Introduction to the ADAM Family

  • Judith White
  • Lance Bridges
  • Douglas DeSimone
  • Monika Tomczuk
  • Tyra Wolfsberg
Part of the Proteases in Biology and Disease book series (PBAD, volume 4)


ADAMs (proteins containing A Disintegrin and A Metalloprotease domain) are multidomain and multifunctional proteins that are emerging as key regulators of critical events that occur at the cell surface. Many ADAMs (roughly half) are active metalloproteases, and several of these (e.g. ADAMs 10, 17, and 19) exert important functions in vivo, for example in development of the heart and brain. The best-characterized in vivo activity of ADAM proteases is as ectodomain sheddases. By shedding cell surface proteins (e.g. cytokines and growth factors), ADAMs initiate extracellular signaling events (e.g. signaling through epidermal growth factor receptors). ADAM-mediated ectodomain shedding (e.g. of Notch) can also set the stage for important intracellular signaling events. ADAMs have also been reported to shed surface proteins involved in both cell-cell and cell-matrix adhesion. The disintegrin and cysteine-rich domains of ADAMs exhibit adhesive activities in tissue culture-based studies. The important roles that several proteolytically inactive ADAMs play in development (ADAMs 2, 3, 14, and 23) suggest that ADAM adhesive activities may be relevant to their function. In this chapter, we first review the history and phylogeny of the ADAMs as well as structural and functional aspects of their major domains. We next review how ADAMs function as ectodomain sheddases, how their protease activities may be regulated, and how ADAMs may function in modulating cell adhesion and cell migration. We end with a very brief discussion of the role of ADAMs in development and disease and conclude by posing some questions for future research. Our goal is to give an appreciation for the widespread, varied, and fascinating means by which ADAMs affect, or may affect, key cell surface events: cell signaling, cell adhesion, and cell migration.

Key words

Disintegrin metalloprotease sheddase signaling cell adhesion 


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  1. Abel, S., Hundhausen, C., Mentlein, R., Schulte, A., Berkhout, T. A., Broadway, N., Hartmann, D., Sedlacek, R., Dietrich, S., Muetze, B., Schuster, B., Kallen, K. J., Saftig, P., Rose-John, S., and Ludwig, A. (2004). The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like d metalloproteinase ADAM10. J Immunol 172, 6362–72.PubMedGoogle Scholar
  2. Alfandari, D., Cousin, H., Gaultier, A., Smith, K., White, J. M., Darribere, T., and DeSimone, D. W. (2001). Xenopus ADAM 13 is a metalloprotease required for cranial neural crest-cell migration. Curr Biol 11, 918–30.PubMedCrossRefGoogle Scholar
  3. Allinson, T. M., Parkin, E. T., Turner, A. J., and Hooper, N. M. (2003). ADAMs family members as amyloid precursor protein alpha-secretases. J Neurosci Res 74, 342–52.PubMedCrossRefGoogle Scholar
  4. Anders, A., Gilbert, S., Garten, W., Postina, R., and Fahrenholz, F. (2001). Regulation of the alpha-secretase ADAM10 by its prodomain and proprotein convertases. Faseb J 15, 1837–9.PubMedGoogle Scholar
  5. Apte, S. S. (2004). A disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motifs: the ADAMTS family. Int J Biochem Cell Biol 36, 981–5.PubMedCrossRefGoogle Scholar
  6. Argast, G. M., Campbell, J. S., Brooling, J. T., and Fausto, N. (2004). Epidermal growth factor receptor transactivation mediates tumor necrosis factor-induced hepatocyte replication. J Biol Chem 279, 34530–6.PubMedCrossRefGoogle Scholar
  7. Asakura, M., Kitakaze, M., Takashima, S., Liao, Y., Ishikura, F., Yoshinaka, T., Ohmoto, H., Node, K., Yoshino, K., Ishiguro, H., Asanuma, H., Sanada, S., Matsumura, Y., Takeda, H., Beppu, S., Tada, M., Hori, M., and Higashiyama, S. (2002). Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy. Nat. Med. 8, 35–40.PubMedCrossRefGoogle Scholar
  8. Baker, A. H., Edwards, D. R., and Murphy, G. (2002). Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci 115, 3719–27.PubMedCrossRefGoogle Scholar
  9. Bao, J., Wolpowitz, D., Role, L. W., and Talmage, D. A. (2003). Back signaling by the Nrg-1 intracellular domain. J Cell Biol 161, 1133–41.PubMedCrossRefGoogle Scholar
  10. Bax, D. V., Messent, A. J., Tart, J., Van Hoang, M., Kott, J., Maciewicz, R. A., and Humphries, M. J. (2004). Integrin {alpha}5{beta}1 and ADAM-17 Interact in Vitro and Co-localize in Migrating HeLa Cells. J Biol Chem 279, 22377–22386.PubMedCrossRefGoogle Scholar
  11. Becherer, J. D., and Blobel, C. P. (2003). Biochemical properties and functions of membrane-anchored metalloprotease-disintegrin proteins (ADAMs). Curr Top Dev Biol 54, 101–23.PubMedGoogle Scholar
  12. Black, R. A., Doedens, J. R., Mahimkar, R., Johnson, R., Guo, L., Wallace, A., Virca, D., Eisenman, J., Slack, J., Castner, B., Sunnarborg, S. W., Lee, D. C., Cowling, R., Jin, G., Charrier, K., Peschon, J. J., and Paxton, R. (2003). Substrate specificity and inducibility of TACE (tumour necrosis factor alpha-converting enzyme) revisited: the Ala-Val preference, and induced intrinsic activity. Biochem Soc Symp 70, 39–52.PubMedGoogle Scholar
  13. Black, R. A., Rauch, C. T., Kozlosky, C. J., Peschon, J. J., Slack, J. L., Wolfson, M. F., Castner, B. J., Stocking, K. L., Reddy, P., Srinivasan, S., Nelson, N., Boiani, N., Schooley, K. A., Gerhart, M., Davis, R., Fitzner, J. N., Johnson, R. S., Paxton, R. J., March, C. J., and Cerretti, D. P. (1997). A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385, 729–733.PubMedCrossRefGoogle Scholar
  14. Bland, C. E., Kimberly, P., and Rand, M. D. (2003). Notch-induced proteolysis and nuclear localization of the Delta ligand. J Biol Chem 278, 13607–10.PubMedCrossRefGoogle Scholar
  15. Blobel, C. P., Wolfsberg, T. G., Turck, C. W., Myles, D. G., Primakoff, P., and White, J. M. (1992). A potential fusion peptide and an integrin ligand domain in a protein active in sperm-egg fusion. Nature 356, 248–252.PubMedCrossRefGoogle Scholar
  16. Bridges, L. C., and Bowditch, R. D. (2004). ADAM-Integrin interactions; Potential integrin regulated ectodomain shedding activity. Current Pharmaceutical Design, in press.Google Scholar
  17. Bridges, L. C., Sheppard, D. and Bowditch, R. D. (2004). ADAM disintegrin-like domain recognition by the lymphocyte integrins alpha4beta1 and alpha4beta7. Biochem J, in press.Google Scholar
  18. Bridges, L. C., Hanson, K. R., Tani, P. H., Mather, T., and Bowditch, R. D. (2003). Integrin alpha4beta1-dependent adhesion to ADAM 28 (MDC-L) requires an extended surface of the disintegrin domain. Biochemistry 42, 3734–41.PubMedCrossRefGoogle Scholar
  19. Cao, Y., Kang, Q., and Zolkiewska, A. (2001). Metalloprotease-disintegrin ADAM 12 interacts with alpha-actinin-1. Biochem. J. 357, 353–361.PubMedCrossRefGoogle Scholar
  20. Cho, C., Bunch, D. O., Faure, J. E., Goulding, E. H., Eddy, E. M., Primakoff, P., and Myles, D. G. (1998). Fertilization defects in sperm from mice lacking fertilin beta. Science 281, 1857–9.PubMedCrossRefGoogle Scholar
  21. Costa, F. F., Verbisck, N. V., Salim, A. C., Ierardi, D. F., Pires, L. C., Sasahara, R. M., Sogayar, M. C., Zanata, S. M., Mackay, A., O’Hare, M., Soares, F., Simpson, A. J., and Camargo, A. A. (2004). Epigenetic silencing of the adhesion molecule ADAM23 is highly frequent in breast tumors. Oncogene 23, 1481–8.PubMedCrossRefGoogle Scholar
  22. Cousin, H., Gaultier, A., Bleux, C., Darribere, T., and Alfandari, D. (2000). PACSIN2 is a regulator of the metalloprotease/disintegrin ADAM13. Dev Biol 227, 197–210.PubMedCrossRefGoogle Scholar
  23. Diaz-Rodriguez, E., Montero, J. C., Esparis-Ogando, A., Yuste, L., and Pandiella, A. (2002). Extracellular signal-regulated Kinase phosphorylates tumor necrosis factor alphaconverting enzyme at threonine 735: a potential role in regulated shedding. Mol Biol Cell 13, 2031–44.PubMedCrossRefGoogle Scholar
  24. Doedens, J. R., Mahimkar, R. M., and Black, R. A. (2003). TACE/ADAM-17 enzymatic activity is increased in response to cellular stimulation. Biochem Biophys Res Commun 308, 331–8.PubMedCrossRefGoogle Scholar
  25. Eble, J. A., Bruckner, P., and Mayer, U. (2003). Vipera lebetina venom contains two disintegrins inhibiting laminin-binding beta1 integrins. J Biol Chem 278, 26488–96.PubMedCrossRefGoogle Scholar
  26. Eto, K., Huet, C., Tarui, T., Kupriyanov, S., Liu, H. Z., Puzon-McLaughlin, W., Zhang, X. P., Sheppard, D., Engvall, E., and Takada, Y. (2002). Functional classification of ADAMs based on a conserved motif for binding to integrin alpha 9beta 1: implications for sperm-egg binding and other cell interactions. J Biol Chem 277, 17804–17810.PubMedCrossRefGoogle Scholar
  27. Eto, K., Puzon-McLaughlin, W., Sheppard, D., Sehara-Fujisawa, A., Zhang, X.-P., and Takada, Y. (2000). RGD-independent binding of integrin a9b1 to the ADAM 12 and-15 disintegrin domains mediates cell-cell interaction. J Biol Chem 275, 34922–34930.PubMedCrossRefGoogle Scholar
  28. Fahrenholz, F., Gilbert, S., Kojro, E., Lammich, S., and Postina, R. (2000). Alpha-secretase activity of the disintegrin metalloprotease ADAM 10. Influences of domain structure. Ann N Y Acad Sci 920, 215–22.PubMedCrossRefGoogle Scholar
  29. Fambrough, D., Pan, D., Rubin, G. M., and Goodman, C. S. (1996). The cell surface metalloprotease/disintegrin Kuzbanian is required for axonal extension in Drosophila Proc Nat’l Acad Sci USA 93, 13233–13238.CrossRefGoogle Scholar
  30. Fan, H., Turck, C. W., and Derynck, R. (2003). Characterization of growth factor-induced serine phosphorylation of tumor necrosis factor-alpha converting enzyme and of an alternatively translated polypeptide. J Biol Chem 278, 18617–18627.PubMedCrossRefGoogle Scholar
  31. Franzke, C. W., Tasanen, K., Borradori, L., Huotari, V., and Bruckner-Tuderman, L. (2004). Shedding of collagen XVII/BP180: structural motifs influence cleavage from cell surface. J Biol Chem 279, 24521–9.PubMedCrossRefGoogle Scholar
  32. Galliano, M. F., Huet, C., Frygelius, J., Polgren, A., Wewer, U. M., and Engvall, E. (2000). Binding of ADAM12, a marker of skeletal muscle regeneration, to the muscle-specific actin-binding protein, alpha-actinin-2, is required for myoblast fusion. J. Biol. Chem. 275, 13933–13939.PubMedCrossRefGoogle Scholar
  33. Gaultier, A., Cousin, H., Darribere, T., and Alfandari, D. (2002). ADAM13 disintegrin and cysteine-rich domains bind to the second heparin-binding domain of fibronectin. J Biol Chem 277, 23336–44.PubMedCrossRefGoogle Scholar
  34. Gonzales, P. E., Solomon, A., Miller, A. B., Leesnitzer, M. A., Sagi, I., and Milla, M. E. (2004). Inhibition of the tumor necrosis factor-alpha-converting enzyme by its pro domain. J Biol Chem 279, 31638–45.PubMedCrossRefGoogle Scholar
  35. Hartmann, D., de Strooper, B., Serneels, L., Craessaerts, K., Herreman, A., Annaert, W., Umans, L., Lubke, T., Lena Illert, A., von Figura, K., and Saftig, P. (2002). The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts. Hum Mol Genet 11, 2615–24.PubMedCrossRefGoogle Scholar
  36. Hattori, M., Osterfield, M., and Flanagan, J. G. (2000). Regulated cleavage of a contact-mediated axon repellent. Science 289, 1360–1365.PubMedCrossRefGoogle Scholar
  37. Herren, B., Garton, K. J., Coats, S., Bowen-Pope, D. F., Ross, R., and Raines, E. W. (2001). ADAM15 overexpression in NIH3T3 cells enhances cell-cell interactions. Exp Cell Res 271, 152–60.PubMedCrossRefGoogle Scholar
  38. Hinkle, C. L., Mohan, M. J., Lin, P., Yeung, N., Rasmussen, F., Milla, M. E., and Moss, M. L. (2003). Multiple metalloproteinases process protransforming growth factor-alpha (proTGF-alpha). Biochemistry 42, 2127–36.PubMedCrossRefGoogle Scholar
  39. Holen, I., Drury, N. L., Hargreaves, P. G., and Croucher, P. I. (2001). Evidence of a role for a non-matrix-type metalloproteinase activity in the shedding of syndecan-1 from human myeloma cells. Br J Haematol 114, 414–21.PubMedCrossRefGoogle Scholar
  40. Hougaard, S., Loechel, F., Xu, X., Tajima, R., Albrechtsen, R., and Wewer, U. M. (2000). Trafficking of human ADAM 12-L: retention in the trans-Golgi network. Biochem Biophys Res Commun 275, 261–267.PubMedCrossRefGoogle Scholar
  41. Howard, L., Maciewicz, R. A., and Blobel, C. P. (2000). Cloning and characterization of ADAM28: evidence for autocatalytic pro-domain removal and for cell surface localization of mature ADAM28. Biochem J 348, 21–27.PubMedCrossRefGoogle Scholar
  42. Huang, X., Huang, P., Robinson, M. K., Stern, M. J., and Jin, Y. (2003). UNC-71, a disintegrin and metalloprotease (ADAM) protein, regulates motor axon guidance and sex myoblast migration in C. elegans. Development 130, 3147–61.PubMedCrossRefGoogle Scholar
  43. Hundhausen, C., Misztela, D., Berkhout, T. A., Broadway, N., Saftig, P., Reiss, K., Hartmann, D., Fahrenholz, F., Postina, R., Matthews, V., Kallen, K. J., Rose-John, S., and Ludwig, A. (2003). The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion. Blood 102, 1186–95.PubMedCrossRefGoogle Scholar
  44. Kaji, K., and Kudo, A. (2004). The mechanism of sperm-oocyte fusion in mammals. Reproduction 127, 423–9.PubMedCrossRefGoogle Scholar
  45. Kajita, M., Itoh, Y., Chiba, T., Mori, H., Okada, A., Kinoh, H., and Seiki, M. (2001). Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration. J Cell Biol 153, 893–904.PubMedCrossRefGoogle Scholar
  46. Kawaguchi, N., Sundberg, C., Kveiborg, M., Moghadaszadeh, B., Asmar, M., Dietrich, N., Thodeti, C. K., Nielsen, F. C., Moller, P., Mercurio, A. M., Albrechtsen, R., and Wewer, U. M. (2003). ADAM12 induces actin cytoskeleton and extracellular matrix reorganization during early adipocyte differentiation by regulating ta1 integrin function. J Cell Sci 116, 3893–3904.PubMedCrossRefGoogle Scholar
  47. Kojro, E., Gimpl, G., Lammich, S., Marz, W., and Fahrenholz, F. (2001). Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha-secretase ADAM 10. Proc Natl Acad Sci U S A 98, 5815–20.PubMedCrossRefGoogle Scholar
  48. LaVoie, M. J., and Selkoe, D. J. (2003). The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments. J Biol Chem 278, 34427–37.PubMedCrossRefGoogle Scholar
  49. Lee, M. H., Dodds, P., Verma, V., Maskos, K., Knauper, V., and Murphy, G. (2003). Tailoring tissue inhibitor of metalloproteinases-3 to overcome the weakening effects of the cysteine-rich domains of tumour necrosis factor-alpha converting enzyme. Biochem J 371, 369–76.PubMedCrossRefGoogle Scholar
  50. Lemjabbar, H., and Basbaum, C. (2002). Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells. Nat Med 8, 41–6.PubMedCrossRefGoogle Scholar
  51. Lemjabbar, H., Li, D., Gallup, M., Sidhu, S., Drori, E., and Basbaum, C. (2003). Tobacco smoke-induced lung cell proliferation mediated by tumor necrosis factor alpha-converting d enzyme and amphiregulin. J Biol Chem 278, 26202–7.PubMedCrossRefGoogle Scholar
  52. Lind, D. L., Choudhry, S., Ung, N., Ziv, E., Avila, P. C., Salari, K., Coyle, N. E., Nazario, S., Rodriguez-Santana, J. R., Salas, J., Selman, M., Boushey, H. A., Weiss, S. T., Chapela, R., Ford, J. G., Rodriguez-Cintron, W., Silverman, E. K., Sheppard, D., Kwok, P. Y., and Burchard, E. G. (2003). ADAM33 is not associated with asthma in puerto rican or mexican populations. Am J Respir Crit Care Med 168, 1312–6PubMedCrossRefGoogle Scholar
  53. Marambaud, P., Wen, P. H., Dutt, A., Shioi, J., Takashima, A., Siman, R., and Robakis, N. K. (2003). A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 114, 635–45.PubMedCrossRefGoogle Scholar
  54. Marcinkiewicz, C. (2004). Functional characteristic of snake venom disintegrins: Potential therapeutic implication. Curr Pharm Design, in press.Google Scholar
  55. Martin, J., Eynstone, L. V., Davies, M., Williams, J. D., and Steadman, R. (2002). The role of ADAM 15 in glomerular mesangial cell migration. J Biol Chem 277, 33683–33689.PubMedCrossRefGoogle Scholar
  56. Maskos, K., Fernandez-Catalan, C., Huber, R., Bourenkov, G. P., Bartunik, H., Ellestad, G. A., Reddy, P., Wolfson, M. F., Rauch, C. T., Castner, B. J., Davis, R., Clarke, H. R. G., Peterson, M., Fitzner, J. N., Cerretti, D. P., March, C. J., Paxton, R. J., Black, R. A., and Bode, W. (1998). Crystal structure of the catalytic domain of human tumor necrosis factor a-converting enzyme. Proc Nat’l Acad Sci USA 95, 3408–3412.CrossRefGoogle Scholar
  57. Matsui, T., Fujimura, Y., and Titani, K. (2000). Snake venom proteases affecting hemostasis and thrombosis. Biochim Biophys Acta 1477, 146–56.PubMedGoogle Scholar
  58. Matthews, V., Schuster, B., Schutze, S., Bussmeyer, I., Ludwig, A., Hundhausen, C., Sadowski, T., Saftig, P., Hartmann, D., Kallen, K. J., and Rose-John, S. (2003). Cellular cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (TACE). J Biol Chem 278, 38829–39.PubMedCrossRefGoogle Scholar
  59. Mechtersheimer, S., Gutwein, P., Agmon-Levin, N., Stoeck, A., Oleszewski, M., Riedle, S., Fogel, M., Lemmon, V., and Altevogt, P. (2001). Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins. J Cell Biol 155, 661–73.PubMedCrossRefGoogle Scholar
  60. Mohammed, F. F., Smookler, D. S., Taylor, S. E., Fingleton, B., Kassiri, Z., Sanchez, O. H., English, J. L., Matrisian, L. M., Au, B., Yeh, W. C., and Khokha, R. (2004). Abnormal TNF activity in Timp3(-/-) mice leads to chronic hepatic inflammation and failure of liver regeneration. Nat Genet 36, 969–77.PubMedCrossRefGoogle Scholar
  61. Mori, S., Tanaka, M., Nanba, D., Nishiwaki, E., Ishiguro, H., Higashiyama, S., and Matsuura, N. (2003). PACSIN3 binds ADAM12/meltrin alpha and upregulates ectodomain shedding of heparin-binding EGF-like growth factor. J Biol Chem 278, 46029–34PubMedCrossRefGoogle Scholar
  62. Moss, M. L., and Bartsch, J. W. (2004). Therapeutic benefits from targeting of ADAM family members. Biochemistry 43, 7227–35.PubMedCrossRefGoogle Scholar
  63. Moss, M. L., Jin, S. L., Milla, M. E., Burkhart, W., Carter, H. L., Chen, W. J., Clay, W. C., Didsbury, J. R., Hassler, D., Hoffman, C. R., Kost, T. A., Lambert, M. H., Leesnitzer, M. A., McCauley, P., McGeehan, G., Mitchell, J., Moyer, M., Pahel, G., Rocque, W., Overton, L. K., Schoenen, F., Seaton, T., Su, J. L., Warner, J., Becherer, J. D., and et, a. (1997). Cloning of a disintegrin metalloproteinase that processes precursor tumournecrosis factor-alpha. Nature 385, 733–736.PubMedCrossRefGoogle Scholar
  64. Murai, T., Miyazaki, Y., Nishinakamura, H., Sugahara, K. N., Miyauchi, T., Sako, Y., Yanagida, T., and Miyasaka, M. (2004). Engagement of CD44 promotes Rac activation and CD44 cleavage during tumor cell migration. J Biol Chem 279, 4541–50PubMedCrossRefGoogle Scholar
  65. Murakami, D., Okamoto, I., Nagano, O., Kawano, Y., Tomita, T., Iwatsubo, T., De Strooper, B., Yumoto, E., and Saya, H. (2003). Presenilin-dependent gamma-secretase activity mediates the intramembranous cleavage of CD44. Oncogene 22, 1511–6.PubMedCrossRefGoogle Scholar
  66. Nagano, O., Murakami, D., Hartmann, D., De Strooper, B., Saftig, P., Iwatsubo, T., Nakajima, M., Shinohara, M., and Saya, H. (2004). Cell-matrix interaction via CD44 is independently regulated by different metalloproteinases activated in response to extracellular Ca2+ influx and PKC activation. J Cell Biol 165, 893–902.PubMedCrossRefGoogle Scholar
  67. Nakamura, H., Suenaga, N., Taniwaki, K., Matsuki, H., Yonezawa, K., Fujii, M., Okada, Y., and Seiki, M. (2004a). Constitutive and induced CD44 shedding by ADAM-like proteases and membrane-type 1 matrix metalloproteinase. Cancer Res 64, 876–82.PubMedCrossRefGoogle Scholar
  68. Nakamura, T., Abe, H., Hirata, A., and Shimoda, C. (2004b). ADAM family protein Mde10 is essential for development of spore envelopes in the fission yeast Schizosaccharomyces pombe. Eukaryot Cell 3, 27–39.PubMedCrossRefGoogle Scholar
  69. Nanba, D., Mammoto, A., Hashimoto, K., and Higashiyama, S. (2003). Proteolytic release of the carboxy-terminal fragment of proHB-EGF causes nuclear export of PLZF. J Cell Biol 163, 489–502.PubMedCrossRefGoogle Scholar
  70. Ni, C. Y., Murphy, M. P., Golde, T. E., and Carpenter, G. (2001). gamma-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 294, 2179–81.PubMedCrossRefGoogle Scholar
  71. Novak, U. (2004). ADAM proteins in the brain. J Clin Neurosci 11, 227–35.PubMedCrossRefGoogle Scholar
  72. Orth, P., Reichert, P., Wang, W., Prosise, W. W., Yarosh-Tomaine, T., Hammond, G., Ingram, R. N., Xiao, L., Mirza, U. A., Zou, J., Strickland, C., Taremi, S. S., Le, H. V., and Madison, V. (2004). Crystal structure of the catalytic domain of human ADAM33. J Mol Biol 335, 129–37.PubMedCrossRefGoogle Scholar
  73. Overall, C. M. (2002). Molecular determinants of metalloproteinase substrate specificity: matrix metalloproteinase substrate binding domains, modules, and exosites. Mol Biotechnol 22, 51–86.PubMedCrossRefGoogle Scholar
  74. Palecek, S. P., Loftus, J. C., Ginsberg, M. H., Lauffenburger, D. A., and Horwitz, A. F. (1997). Integrin-ligand binding properties govern cell migration speed through cell-substratum adhesiveness. Nature 385, 537–40.PubMedCrossRefGoogle Scholar
  75. Pan, D., and Rubin, G. M. (1997). Kuzbanian controls proteolytic processing of notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis. Cell 90, 271–280.PubMedCrossRefGoogle Scholar
  76. Peiretti, F., Deprez-Beauclair, P., Bonardo, B., Aubert, H., Juhan-Vague, I., and Nalbone, G. (2003). Identification of SAP97 as an intracellular binding partner of TACE. J Cell Sci 116, 1949–57.PubMedCrossRefGoogle Scholar
  77. Peschon, J. J., Slack, J. L., Reddy, P., Stocking, K. L., Sunnarborg, B. J., Lee, D. C., Russell, W. E., Castner, B. J., Johnson, R. S., Fitzner, J. N., Boyce, R. W., Nelson, N., Kozlsky, C. J., Wolfson, M. F., Rauch, C. T., Cerretti, D. P., Paxton, R. J., March, C. J., and Black, R. A. (1998). An essential role for ectodomain shedding in mammalian development. Science 282, 1281–1284.PubMedCrossRefGoogle Scholar
  78. Poghosyan, Z., Robbins, S. M., Houslay, M. D., Webster, A., Murphy, G., and Edwards, D. R. (2002). Phosphorylation-dependent interactions between ADAM15 cytoplasmic domain and Src family protein-tyrosine kinases. J Biol Chem 277, 4999–5007.PubMedCrossRefGoogle Scholar
  79. Postina, R., Schroeder, A., Dewachter, I., Bohl, J., Schmitt, U., Kojro, E., Prinzen, C., Endres, K., Hiemke, C., Blessing, M., Flamez, P., Dequenne, A., Godaux, E., van Leuven, F., and Fahrenholz, F. (2004). A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest 113, 1456–64.PubMedCrossRefGoogle Scholar
  80. Prenzel, N., Zwick, E., Daub, H., Leserer, M., Abraham, R., Wallasch, C., and Ullrich, A. (1999). EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402, 884–888.PubMedGoogle Scholar
  81. Primakoff, P., Hyatt, H., and Tredick-Kline, J. (1987). Identification and purification of a sperm surface protein with a potential role in sperm-egg membrane fusion. J Cell Biol 104, 141–149.PubMedCrossRefGoogle Scholar
  82. Reddy, P., Slack, J. L., Davis, R., Cerretti, D. P., Kozlosky, C. J., Blanton, R. A., Shows, D., Peschon, J. J., and Black, R. A. (2000). Functional analysis of the domain structure of tumor necrosis factor-alpha converting enzyme. J Biol Chem 275, 14608–14.PubMedCrossRefGoogle Scholar
  83. Rooke, J., Pan, D., Xu, T., and Rubin, G. M. (1996). KUZ, a conserved metalloprotease-disintegrin protein with two roles in Drosophila neurogenesis. Science 273, 1227–31.PubMedGoogle Scholar
  84. Sahin, U., Weskamp, G., Kelly, K., Zhou, H. M., Higashiyama, S., Peschon, J., Hartmann, D., Saftig, P., and Blobel, C. P. (2004). Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands. J Cell Biol 164, 769–79.PubMedCrossRefGoogle Scholar
  85. Schafer, B., Gschwind, A., and Ullrich, A. (2004a). Multiple G-protein-coupled receptor signals converge on the epidermal growth factor receptor to promote migration and invasion. Oncogene 23, 991–9.PubMedCrossRefGoogle Scholar
  86. Schafer, B., Marg, B., Gschwind, A., and Ullrich, A. (2004b). Distinct ADAM metalloproteinases regulate G protein coupled receptor-induced cell proliferation and survival. J Biol Chem, in pressGoogle Scholar
  87. Schlomann, U., Rathke-Hartlieb, S., Yamamoto, S., Jockusch, H., and Bartsch, J. W. (2000). Tumor necrosis factor alpha induces a metalloprotease-disintegrin, ADAM8 (CD 156): implications for neuron-glia interactions during neurodegeneration. J Neurosci 20, 7964–7971.PubMedGoogle Scholar
  88. Schlomann, U., Wildeboer, D., Webster, A., Antropova, O., Zeuschner, D., Knight, C. G., Docherty, A. J., Lambert, M., Skelton, L., Jockusch, H., and Bartsch, J. W. (2002). The metalloprotease disintegrin ADAM8. Processing by autocatalysis is required for proteolytic activity and cell adhesion. J Biol Chem 277, 48210–9.PubMedCrossRefGoogle Scholar
  89. Seals, D. F., and Courtneidge, S. A. (2003). The ADAMs family of metalloproteases: multidomain proteins with multiple functions. Genes Dev 17, 7–30.PubMedCrossRefGoogle Scholar
  90. Shao, M. X., Nakanaga, T., and Nadel, J. A. (2004). Cigarette smoke induces MUC5AC mucin overproduction via tumor necrosis factor-alpha-converting enzyme in human f airway epithelial (NCI-H292) cells. Am J Physiol Lung Cell Mol Physiol 287, L420–7.PubMedCrossRefGoogle Scholar
  91. Six, E., Ndiaye, D., Laabi, Y., Brou, C., Gupta-Rossi, N., Israel, A., and Logeat, F. (2003). The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and gammasecretase. Proc Natl Acad Sci U S A 100, 7638–43.PubMedCrossRefGoogle Scholar
  92. Smith, K. M., Gaultier, A., Cousin, H., Alfandari, D., White, J. M., and DeSimone, D. (2002). The cysteine-rich domain regulates ADAM protease function in vivo. J Cell Biol 159, 893–902.PubMedCrossRefGoogle Scholar
  93. Soejima, K., Matsumoto, M., Kokame, K., Yagi, H., Ishizashi, H., Maeda, H., Nozaki, C., Miyata, T., Fujimura, Y., and Nakagaki, T. (2003). ADAMTS-13 cysteine-rich/spacer domains are functionally essential for von Willebrand factor cleavage. Blood 102, 3232–7.PubMedCrossRefGoogle Scholar
  94. Solomon, A., Rosenblum, G., Gonzales, P. E., Leonard, J. D., Mobashery, S., Milla, M. E., and Sagi, I. (2004). Pronounced diversity in electronic and chemical properties between the catalytic zinc sites of tumor necrosis factor-alpha-converting enzyme and matrix metalloproteinases despite their high structural similarity. J Biol Chem 279, 31646–54.PubMedCrossRefGoogle Scholar
  95. Somerville, R. P., Longpre, J. M., Jungers, K. A., Engle, J. M., Ross, M., Evanko, S., Wight, T. N., Leduc, R., and Apte, S. S. (2003). Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1. J Biol Chem 278, 9503–13.PubMedCrossRefGoogle Scholar
  96. Tanaka, M., Nanba, D., Mori, S., Shiba, F., Ishiguro, H., Yoshino, K., Matsuura, N., and Higashiyama, S. (2004). ADAM-binding protein eve-1 is required for ectodomain shedding of EGF receptor ligands. J Biol Chem, in pressGoogle Scholar
  97. Thodeti, C. K., Albrechtsen, R., Grauslund, M., Asmar, M., Larsson, C., Takada, Y., Mercurio, A. M., Couchman, J. R., and Wewer, U. M. (2003). ADAM12/syndecan-4 signaling promotes beta 1 integrin-dependent cell spreading through protein kinase Calpha and RhoA. J Biol Chem 278, 9576–84.PubMedCrossRefGoogle Scholar
  98. Tomczuk, M., Takahashi, Y., Huang, J., Murase, S., Mistretta, M., Klaffky, E., Sutherland, A., Bolling, L., Coonrod, S., Marcinkiewicz, C., Sheppard, D., Stepp, M. A., and White, J. M. (2003). Role of multiple beta1 integrins in cell adhesion to the disintegrin domains of ADAMs 2 and 3. Exp Cell Res 290, 68–81.PubMedCrossRefGoogle Scholar
  99. Tomczuk, M. (2004) ADAMs in early mouse development. University of Virginia PhD thesis, pp.278.Google Scholar
  100. Tschumperlin, D. J., Dai, G., Maly, I. V., Kikuchi, T., Laiho, L. H., McVittie, A. K., Haley, K. J., Lilly, C. M., So, P. T., Lauffenburger, D. A., Kamm, R. D., and Drazen, J. M. (2004). Mechanotransduction through growth-factor shedding into the extracellular space. Nature 429, 83–86.PubMedCrossRefGoogle Scholar
  101. Van Eerdewegh, P., Little, R. D., Dupuis, J., Del Mastro, R. G., Falls, K., Simon, J., Torrey, D., Pandit, S., McKenny, J., Braunschweiger, K., Walsh, A., Liu, Z., Hayward, B., Folz, C., Manning, S. P., Bawa, A., Saracino, L., Thackston, M., Benchekroun, Y., Capparell, N., Wang, M., Adair, R., Feng, Y., Dubois, J., FitzGerald, M. G., Huang, H., Gibson, R., Allen, K. M., Pedan, A., Danzig, M. R., Umland, S. P., Egan, R. W., Cuss, F. M., Rorke, S., Clough, J. B., Holloway, J. W., Holgate, S. T., and Keith, T. P. (2002). Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 418, 426–430.PubMedCrossRefGoogle Scholar
  102. Varney, T. R., Casademunt, E., Ho, H. N., Petty, C., Dolman, J., and Blumberg, D. D. (2002). A novel Dictyostelium gene encoding multiple repeats of adhesion inhibitor-like domains has effects on cell-cell and cell-substrate adhesion. Dev Biol 243, 226–48.PubMedCrossRefGoogle Scholar
  103. Wakatsuki, S., Kurisaki, T., and Sehara-Fujisawa, A. (2004). Lipid rafts identified as locations of ectodomain shedding mediated by Meltrin beta/ADAM19. J Neurochem 89, 119–23.PubMedCrossRefGoogle Scholar
  104. White, J. M. (2003). ADAMs: modulators of cell-cell and cell-matrix interactions. Curr Opin Cell Biol 15, 598–606.PubMedCrossRefGoogle Scholar
  105. Wolfsberg, T. G., Bazan, J. J., Blobel, C. P., Myles, D. G., Primakoff, P., and White, J. M. (1993). The precursor region of a protein active in sperm-egg fusion contains a metalloprotease and a disintegrin domain: Structural, functional and evolutionary implications. Proc. Natl. Acad. Sci. USA 90, 10783–10787.PubMedCrossRefGoogle Scholar
  106. Wolfe, M. S., and Kopan, R. (2004). Intramembrane proteolysis: Theme and variations. Science 305, 1119–1123.PubMedCrossRefGoogle Scholar
  107. Wolfsberg, T. G., Straight, P. D., Gerena, R. L., Huovila, A.-P. J., Primakoff, P., Myles, D. G., and White, J. M. (1995). ADAM, a widely distributed and developmentally regulated gene family encoding membrane proteins with a disintegrin and metalloprotease domain. Dev. Biol. 169, 378–383.PubMedCrossRefGoogle Scholar
  108. Yagami-Hiromasa, T., Sato, T., Kurisaki, T., Kamijo, K., Nabeshima, Y., and Fujisawa-Sehara, A. (1995). A metalloprotease-disintegrin participating in myoblast fusion. Nature 377, 652–656.PubMedCrossRefGoogle Scholar
  109. Yan, Y., Shirakabe, K., and Werb, Z. (2002). The metalloprotease Kuzbanian (ADAM10) mediates the transactivation of EGF receptor by G protein-coupled receptors. J Cell Biol 158, 221–6.PubMedCrossRefGoogle Scholar
  110. Zhao, L., Shey, M., Farnsworth, M., and Dailey, M. O. (2001). Regulation of membrane metalloproteolytic cleavage of L-selectin (CD62l) by the epidermal growth factor domain. J Biol Chem 276, 30631–40.PubMedCrossRefGoogle Scholar
  111. Zheng, Y., Schlondorff, J., and Blobel, C. P. (2002). Evidence for regulation of the tumor necrosis factor alpha-convertase (TACE) by protein-tyrosine phosphatase PTPH1. J Biol Chem 277, 42463–70.PubMedCrossRefGoogle Scholar
  112. Zhu, P., Sun, Y., Xu, R., Sang, Y., Zhao, J., Liu, G., Cai, L., Li, C., and Zhao, S. (2003). The interaction between ADAM 22 and 14-3-3zeta: regulation of cell adhesion and spreading. Biochem Biophys Res Commun 301, 991–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Judith White
    • 1
  • Lance Bridges
    • 1
  • Douglas DeSimone
    • 1
  • Monika Tomczuk
    • 1
  • Tyra Wolfsberg
    • 2
  1. 1.Department of Cell BiologyUniversity of VirginiaUSA
  2. 2.NIHNational Human Genome Research InstituteUSA

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