Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

ADAMs: key components in EGFR signalling and development

Nature Reviews Molecular Cell Biology volume 6, pages 32–43 (2005)Cite this article

Key Points

  • ADAMs are a family of membrane-anchored glycoproteins that contain a metalloprotease and a disintegrin domain. They have been implicated in fertilization, heart development, angiogenesis, neurogenesis and cancer, and can function as post-translational regulators of other membrane proteins including growth factors such as transforming growth factor (TGF)α and heparin-bound epidermal growth factor (HB-EGF), cytokines such as tumour necrosis factor α (TNFα), and receptors such as Notch and TNF receptor-I.

  • About half of the currently known ADAMs have a catalytic-site consensus sequence (HEXXH), and many of these ADAMs have also been shown to possess catalytic activity. The remaining ADAMs lack a catalytic site in their otherwise conserved metalloprotease-like domain.

  • This review focuses on catalytically active ADAMs, which can function as molecular signalling switches by cleaving and releasing the ectodomain of other membrane proteins. This process, which is referred to as 'protein ectodomain shedding', might activate or inactivate the substrate protein, or dramatically change its functional properties.

  • The EGF-receptor ligands TGFα, HB-EGF and amphiregulin are excellent examples of membrane proteins that are regulated by ectodomain shedding. Biochemical and cell-biological studies, as well as the analysis of knockout mice, have uncovered a key role for ADAM17 (which is also referred to as TNFα-converting enzyme (TACE)) in activating these growth factors during mouse development and potentially also in diseases such as cancer.

  • The EGF receptor has an unusual mechanism of dimerizing compared with other tyrosine kinase receptors, which might explain why signalling through this receptor is particularly sensitive to proteolytic processing of its ligands.

  • ADAMs also have important roles in heart development, angiogenesis and pathological neovascularization. This raises questions about the role of shedding in regulating the function of membrane proteins that are involved in these processes, such as ErbB2, vascular endothelial growth factor receptor-2 (VEGFR2), TIE2, ephrinB2 or EphB2.

Abstract

ADAM (a disintegrin and metalloprotease) proteins are membrane-anchored metalloproteases that process and shed the ectodomains of membrane-anchored growth factors, cytokines and receptors. ADAMs also have essential roles in fertilization, angiogenesis, neurogenesis, heart development and cancer. Research on ADAMs and their role in protein ectodomain shedding is emerging as a fertile ground for gathering new insights into the functional regulation of membrane proteins.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: ADAM domain structure.
Figure 2: Protein ectodomain shedding.
Figure 3: EGFR dimerization and shedding.
Figure 4: Juxtacrine signalling through TNFα.
Figure 5: Is shedding essential for signalling through all EGFR ligands?

Similar content being viewed by others

References

  1. Massague, J. & Pandiella, A. Membrane-anchored growth factors. Annu. Rev. Biochem. 62, 515–541 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Hooper, N. M., Karran, E. H. & Turner, A. J. Membrane protein secretases. Biochem. J. 321, 265–279 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hooper, N. M. & Turner, A. J. Protein processing mechanisms: from angiotensin-converting enzyme to Alzheimer's disease. Biochem. Soc. Trans. 28, 441–446 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Schlöndorff, J. & Blobel, C. P. Metalloprotease-disintegrins: modular proteins capable of promoting cell–cell interactions and triggering signals by protein ectodomain shedding. J. Cell Sci. 112, 3603–3617 (1999).

    Article  PubMed  Google Scholar 

  5. Black, R. A. & White, J. M. ADAMs: focus on the protease domain. Curr. Opin. Cell. Biol. 10, 654–659 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Becherer, J. D. & Blobel, C. P. Biochemical properties and functions of membrane-anchored metalloprotease-disintegrin proteins (ADAMs). Curr. Top. Dev. Biol. 54, 101–123 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Seals, D. F. & Courtneidge, S. A. The ADAMs family of metalloproteases: multidomain proteins with multiple functions. Genes Dev. 17, 7–30 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Kheradmand, F. & Werb, Z. Shedding light on sheddases: role in growth and development. Bioessays 24, 8–12 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Moss, M. L. & Bartsch, J. W. Therapeutic benefits from targeting of ADAM family members. Biochemistry 43, 7227–7235 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Yarden, Y. & Sliwkowski, M. X. Untangling the ErbB signalling network. Nature Rev. Mol. Cell Biol. 2, 127–137 (2001).

    Article  CAS  Google Scholar 

  11. Gschwind, A., Fischer, O. M. & Ullrich, A. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nature Rev. Cancer 4, 361–370 (2004).

    Article  CAS  Google Scholar 

  12. Schlessinger, J. Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell 110, 669–672 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Burgess, A. W. et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol. Cell 12, 541–552 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. White, J. M. ADAMs: modulators of cell–cell and cell–matrix interactions. Curr. Opin. Cell Biol. 15, 598–606 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Mumm, J. S. & Kopan, R. Notch signaling: from the outside in. Dev. Biol. 228, 151–165 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. McFarlane, S. Metalloproteases: carving out a role in axon guidance. Neuron 37, 559–562 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Hartmann, D., Tournoy, J., Saftig, P., Annaert, W. & de Strooper, B. Implication of APP secretases in notch signaling. J. Mol. Neurosci. 17, 171–181 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Wolfsberg, T. G. et al. ADAM, a widely distributed and developmentally regulated gene family encoding membrane proteins with a disintegrin domain and a metalloprotease domain. Dev. Biol. 169, 378–383 (1995).

    Article  CAS  PubMed  Google Scholar 

  19. Blobel, C. P., Myles, D. G., Primakoff, P. & White, J. W. Proteolytic processing of a protein involved in sperm–egg fusion correlates with acquisition of fertilization competence. J. Cell Biol. 111, 69–78 (1990).

    Article  CAS  PubMed  Google Scholar 

  20. Blobel, C. P. et al. A potential fusion peptide and an integrin ligand domain in a protein active in sperm–egg fusion. Nature 356, 248–252 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. Wolfsberg, T. G. et al. 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 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nakamura, T., Abe, H., Hirata, A. & Shimoda, C. ADAM family protein Mde10 is essential for development of spore envelopes in the fission yeast Schizosaccharomyces pombe. Eukaryot. Cell 3, 27–39 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wen, C., Metzstein, M. M. & Greenwald, I. SUP-17, a Caenorhabditis elegans ADAM protein related to Drosophila KUZBANIAN, and its role in LIN-12/NOTCH signaling. Development 124, 4759–4767 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Pan, D. & Rubin, J. KUZBANIAN controls proteolytic processing of NOTCH and mediates lateral inhibition during Drosophila and vertebrate neurogenesis. Cell 90, 271–280 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Howard, L., Lu, X., Mitchell, S., Griffiths, S. & Glynn, P. Molecular cloning of MADM: a catalytically active disintegrin-metalloprotease expressed in various cell types. Biochem. J. 317, 45–50 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Black, R. et al. A metalloprotease disintegrin that releases tumour-necrosis factor-α from cells. Nature 385, 729–733 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Moss, M. L. et al. Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-α. Nature 385, 733–736 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. Loechel, F., Gilpin, B. J., Engvall, E., Albrechtsen, R. & Wewer, U. M. Human ADAM 12 (meltrin-α) is an active metalloprotease. J. Biol. Chem. 273, 16993–16997 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Roghani, M. et al. Metalloprotease-disintegrin MDC9: intracellular maturation and catalytic activity. J. Biol. Chem. 274, 3531–3540 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Howard, L., Zheng, Y., Horrocks, M., Maciewicz, R. A. & Blobel, C. P. Catalytic activity of ADAM28. FEBS Lett. 498, 82–86 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Wei, P., Zhao, Y. G., Zhuang, L., Ruben, S. & Sang, Q. X. Expression and enzymatic activity of human disintegrin and metalloproteinase ADAM19/meltrin-β. Biochem. Biophys. Res. Commun. 280, 744–755 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Schlomann, U. et al. The metalloprotease disintegrin ADAM8. Processing by autocatalysis is required for proteolytic activity and cell adhesion. J. Biol. Chem. 277, 48210–48219 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Chesneau, V. et al. Catalytic properties of ADAM19. J. Biol. Chem. 278, 22331–22340 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Zou, J. et al. Catalytic activity of human ADAM33. J. Biol. Chem. 279, 9818–9830 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Murphy, G. et al. Role of TIMPs (tissue inhibitors of metalloproteinases) in pericellular proteolysis: the specificity is in the detail. Biochem. Soc. Symp. 65–80 (2003).

  36. Loechel, F., Overgaard, M. T., Oxvig, C., Albrechtsen, R. & Wewer, U. M. Regulation of human ADAM 12 protease by the prodomain. Evidence for a functional cysteine switch. J. Biol. Chem. 274, 13427–13433 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. Milla, M. E. et al. Specific sequence elements are required for the expression of functional tumor necrosis factor-α-converting enzyme (TACE). J. Biol. Chem. 274, 30563–30570 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Howard, L., Maciewicz, R. A. & Blobel, C. P. Cloning and characterization of ADAM28: evidence for autocatalytic pro-domain removal and for cell surface localization of mature ADAM28. Biochem. J. 348, 21–27 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gonzales, P. E. et al. Inhibition of the TNFα converting enzyme (TACE) by its pro domain. J. Biol. Chem. 279, 31638–31645 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Niewiarowski, S., McLane, M. A., Kloczewiak, M. & Stewart, G. J. Disintegrins and other naturally occurring antagonists of platelet fibrinogen receptors. Semin. Hematol. 31, 289–300 (1994).

    CAS  PubMed  Google Scholar 

  41. Blobel, C. P. & White, J. M. Structure, function and evolutionary relationship of proteins containing a disintegrin domain. Curr. Opin. Cell Biol. 4, 760–765 (1992).

    Article  CAS  PubMed  Google Scholar 

  42. Krätzschmar, J., Lum, L. & Blobel, C. P. Metargidin, a membrane-anchored metalloprotease-disintegrin protein with an RGD integrin binding sequence. J. Biol. Chem. 271, 4593–4596 (1996).

    Article  PubMed  Google Scholar 

  43. Herren, B., Raines, E. W. & Ross, R. Expression of a disintegrin-like protein in cultured human vascular cells in vivo. FASEB J. 11, 173–180 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Smith, K. M. et al. The cysteine-rich domain regulates ADAM protease function in vivo. J. Cell Biol. 159, 893–902 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Reddy, P. et al. Functional analysis of the domain structure of tumor necrosis factor-α converting enzyme. J. Biol. Chem. 275, 14608–14614 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Weskamp, G., Krätzschmar, J. R., Reid, M. & Blobel, C. P. MDC9, a widely expressed cellular disintegrin containing cytoplasmic SH3 ligand domains. J. Cell Biol. 132, 717–726 (1996).

    Article  CAS  PubMed  Google Scholar 

  47. Cho, C. et al. Fertilization defects in sperm from mice lacking fertilin β. Science 281, 1857–1859 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Cho, C., Ge, H., Branciforte, D., Primakoff, P. & Myles, D. G. Analysis of mouse fertilin in wild-type and fertilin β (−/−) sperm: evidence for C-terminal modification, α/β dimerization, and lack of essential role of fertilin α in sperm–egg fusion. Dev. Biol. 222, 289–295. (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Nishimura, H., Cho, C., Branciforte, D. R., Myles, D. G. & Primakoff, P. Analysis of loss of adhesive function in sperm lacking cyritestin or fertilin β. Dev. Biol. 233, 204–213 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Zhu, G. Z., Lin, Y., Myles, D. G. & Primakoff, P. Identification of four novel ADAMs with potential roles in spermatogenesis and fertilization. Gene 234, 227–237 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Shamsadin, R. et al. Male mice deficient for germ-cell cyritestin are infertile. Biol. Reprod. 61, 1445–1451 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. Leighton, P. A. et al. Defining brain wiring patterns and mechanisms through gene trapping in mice. Nature 410, 174–179 (2001).

    CAS  PubMed  Google Scholar 

  53. Pandiella, A., Bosenberg, M., Huang, E. J., Besmer, P. & Massague, J. Cleavage of membrane-anchored growth factors involves distinct protease activities regulated through common mechanisms. J. Biol. Chem. 267, 24028–24033 (1992).

    Article  CAS  PubMed  Google Scholar 

  54. Arribas, J. & Massague, J. Transforming growth factor-α and β-amyloid precursor share a secretory mechanism. J. Cell Biol. 128, 433–441 (1995).

    Article  CAS  PubMed  Google Scholar 

  55. Anklesaria, P. et al. Cell–cell adhesion mediated by binding of membrane-anchored transforming growth factor α to epidermal growth factor receptors promotes cell proliferation. Proc. Natl Acad. Sci. USA 87, 3289–3293 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wiley, H. S. et al. Removal of the membrane-anchoring domain of epidermal growth factor leads to intracrine signaling and disruption of mammary epithelial cell organization. J. Cell Biol. 143, 1317–1328 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Borrell-Pages, M., Rojo, F., Albanell, J., Baselga, J. & Arribas, J. TACE is required for the activation of the EGFR by TGF-α in tumors. EMBO J. 22, 1114–1124 (2003). Presents compelling evidence for an unexpected contribution of ectodomain shedding to juxtacrine signalling between TGFα and the EGFR.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. McDermott, M. F. et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97, 133–144 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Hartmann, D. et al. The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for α-secretase activity in fibroblasts. Hum. Mol. Genet. 11, 2615–2624 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Lieber, T., Kidd, S. & Young, M. W. kuzbanian-mediated cleavage of Drosophila Notch. Genes Dev. 16, 209–221 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Brown, M. S., Ye, J., Rawson, R. B. & Goldstein, J. L. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100, 391–398 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Xia, W. & Wolfe, M. S. Intramembrane proteolysis by presenilin and presenilin-like proteases. J. Cell Sci. 116, 2839–2844 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Selkoe, D. & Kopan, R. Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu. Rev. Neurosci. 26, 565–597 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Bao, J., Wolpowitz, D., Role, L. W. & Talmage, D. A. Back signaling by the Nrg-1 intracellular domain. J. Cell Biol. 161, 1133–1141 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Nanba, D., Mammoto, A., Hashimoto, K. & Higashiyama, S. Proteolytic release of the carboxy-terminal fragment of proHB-EGF causes nuclear export of PLZF. J. Cell Biol. 163, 489–502 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Harris, R. C., Chung, E. & Coffey, R. J. EGF receptor ligands. Exp. Cell Res. 284, 2–13 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Sahin, U. et al. Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR-ligands. J. Cell Biol. 164, 769–779 (2004). Explores the contribution of different ADAMs to the shedding of six EGFR ligands using a loss-of-function approach with cells isolated from different ADAM-knockout mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Dong, J. et al. Metalloprotease-mediated ligand release regulates autocrine signaling through the epidermal growth factor receptor. Proc. Natl Acad. Sci. USA 96, 6235–6240 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Fischer, O. M., Hart, S., Gschwind, A. & Ullrich, A. EGFR signal transactivation in cancer cells. Biochem. Soc. Trans. 31, 1203–1208 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Peschon, J. J. et al. An essential role for ectodomain shedding in mammalian development. Science 282, 1281–1284 (1998). Evaluation of mice lacking ADAM17 that uncovers a crucial role for ADAM17 in activating TGFα and the EGFR during mouse development.

    Article  CAS  PubMed  Google Scholar 

  71. Zhao, J. et al. Pulmonary hypoplasia in mice lacking tumor necrosis factor-α converting enzyme indicates an indispensable role for cell surface protein shedding during embryonic lung branching morphogenesis. Dev. Biol. 232, 204–218 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Jackson, L. F. et al. Defective valvulogenesis in HB-EGF and TACE-null mice is associated with aberrant BMP signaling. EMBO J. 22, 2704–2716 (2003). Elegant analysis of mice that lack HB-EGF or ADAM17 points towards a crucial role of ADAM17-dependent activation of HB-EGF during morphogenesis of heart valves in mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Iwamoto, R. et al. Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function. Proc. Natl Acad. Sci. USA 100, 3221–3226 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Shi, W. et al. TACE is required for fetal murine cardiac development and modeling. Dev. Biol. 261, 371–380 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Luetteke, N. C. et al. Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles for EGF receptor ligands in mouse mammary gland development. Development 126, 2739–2750 (1999).

    CAS  PubMed  Google Scholar 

  76. Merlos-Suarez, A., Ruiz-Paz, S., Baselga, J. & Arribas, J. Metalloprotease-dependent protransforming growth factor-α ectodomain shedding in the absence of tumor necrosis factor-α-converting enzyme. J. Biol. Chem. 276, 48510–48517 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Sunnarborg, S. W. et al. Tumor necrosis factor-α converting enzyme (TACE) regulates epidermal growth factor receptor ligand availability. J. Biol. Chem. 277, 12838–12845 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. Yamazaki, S. et al. Mice with defects in HB-EGF ectodomain shedding show severe developmental abnormalities. J. Cell Biol. 163, 469–475 (2003). Mice with a knock-in mutation that renders HB-EGF uncleavable have defects in heart-valve development that resemble those in mice that completely lack HB-EGF or ADAM17. This further corroborates the essential role of ectodomain shedding in the functional activation of HB-EGF.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Brachmann, R. et al. Transmembrane TGF-α precursors activate EGF/TGF-α receptors. Cell 56, 691–700 (1989).

    Article  CAS  PubMed  Google Scholar 

  80. Wong, S. T. et al. The TGF-α precursor expressed on the cell surface binds to the EGF receptor on adjacent cells, leading to signal transduction. Cell 56, 495–506 (1989).

    Article  CAS  PubMed  Google Scholar 

  81. Blasband, A. J. et al. Expression of the TGFα integral membrane precursor induces transformation of NRK cells. Oncogene 5, 1213–1221 (1990).

    CAS  PubMed  Google Scholar 

  82. Yang, H. et al. Defective cleavage of membrane bound TGFα leads to enhanced activation of the EGF receptor in malignant cells. Oncogene 19, 1901–1914 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Higashiyama, S. et al. The membrane protein CD9/DRAP 27 potentiates the juxtacrine growth factor activity of the membrane-anchored heparin-binding EGF-like growth factor. J. Cell Biol. 128, 929–938 (1995).

    Article  CAS  PubMed  Google Scholar 

  84. Shi, W., Fan, H., Shum, L. & Derynck, R. The tetraspanin CD9 associates with transmembrane TGF-α and regulates TGF-α-induced EGF receptor activation and cell proliferation. J. Cell Biol. 148, 591–602 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Garrett, T. P. et al. Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor α. Cell 110, 763–773 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Ogiso, H. et al. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell 110, 775–787 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Jorissen, R. N. et al. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp. Cell Res. 284, 31–53 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Mendelsohn, J. & Baselga, J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J. Clin. Oncol. 21, 2787–2799 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Izumi, Y. et al. A metalloprotease–disintegrin, MDC9/meltrin-γ/ADAM9 and PKCδ are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. EMBO J. 17, 7260–7272 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Asakura, M. et al. Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy. Nature Med. 8, 35–40 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Kurisaki, T. et al. Phenotypic analysis of Meltrin α (ADAM12)-deficient mice: involvement of Meltrin α in adipogenesis and myogenesis. Mol. Cell. Biol. 23, 55–61 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lemjabbar, H. & Basbaum, C. Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells. Nature Med. 8, 41–46 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Yan, Y., Shirakabe, K. & Werb, Z. The metalloprotease Kuzbanian (ADAM10) mediates the transactivation of EGF receptor by G protein-coupled receptors. J. Cell Biol. 158, 221–226 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lemjabbar, H. et al. Tobacco smoke-induced lung cell proliferation mediated by tumor necrosis factor α-converting enzyme and amphiregulin. J. Biol. Chem. 278, 26202–26207 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Schafer, B., Gschwind, A. & Ullrich, A. Multiple G-protein-coupled receptor signals converge on the epidermal growth factor receptor to promote migration and invasion. Oncogene 23, 991–999 (2004).

    Article  PubMed  CAS  Google Scholar 

  96. Gschwind, A., Hart, S., Fischer, O. M. & Ullrich, A. TACE cleavage of proamphiregulin regulates GPCR-induced proliferation and motility of cancer cells. EMBO J. 22, 2411–2421 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Cho, H. S. et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421, 756–760 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. Citri, A., Skaria, K. B. & Yarden, Y. The deaf and the dumb: the biology of ErbB-2 and ErbB-3. Exp. Cell Res. 284, 54–65 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Falls, D. L. Neuregulins: functions, forms, and signaling strategies. Exp. Cell Res. 284, 14–30 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Shirakabe, K., Wakatsuki, S., Kurisaki, T. & Fujisawa-Sehara, A. Roles of Meltrin β /ADAM19 in the processing of neuregulin. J. Biol. Chem. 276, 9352–9358 (2001).

    Article  CAS  PubMed  Google Scholar 

  101. Kurohara, K. et al. Essential roles of Meltrin β (ADAM19) in heart development. Dev. Biol. 267, 14–28 (2004).

    Article  CAS  PubMed  Google Scholar 

  102. Zhou, H. M. et al. Essential role for ADAM19 in cardiovascular morphogenesis. Mol. Cell. Biol. 24, 96–104 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Diaz-Rodriguez, E., Esparis-Ogando, A., Montero, J. C., Yuste, L. & Pandiella, A. Stimulation of cleavage of membrane proteins by calmodulin inhibitors. Biochem. J. 346, 359–367 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Montero, J. C., Yuste, L., Diaz-Rodriguez, E., Esparis-Ogando, A. & Pandiella, A. Differential shedding of transmembrane neuregulin isoforms by the tumor necrosis factor-α-converting enzyme. Mol. Cell. Neurosci. 16, 631–648 (2000).

    Article  CAS  PubMed  Google Scholar 

  105. Molina, M. A. et al. Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res. 61, 4744–4749 (2001).

    CAS  PubMed  Google Scholar 

  106. Vecchi, M., Baulida, J. & Carpenter, G. Selective cleavage of the heregulin receptor ErbB-4 by protein kinase C activation. J. Biol. Chem. 271, 18989–18995 (1996).

    Article  CAS  PubMed  Google Scholar 

  107. Vecchi, M., Rudolph-Owen, L. A., Brown, C. L., Dempsey, P. J. & Carpenter, G. Tyrosine phosphorylation and proteolysis. Pervanadate-induced, metalloprotease-dependent cleavage of the ErbB-4 receptor and amphiregulin. J. Biol. Chem. 273, 20589–20595 (1998).

    Article  CAS  PubMed  Google Scholar 

  108. Ni, C. Y., Murphy, M. P., Golde, T. E. & Carpenter, G. γ-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase. Science 294, 2179–2181 (2001).

    Article  CAS  PubMed  Google Scholar 

  109. Carpenter, G. Nuclear localization and possible functions of receptor tyrosine kinases. Curr. Opin. Cell Biol. 15, 143–148 (2003).

    Article  CAS  PubMed  Google Scholar 

  110. Urban, S., Lee, J. R. & Freeman, M. A family of Rhomboid intramembrane proteases activates all Drosophila membrane-tethered EGF ligands. EMBO J. 21, 4277–4286 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Urban, S., Lee, J. R. & Freeman, M. Drosophila rhomboid-1 defines a family of putative intramembrane serine proteases. Cell 107, 173–182 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Lee, J. R., Urban, S., Garvey, C. F. & Freeman, M. Regulated intracellular ligand transport and proteolysis control EGF signal activation in Drosophila. Cell 107, 161–171 (2001).

    Article  CAS  PubMed  Google Scholar 

  113. Horiuchi, K. et al. Potential role for ADAM15 in pathological neovascularization in mice. Mol. Cell Biol. 23, 5614–5624 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Van Eerdewegh, P. et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 418, 426–430 (2002).

    Article  CAS  PubMed  Google Scholar 

  115. Arribas, J. et al. Diverse cell surface protein ectodomains are shed by a system sensitive to metalloprotease inhibitors. J. Biol. Chem. 271, 11376–11382 (1996).

    Article  CAS  PubMed  Google Scholar 

  116. Pandiella, A. & Massague, J. Cleavage of the membrane precursor for transforming growth factor α is a regulated process. Proc. Natl Acad. Sci. USA 88, 1726–1730 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Doedens, J. R., Mahimkar, R. M. & Black, R. A. TACE/ADAM-17 enzymatic activity is increased in response to cellular stimulation. Biochem. Biophys. Res. Commun. 308, 331–338 (2003).

    Article  CAS  PubMed  Google Scholar 

  118. Black, R. A. et al. Substrate specificity and inducibility of TACE (tumour necrosis factor α-converting enzyme) revisited: the Ala-Val preference, and induced intrinsic activity. Biochem. Soc. Symp. 70, 39–52 (2003).

    Article  CAS  Google Scholar 

  119. Fan, H. & Derynck, R. Ectodomain shedding of TGF-α and other transmembrane proteins is induced by receptor tyrosine kinase activation and MAP kinase signaling cascades. EMBO J. 18, 6962–6972 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Peiretti, F. et al. Identification of SAP97 as an intracellular binding partner of TACE. J. Cell Sci. 116, 1949–1957 (2003).

    Article  CAS  PubMed  Google Scholar 

  121. Nelson, K. K., Schlondorff, J. & Blobel, C. P. Evidence for an interaction of the metalloprotease-disintegrin tumour necrosis factor α convertase (TACE) with mitotic arrest deficient 2 (MAD2), and of the metalloprotease-disintegrin MDC9 with a novel MAD2-related protein, MAD2β. Biochem. J. 343, 673–680 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Zheng, Y., Schlondorff, J. & Blobel, C. P. Evidence for regulation of the tumor necrosis factor α-convertase (TACE) by protein-tyrosine phosphatase PTPH1. J. Biol. Chem. 277, 42463–42470 (2002).

    Article  CAS  PubMed  Google Scholar 

  123. Cousin, H., Gaultier, A., Bleux, C., Darribere, T. & Alfandari, D. PACSIN2 is a regulator of the metalloprotease/disintegrin ADAM13. Dev. Biol. 227, 197–210 (2000).

    Article  CAS  PubMed  Google Scholar 

  124. Abram, C. L. et al. The adaptor protein Fish associates with members of the ADAMs family and localizes to podosomes of Src-transformed cells. J. Biol. Chem. 278, 16844–16851 (2003).

    Article  CAS  PubMed  Google Scholar 

  125. Mori, S. et al. PACSIN3 binds ADAM12/meltrin α and up-regulates ectodomain shedding of heparin-binding epidermal growth factor-like growth factor. J. Biol. Chem. 278, 46029–46034 (2003).

    Article  CAS  PubMed  Google Scholar 

  126. Howard, L., Nelson, K. K., Maciewicz, R. A. & Blobel, C. P. Interaction of the metalloprotease disintegrins MDC9 and MDC15 with two SH3 domain-containing proteins, endophilin I and SH3PX1. J. Biol. Chem. 274, 31693–31699 (1999).

    Article  CAS  PubMed  Google Scholar 

  127. Poghosyan, Z. et al. Phosphorylation-dependent interactions between ADAM15 cytoplasmic domain and Src family protein-tyrosine kinases. J. Biol. Chem. 277, 4999–5007 (2002).

    Article  CAS  PubMed  Google Scholar 

  128. Lammich, S. et al. Constitutive and regulated α-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. Proc. Natl Acad. Sci. USA 96, 3922–3927 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Kojro, E., Gimpl, G., Lammich, S., Marz, W. & Fahrenholz, F. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10. Proc. Natl Acad. Sci. USA 98, 5815–5820 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Matthews, V. et al. Cellular cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (TACE). J. Biol. Chem. 278, 38829–38839 (2003).

    Article  CAS  PubMed  Google Scholar 

  131. Schlöndorff, J. S., Lum, L. & Blobel, C. P. Biochemical and pharmacological criteria define two shedding activities for TRANCE/OPGL that are distinct from the TNFα convertase (TACE). J. Biol. Chem. 276, 14665–14674 (2001).

    Article  PubMed  Google Scholar 

  132. Weskamp, G. et al. Evidence for a critical role of the TNFα convertase (TACE) in ectodomain shedding of the p75 neurotrophin receptor (p75NTR). J. Biol. Chem. 279, 4241–4249 (2004).

    Article  CAS  PubMed  Google Scholar 

  133. Zheng, Y., Saftig, P., Hartmann, D. & Blobel, C. Evaluation of the contribution of different ADAMs to TNFα shedding and of the function of the TNFα ectodomain in ensuring selective stimulated shedding by the TNFα convertase (TACE/ADAM17). J. Biol. Chem. 279, 42898–42906 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. Alfalah, M. et al. A point mutation in the juxtamembrane stalk of human angiotensin I-converting enzyme invokes the action of a distinct secretase. J. Biol. Chem. 276, 21105–21109 (2001).

    Article  CAS  PubMed  Google Scholar 

  135. Petricoin, E. F. & Liotta, L. A. Proteomic analysis at the bedside: early detection of cancer. Trends Biotechnol. 20, S30–S34 (2002).

    Article  CAS  PubMed  Google Scholar 

  136. Liotta, L. A., Ferrari, M. & Petricoin, E. Clinical proteomics: written in blood. Nature 425, 905 (2003).

    Article  CAS  PubMed  Google Scholar 

  137. Tam, E. M., Morrison, C. J., Wu, Y. I., Stack, M. S. & Overall, C. M. Membrane protease proteomics: Isotope-coded affinity tag MS identification of undescribed MT1-matrix metalloproteinase substrates. Proc. Natl Acad. Sci. USA 101, 6917–6922 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Kelly, K. et al. Metalloprotease-disintegrin ADAM8: Expression analysis and targeted deletion in mice. Dev. Dyn. (in the press).

  139. Weskamp, G. et al. Mice lacking the metalloprotease-disintegrin MDC9 (ADAM9) have no evident major abnormalities during development or adult life. Mol. Cell. Biol. 22, 1537–1544 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Prenzel, N. et al. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402, 884–888 (1999). Crosstalk between GPCRs and the EGFR is shown to require the metalloprotease-dependent concept of a triple-membrane-passing signal.

    Article  CAS  PubMed  Google Scholar 

  141. Ferguson, K. M. et al. EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Mol. Cell 11, 507–517 (2003).

    Article  CAS  PubMed  Google Scholar 

  142. Locksley, R. M., Killeen, N. & Lenardo, M. J. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104, 487–501 (2001).

    Article  CAS  PubMed  Google Scholar 

  143. Ruuls, S. R. et al. Membrane-bound TNF supports secondary lymphoid organ structure but is subservient to secreted TNF in driving autoimmune inflammation. Immunity 15, 533–543 (2001). Mice with a knock-in mutation that inactivates the cleavage site of TNFα are used to carefully dissect juxtacrine versus paracrine activities of this pro-inflammatory cytokine.

    Article  CAS  PubMed  Google Scholar 

  144. Blobel, C. P. Metalloprotease-disintegrins: links to cell adhesion and cleavage of TNFα and Notch. Cell 90, 589–592 (1997).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I wish to thank G. Weskamp, T. Ludwig, D. Lee and my cousin G. A. Blobel for their suggestions and comments during the preparation of this manuscript.

Author information

Authors and Affiliations

  1. Arthritis and Tissue Degeneration Program and Cell Biology Program, Hospital for Special Surgery, Weill Medical College of Cornell University, 535 East 70th Street, New York, 10021, New York, USA

    Carl P. Blobel

Authors
  1. Carl P. Blobel
    View author publications

    You can also search for this author inPubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

DATABASES

Entrez

Adam17

Adam19

Swiss-Prot

ADAM10

ADAM15

ADAM17

ADAM19

ADAM23

amphiregulin

CD9

EGFR

HB-EGF

PACSIN2

PACSIN3

TGFα

TNFR1

FURTHER INFORMATION

Carl Blobel's laboratory

White Laboratory

Glossary

METALLOPROTEASE

A peptidase that depends on a coordinated metal ion (Zn2+) for its catalytic mechanism.

ANGIOGENESIS

The process of forming new blood vessels by sprouting from pre-existing ones.

EGF-LIKE DOMAIN

A motif with ∼50 amino acids, including six cysteine residues and a mainly β-sheet structure, found in all ErbB-binding growth factors and in extracellular matrix proteins.

PRO-PROTEIN CONVERTASE

Member of the family of Ca2+-dependent, subtilisin-like serine endoproteases that are structurally related to KEX2 and furin and that cleave pro-protein substrates at the C-terminal side of doublets or clusters of basic amino acids.

TRANS-GOLGI NETWORK

Membranous compartment from which vesicles bud to deliver proteins and other materials to the cell surface or to the late endosomes for delivery to lysosomes.

SRC-HOMOLOGY-3 (SH3) DOMAIN

A protein–protein interaction domain that recognizes a unique proline-rich peptide motif. This domain is found in many proteins that are involved in signal transduction and membrane–cytoskeleton interactions.

NEOVASCULARIZATION

De novo stimulation of new blood supplies to a growing tumour.

G-PROTEIN-COUPLED RECEPTOR

A seven-helix membrane-spanning cell-surface receptor that signals through heterotrimeric GTP-binding and -hydrolysing G-proteins to stimulate or inhibit the activity of a downstream enzyme.

ENDOCARDIAL CUSHION

Discrete cushion-like swelling that forms in the developing heart and that gives rise to mature heart valves and to the membranous part of the ventricular septum. The ventricular septum is a wall that separates the left and right ventricles of the heart.

GRAM-POSITIVE BACTERIA

The cell walls of these bacteria retain a basic blue dye during the Gram-stain procedure. These cell walls are relatively thick (15–80 nm) and consist of a network of peptidoglycans.

TETRASPANIN FAMILY

The tetraspanin family contains proteins that span the membrane four times with two exoplasmic loops, and that can be found at the cell surface. Whereas some are highly restricted to specific tissues, others are widely distributed. Members of this family have been implicated in cell activation and proliferation, adhesion, motility, differentiation and cancer.

PHORBOL ESTER

A polycyclic ester that is isolated from croton oil. The most common are phorbol-12-myristate-13-acetate (PMA) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA). These are potent carcinogens or tumour promoters because they mimic diacylglycerol, and thereby irreversibly activate protein kinase C.

YEAST TWO-HYBRID SCREEN

A technique used to test if two proteins physically interact with each other. One protein is fused to the GAL4 activation domain and the other to the GAL4 DNA-binding domain, and both fusion proteins are introduced into yeast. Expression of a GAL4-regulated reporter gene indicates that the two proteins physically interact.

ORTHOLOGUES

Functionally related genes with extensive sequence similarity, which indicates a common ancestor. The term orthologues is often used to indicate the most closely related members of larger gene families in different species.

RETINOPATHY

A non-inflammatory degenerative disease of the retina, commonly found as a complication of diabetes.

RNA INTERFERENCE

A form of post-transcriptional gene silencing in which expression or transfection of double-stranded RNA induces degradation, by nucleases, of the homologous endogenous transcripts, mimicking the effect of the reduction, or loss, of gene activity.

COS CELLS

Cells from the monkey CV1 cell line that have an integrated SV40 genome that lacks an origin of replication. Plasmids with an SV40 origin of replication are replicated to a high copy number when transfected.

ISOTOPE-CODED-AFFINITY-TAG MASS SPECTROMETRY

A method to identify candidate protease substrates by comparing the relative levels of proteins in two samples, such as a supernatant of cells that overexpress a protease and a supernatant of control cells. It relies on marking proteins in each sample with chemically identical affinity tags (such as biotin) of different isotopic composition and mass.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Blobel, C. ADAMs: key components in EGFR signalling and development. Nat Rev Mol Cell Biol 6, 32–43 (2005). https://doi.org/10.1038/nrm1548

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm1548

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing