/pnas.151270098Search in Google Scholar PubMed PubMed Central

Letzelter, F., Wang, Y., and Sebald, W. (1998). The interleukin-4 site-2 epitope determining binding of the common receptor γ chain. Eur. J. Biochem.257, 11–20.10.1046/j.1432-1327.1998.2570011.xSearch in Google Scholar PubMed

Lewis, K. A., Gray, P. C., Blount, A. L., MacConell, L. A., Wiater, E., Bilezikjian, L. M., and Vale, W. (2000). Betaglycan binds inhibin and can mediate functional antagonism of activin signalling. Nature404, 411–414.10.1038/35006129Search in Google Scholar PubMed

Liu, F., Ventura, F., Doody, J., and Massague, J. (1995). Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs. Mol. Cell. Biol.15, 3479–3486.10.1128/MCB.15.7.3479Search in Google Scholar PubMed PubMed Central

Livnah, O., Stura, E. A., Middleton, S. A., Johnson, D. L., Jolliffe, L. K., and Wilson, I. A. (1999). Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation. Science283, 987–990.10.1126/science.283.5404.987Search in Google Scholar PubMed

Lo, R. S., and Massague, J. (1999). Ubiquitin-dependent degradation of TGF-β-activated smad2. Nat. Cell Biol.1, 472–478.10.1038/70258Search in Google Scholar PubMed

Luo, K., and Lodish, H. F. (1997). Positive and negative regulation of type II TGF-β receptor signal transduction by autophosphorylation on multiple serine residues. EMBO J.16, 1970–1981.10.1093/emboj/16.8.1970Search in Google Scholar PubMed PubMed Central

Macias-Silva, M., Hoodless, P. A., Tang, S. J., Buchwald, M., and Wrana, J. L. (1998). Specific activation of Smad1 signaling pathways by the BMP7 type I receptor, ALK2. J. Biol. Chem.273, 25628–25636.10.1074/jbc.273.40.25628Search in Google Scholar PubMed

Massague, J. (1998). TGF-β signal transduction. Annu. Rev. Biochem.67, 753–791.10.1146/annurev.biochem.67.1.753Search in Google Scholar PubMed

Massague, J., and Chen, Y. G. (2000). Controlling TGF-β signaling. Genes Dev.14, 627–644.10.1101/gad.14.6.627Search in Google Scholar

Massague, J., Attisano, L., and Wrana, J. L. (1994). The TGF-β family and its composite receptors. Trends Cell Biol.4, 172–178.10.1016/0962-8924(94)90202-XSearch in Google Scholar

Massague, J., Blain, S. W., and Lo, R. S. (2000). TGF-β signaling in growth control, cancer, and heritable disorders. Cell103, 295–309.10.1016/S0092-8674(00)00121-5Search in Google Scholar

McDonald, N. Q., and Hendrickson, W. A. (1993). A structural superfamily of growth factors containing a cystine knot motif. Cell73, 421–424.10.1016/0092-8674(93)90127-CSearch in Google Scholar

McDonald, N. Q., Lapatto, R., Murray-Rust, J., Gunning, J., Wlodawer, A., and Blundell, T. L. (1991). New protein fold revealed by a 2.3-Å resolution crystal structure of nerve growth factor. Nature354, 411–414.Search in Google Scholar

Mittl, P. R., Priestle, J. P., Cox, D. A., McMaster, G., Cerletti, N., and Grutter, M. G. (1996). The crystal structure of TGF-β 3 and comparison to TGF-β 2: implications for receptor binding. Protein Sci.5, 1261–1271.10.1002/pro.5560050705Search in Google Scholar

Miyazono, K., Kusanagi, K., and Inoue, H. (2001). Divergence and convergence of TGF-β/BMP signaling. J. Cell Physiol.187, 265–276.10.1002/jcp.1080Search in Google Scholar

Miyazono, K., ten Dijke, P., and Heldin, C. H. (2000). TGF-β signaling by Smad proteins. Adv. Immunol.75, 115–157.10.1016/S0065-2776(00)75003-6Search in Google Scholar

Mortlock, D. P., Guenther, C., and Kingsley, D. M. (2003). A general approach for identifying distant regulatory elements applied to the Gdf6 gene. Genome Res.13, 2069–2081.10.1101/gr.1306003Search in Google Scholar PubMed PubMed Central

Moustakas, A., Souchelnytskyi, S., and Heldin, C. H. (2001). Smad regulation in TGF-β signal transduction. J. Cell Sci.114, 4359–4369.10.1242/jcs.114.24.4359Search in Google Scholar PubMed

Muller, Y. A., Li, B., Christinger, H. W., Wells, J. A., Cunningham, B. C., and de Vos, A. M. (1997). Vascular endothelial growth factor: crystal structure and functional mapping of the kinase domain receptor binding site. Proc. Natl. Acad. Sci. USA94, 7192–7197.10.1073/pnas.94.14.7192Search in Google Scholar PubMed PubMed Central

Nakamura, K., Shirai, T., Morishita, S., Uchida, S., Saeki-Miura, K., and Makishima, F. (1999). p38 mitogen-activated protein kinase functionally contributes to chondrogenesis induced by growth/differentiation factor-5 in ATDC5 cells. Exp. Cell Res.250, 351–363.10.1006/excr.1999.4535Search in Google Scholar

Newfeld, S. J., Wisotzkey, R. G., and Kumar, S. (1999). Molecular evolution of a developmental pathway: phylogenetic analyses of transforming growth factor-β family ligands, receptors and Smad signal transducers. Genetics152, 783–795.10.1093/genetics/152.2.783Search in Google Scholar

Nishitoh, H., Ichijo, H., Kimura, M., Matsumoto, T., Makishima, F., Yamaguchi, A., Yamashita, H., Enomoto, S., and Miyazono, K. (1996). Identification of type I and type II serine/threonine kinase receptors for growth/differentiation factor-5. J. Biol. Chem.271, 21345–21352.10.1074/jbc.271.35.21345Search in Google Scholar

Nohe, A., Hassel, S., Ehrlich, M., Neubauer, F., Sebald, W., Henis, Y. I., and Knaus, P. (2002). The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways. J. Biol. Chem.277, 5330–5338.10.1074/jbc.M102750200Search in Google Scholar

Nohno, T., Ishikawa, T., Saito, T., Hosokawa, K., Noji, S., Wolsing, D. H., and Rosenbaum, J. S. (1995). Identification of a human type II receptor for bone morphogenetic protein-4 that forms differential heteromeric complexes with bone morphogenetic protein type I receptors. J. Biol. Chem.270, 22522–22526.10.1074/jbc.270.38.22522Search in Google Scholar

Oelgeschlager, M., Reversade, B., Larrain, J., Little, S., Mullins, M. C., and De Robertis, E. M. (2003). The pro-BMP activity of Twisted gastrulation is independent of BMP binding. Development130, 4047–4056.10.1242/dev.00633Search in Google Scholar

Ohkawara, B., Iemura, S., ten Dijke, P., and Ueno, N. (2002). Action range of BMP is defined by its N-terminal basic amino acid core. Curr. Biol. 12, 205–209.10.1016/S0960-9822(01)00684-4Search in Google Scholar

Onichtchouk, D., Chen, Y. G., Dosch, R., Gawantka, V., Delius, H., Massague, J., and Niehrs, C. (1999). Silencing of TGF-β signalling by the pseudoreceptor BAMBI. Nature401, 480–485.10.1038/46794Search in Google Scholar

Paques, M., Massin, P., and Gaudric, A. (1997). Growth factors and diabetic retinopathy. Diabetes Metab.23, 125–130.Search in Google Scholar

Patterson, G. I., and Padgett, R. W. (2000). TGF β-related pathways. Roles in Caenorhabditis elegans development. Trends Genet.16, 27–33.Search in Google Scholar

Piek, E., Afrakhte, M., Sampath, K., van Zoelen, E. J., Heldin, C. H., and ten Dijke, P. (1999). Functional antagonism between activin and osteogenic protein-1 in human embryonal carcinoma cells. J. Cell Physiol.180, 141–149.10.1002/(SICI)1097-4652(199908)180:2<141::AID-JCP1>3.0.CO;2-ISearch in Google Scholar

Rebbapragada, A., Benchabane, H., Wrana, J. L., Celeste, A. J., and Attisano, L. (2003). Myostatin signals through a transforming growth factor β-like signaling pathway to block adipogenesis. Mol. Cell. Biol.23, 7230–7242.10.1128/MCB.23.20.7230-7242.2003Search in Google Scholar

Reddi, A. H. (1998). Role of morphogenetic proteins in skeletal tissue engineering and regeneration. Nat. Biotechnol.16, 247–252.10.1038/nbt0398-247Search in Google Scholar

Rosen, V., and Thies, R. S. (1992). The BMP proteins in bone formation and repair. Trends Genet.8, 97–102.10.1016/0168-9525(92)90063-ASearch in Google Scholar

Rotzer, D., Roth, M., Lutz, M., Lindemann, D., Sebald, W., and Knaus, P. (2001). Type III TGF-β receptor-independent signalling of TGF-β2 via TβRII-B, an alternatively spliced TGF-β type II receptor. EMBO J.20, 480–490.10.1093/emboj/20.3.480Search in Google Scholar

Ruppert, R., Hoffmann, E., and Sebald, W. (1996). Human bone morphogenetic protein 2 contains a heparin-binding site which modifies its biological activity. Eur. J. Biochem.237, 295–302.10.1111/j.1432-1033.1996.0295n.xSearch in Google Scholar

Scheufler, C., Sebald, W., and Hulsmeyer, M. (1999). Crystal structure of human bone morphogenetic protein-2 at 2.7 Å resolution. J. Mol. Biol.287, 103–115.Search in Google Scholar

Schlessinger, J. (1988). Signal transduction by allosteric receptor oligomerization. Trends Biochem. Sci.13, 443–447.10.1016/0968-0004(88)90219-8Search in Google Scholar

Schlessinger, J., Lax, I., and Lemmon, M. (1995). Regulation of growth factor activation by proteoglycans: what is the role of the low affinity receptors? Cell83, 357–360.10.1016/0092-8674(95)90112-4Search in Google Scholar

Schlunegger, M. P., and Grutter, M. G. (1992). An unusual feature revealed by the crystal structure at 2.2 Å resolution of human transforming growth factor-β 2. Nature358, 430–434.Search in Google Scholar

Sebald, W., and Mueller, T. D. (2003). The interaction of BMP-7 and ActRII implicates a new mode of receptor assembly. Trends Biochem. Sci.28, 518–521.10.1016/j.tibs.2003.08.001Search in Google Scholar

Settle, S. H., Jr., Rountree, R. B., Sinha, A., Thacker, A., Higgins, K., and Kingsley, D. M. (2003). Multiple joint and skeletal patterning defects caused by single and double mutations in the mouse Gdf6 and Gdf5 genes. Dev. Biol.254, 116–130.10.1016/S0012-1606(02)00022-2Search in Google Scholar

Shi, Y., and Massague, J. (2003). Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell113, 685–700.10.1016/S0092-8674(03)00432-XSearch in Google Scholar

Solloway, M. J., and Robertson, E. J. (1999). Early embryonic lethality in Bmp5;Bmp7 double mutant mice suggests functional redundancy within the 60A subgroup. Development126, 1753–1768.10.1242/dev.126.8.1753Search in Google Scholar PubMed

Souchelnytskyi, S., Moustakas, A., and Heldin, C. H. (2002). TGF-β signaling from a three-dimensional perspective: insight into selection of partners. Trends Cell Biol.12, 304–307.10.1016/S0962-8924(02)02300-0Search in Google Scholar

Stahl, N., and Yancopoulos, G. D. (1993). The alphas, betas, and kinases of cytokine receptor complexes. Cell74, 587–590.10.1016/0092-8674(93)90506-LSearch in Google Scholar

Stelzer, C., Winterpacht, A., Spranger, J., and Zabel, B. (2003). Grebe dysplasia and the spectrum of CDMP1 mutations. Pediatr. Pathol. Mol. Med.22, 77–85.10.1080/pdp.22.1.77.85Search in Google Scholar

Storm, E. E., and Kingsley, D. M. (1996). Joint patterning defects caused by single and double mutations in members of the bone morphogenetic protein (BMP) family. Development122, 3969–3979.10.1242/dev.122.12.3969Search in Google Scholar

Syed, R. S., Reid, S. W., Li, C., Cheetham, J. C., Aoki, K. H., Liu, B., Zhan, H., Osslund, T. D., Chirino, A. J., Zhang, J. et al. (1998). Efficiency of signalling through cytokine receptors depends critically on receptor orientation. Nature395, 511–516.10.1038/26773Search in Google Scholar

ten Dijke, P., Yamashita, H., Sampath, T. K., Reddi, A. H., Estevez, M., Riddle, D. L., Ichijo, H., Heldin, C. H., and Miyazono, K. (1994). Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. J. Biol. Chem.269, 16985–16988.10.1016/S0021-9258(17)32506-1Search in Google Scholar

ten Dijke, P., Miyazono, K., and Heldin, C. H. (1996). Signaling via hetero-oligomeric complexes of type I and type II serine/threonine kinase receptors. Curr. Opin. Cell Biol.8, 139–145.10.1016/S0955-0674(96)80058-5Search in Google Scholar

Thomas, J. T., Kilpatrick, M. W., Lin, K., Erlacher, L., Lembessis, P., Costa, T., Tsipouras, P., and Luyten, F. P. (1997). Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1. Nat. Genet.17, 58–64.10.1038/ng0997-58Search in Google Scholar PubMed

Thompson, T. B., Woodruff, T. K., and Jardetzky, T. S. (2003). Structures of an ActRIIB:activin A complex reveal a novel binding mode for TGF-β ligand:receptor interactions. EMBO J.22, 1555–1566.10.1093/emboj/cdg156Search in Google Scholar PubMed PubMed Central

Turgeman, G., Zilberman, Y., Zhou, S., Kelly, P., Moutsatsos, I. K., Kharode, Y. P., Borella, L. E., Bex, F. J., Komm, B. S., Bodine, P. V., and Gazit, D. (2002). Systemically administered rhBMP-2 promotes MSC activity and reverses bone and cartilage loss in osteopenic mice. J. Cell Biochem.86, 461–474.10.1002/jcb.10231Search in Google Scholar PubMed

Warren, S. M., Brunet, L. J., Harland, R. M., Economides, A. N., and Longaker, M. T. (2003). The BMP antagonist noggin regulates cranial suture fusion. Nature422, 625–629.10.1038/nature01545Search in Google Scholar PubMed

Weis Garcia, F., and Massague, J. (1996). Complementation between kinase-defective and activation-defective TGF-β receptors reveals a novel form of receptor cooperativity essential for signaling. EMBO J.15, 276–289.10.1002/j.1460-2075.1996.tb00358.xSearch in Google Scholar

Wells, J. A., Cunningham, B. C., Fuh, G., Lowman, H. B., Bass, S. H., Mulkerrin, M. G., Ultsch, M., and deVos, A. M. (1993). The molecular basis for growth hormone-receptor interactions. Recent Prog. Horm. Res.48, 253–275.10.1016/B978-0-12-571148-7.50013-0Search in Google Scholar

Wiater, E., and Vale, W. (2003). Inhibin is an antagonist of bone morphogenetic protein signaling. J. Biol. Chem.278, 7934–7941.10.1074/jbc.M209710200Search in Google Scholar PubMed

Wieser, R., Wrana, J. L., and Massague, J. (1995). GS domain mutations that constitutively activate T β R-I, the downstream signaling component in the TGF-β receptor complex. EMBO J.14, 2199–2208.10.1002/j.1460-2075.1995.tb07214.xSearch in Google Scholar PubMed PubMed Central

Winkler, D. G., Sutherland, M. K., Geoghegan, J. C., Yu, C., Hayes, T., Skonier, J. E., Shpektor, D., Jonas, M., Kovacevich, B. R., Staehling-Hampton, K. et al. (2003). Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J.22, 6267–6276.10.1093/emboj/cdg599Search in Google Scholar PubMed PubMed Central

Woodcock, J. M., Bagley, C. J., Zacharakis, B., and Lopez, A. F. (1996). A single tyrosine residue in the membrane-proximal domain of the granulocyte-macrophage colony-stimulating factor, interleukin (IL)-3, and IL-5 receptor common β-chain is necessary and sufficient for high affinity binding and signaling by all three ligands. J. Biol. Chem.271, 25999–26006.10.1074/jbc.271.42.25999Search in Google Scholar PubMed

Wrana, J. L., Attisano, L., Wieser, R., Ventura, F., and Massague, J. (1994). Mechanism of activation of the TGF-β receptor. Nature370, 341–347.10.1038/370341a0Search in Google Scholar PubMed

Wu, X. B., Li, Y., Schneider, A., Yu, W., Rajendren, G., Iqbal, J., Yamamoto, M., Alam, M., Brunet, L. J., Blair, H. C. et al. (2003). Impaired osteoblastic differentiation, reduced bone formation, and severe osteoporosis in noggin-overexpressing mice. J. Clin. Invest.112, 924–934.10.1172/JCI15543Search in Google Scholar PubMed PubMed Central

Wuytens, G., Verschueren, K., de Winter, J. P., Gajendran, N., Beek, L., Devos, K., Bosman, F., de Waele, P., Andries, M., van den Eijnden van Raaij, A. J. et al. (1999). Identification of two amino acids in activin A that are important for biological activity and binding to the activin type II receptors. J. Biol. Chem.274, 9821–9827.10.1074/jbc.274.14.9821Search in Google Scholar PubMed

Xiong, J. P., Stehle, T., Zhang, R., Joachimiak, A., Frech, M., Goodman, S. L., and Arnaout, M. A. (2002). Crystal structure of the extracellular segment of integrin αVβ3 in complex with an Arg-Gly-Asp ligand. Science296, 151–155.10.1126/science.1069040Search in Google Scholar

Yamaguchi, K., Shirakabe, K., Shibuya, H., Irie, K., Oishi, I., Ueno, N., Taniguchi, T., Nishida, E., and Matsumoto, K. (1995). Identification of a member of the MAPKKK family as a potential mediator of TGF-β signal transduction. Science270, 2008–2011.10.1126/science.270.5244.2008Search in Google Scholar

Yi, S. E., Daluiski, A., Pederson, R., Rosen, V., and Lyons, K. M. (2000). The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb. Development127, 621–630.10.1242/dev.127.3.621Search in Google Scholar

Yoshimura, Y., Nomura, S., Kawasaki, S., Tsutsumimoto, T., Shimizu, T., and Takaoka, K. (2001). Colocalization of noggin and bone morphogenetic protein-4 during fracture healing. J. Bone Miner. Res. 16, 876–884.10.1359/jbmr.2001.16.5.876Search in Google Scholar

Yu, M., Wu, P., Widelitz, R. B., and Chuong, C. M. (2002). The morphogenesis of feathers. Nature420, 308–312.10.1038/nature01196Search in Google Scholar

Zhu, H., Kavsak, P., Abdollah, S., Wrana, J. L., and Thomsen, G. H. (1999). A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature400, 687–693.10.1038/23293Search in Google Scholar

Zimmerman, L. B., De Jesus Escobar, J. M., and Harland, R. M. (1996). The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell86, 599–606.10.1016/S0092-8674(00)80133-6Search in Google Scholar

Zimmers, T. A., Davies, M. V., Koniaris, L. G., Haynes, P., Esquela, A. F., Tomkinson, K. N., McPherron, A. C., Wolfman, N. M., and Lee, S. J. (2002). Induction of cachexia in mice by systemically administered myostatin. Science296, 1486–1488.10.1126/science.1069525Search in Google Scholar PubMed

Published Online: 2005-06-01
Published in Print: 2004-08-01

© Walter de Gruyter

Downloaded on 25.4.2024 from https://www.degruyter.com/document/doi/10.1515/BC.2004.086/html
Scroll to top button