A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE.

The Notch1 receptor is presented at the cell membrane as a heterodimer after constitutive processing by a furin-like convertase. Ligand binding induces the proteolytic release of Notch intracellular domain by a gamma-secretase-like activity. This domain translocates to the nucleus and interacts with the DNA-binding protein CSL, resulting in transcriptional activation of target genes. Here we show that an additional processing event occurs in the extracellular part of the receptor, preceding cleavage by the gamma-secretase-like activity. Purification of the activity accounting for this cleavage in vitro shows that it is due to TACE (TNFalpha-converting enzyme), a member of the ADAM (a disintegrin and metalloprotease domain) family of metalloproteases. Furthermore, experiments carried out on TACE-/- bone marrow-derived monocytic precursor cells suggest that this metalloprotease plays a prominent role in the activation of the Notch pathway.

[1]  P. Bray-Ward,et al.  Human metalloprotease-disintegrin Kuzbanian regulates sympathoadrenal cell fate in development and neoplasia. , 1998, Human molecular genetics.

[2]  H. Weintraub,et al.  The intracellular domain of mouse Notch: a constitutively activated repressor of myogenesis directed at the basic helix-loop-helix region of MyoD. , 1994, Development.

[3]  A. Israël,et al.  The Notch1 receptor is cleaved constitutively by a furin-like convertase. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[4]  B. Yankner,et al.  Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[5]  A. Israël,et al.  Delta-1 Activation of Notch-1 Signaling Results inHES-1 Transactivation , 1998, Molecular and Cellular Biology.

[6]  D. Selkoe,et al.  The cell biology of β-amyloid precursor protein and presenilin in Alzheimer's disease , 1998 .

[7]  G. Struhl,et al.  Nuclear Access and Action of Notch In Vivo , 1998, Cell.

[8]  G. Seydoux,et al.  Analysis of gain-of-function mutations of the lin-12 gene of Caenorhabditis elegans , 1990, Nature.

[9]  J. Nye,et al.  Neuronal specification: Notch signals Kuz it's cleaved , 1997, Current Biology.

[10]  S. Campuzano,et al.  The metalloprotease-disintegrin Kuzbanian participates in Notch activation during growth and patterning of Drosophila imaginal discs. , 1997, Development.

[11]  Iva Greenwald,et al.  Presenilin is required for activity and nuclear access of Notch in Drosophila , 1999, Nature.

[12]  T. Ohtsuka,et al.  Hes1 and Hes5 as Notch effectors in mammalian neuronal differentiation , 1999, The EMBO journal.

[13]  M. Lambert,et al.  Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-α , 1997, Nature.

[14]  F. Schweisguth,et al.  Indirect evidence for Delta-dependent intracellular processing of Notch in Drosophila embryos , 1998, Current Biology.

[15]  S. Minoguchi,et al.  Delta-induced Notch Signaling Mediated by RBP-J Inhibits MyoD Expression and Myogenesis* , 1999, The Journal of Biological Chemistry.

[16]  E. Kojro,et al.  Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[17]  J. Posakony,et al.  Suppressor of hairless directly activates transcription of enhancer of split complex genes in response to Notch receptor activity. , 1995, Genes & development.

[18]  J. Sklar,et al.  Notch1-Induced Delay of Human Hematopoietic Progenitor Cell Differentiation Is Associated With Altered Cell Cycle Kinetics , 1999 .

[19]  David Ish-Horowicz,et al.  Primary neurogenesis in Xenopus embryos regulated by a homologue of the Drosophila neurogenic gene Delta , 1995, Nature.

[20]  T G Wolfsberg,et al.  ADAM, a novel family of membrane proteins containing A Disintegrin And Metalloprotease domain: multipotential functions in cell-cell and cell- matrix interactions , 1995, The Journal of cell biology.

[21]  William J. Ray,et al.  A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain , 1999, Nature.

[22]  Nicole Nelson,et al.  A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells , 1997, Nature.

[23]  E. Engvall,et al.  Human ADAM 12 (Meltrin α) Is an Active Metalloprotease* , 1998, The Journal of Biological Chemistry.

[24]  B. Trask,et al.  The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1. , 1998, Immunity.

[25]  G. Rubin,et al.  Kuzbanian Controls Proteolytic Processing of Notch and Mediates Lateral Inhibition during Drosophila and Vertebrate Neurogenesis , 1997, Cell.

[26]  S. Artavanis-Tsakonas,et al.  Intracellular Cleavage of Notch Leads to a Heterodimeric Receptor on the Plasma Membrane , 1997, Cell.

[27]  Raphael Kopan,et al.  Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain , 1998, Nature.

[28]  Céline Gélinas,et al.  Rel/NF‐κB can trigger the Notch signaling pathway by inducing the expression of Jagged1, a ligand for Notch receptors , 1999, The EMBO journal.

[29]  E. Kieff,et al.  Oncogenic Forms of NOTCH1 Lacking Either the Primary Binding Site for RBP-Jκ or Nuclear Localization Sequences Retain the Ability to Associate with RBP-Jκ and Activate Transcription* , 1997, The Journal of Biological Chemistry.

[30]  David C. Lee,et al.  An essential role for ectodomain shedding in mammalian development. , 1998, Science.

[31]  G. Rubin,et al.  KUZ, a Conserved Metalloprotease-Disintegrin Protein with Two Roles in Drosophila Neurogenesis , 1996, Science.

[32]  S. Bray,et al.  Synergy between suppressor of Hairless and Notch in regulation of Enhancer of split m gamma and m delta expression , 1997, Molecular and cellular biology.

[33]  S. Artavanis-Tsakonas,et al.  Notch signaling: cell fate control and signal integration in development. , 1999, Science.

[34]  M. Fortini,et al.  Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants , 1999, Nature.

[35]  P. Rakic,et al.  Processing of the notch ligand delta by the metalloprotease Kuzbanian. , 1999, Science.

[36]  Christel Brou,et al.  Signalling downstream of activated mammalian Notch , 1995, Nature.

[37]  N. Webster,et al.  The human estrogen receptor has two independent nonacidic transcriptional activation functions , 1989, Cell.

[38]  H. Birkedal‐Hansen,et al.  The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[39]  P. Glynn,et al.  Molecular cloning of MADM: a catalytically active mammalian disintegrin-metalloprotease expressed in various cell types. , 1996, The Biochemical journal.

[40]  P. Slocombe,et al.  TNF‐α converting enzyme (TACE) is inhibited by TIMP‐3 , 1998 .

[41]  Raphael Kopan,et al.  A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. , 2000, Molecular cell.

[42]  H. Weintraub,et al.  Signal transduction by activated mNotch: importance of proteolytic processing and its regulation by the extracellular domain. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[43]  F. Schweisguth,et al.  The neurogenic suppressor of hairless DNA-binding protein mediates the transcriptional activation of the enhancer of split complex genes triggered by Notch signaling. , 1995, Genes & development.

[44]  M. W. Young,et al.  Ligand-induced cleavage and regulation of nuclear entry of Notch in Drosophila melanogaster embryos. , 1998, Genes & development.

[45]  Joseph D. Buxbaum,et al.  Evidence That Tumor Necrosis Factor α Converting Enzyme Is Involved in Regulated α-Secretase Cleavage of the Alzheimer Amyloid Protein Precursor* , 1998, The Journal of Biological Chemistry.

[46]  R. Silber,et al.  Human B lymphocytes show greater susceptibility to H2O2 toxicity than T lymphocytes. , 1984, Journal of immunology.

[47]  S. Minoguchi,et al.  Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-Jκ/Su(H) , 1995, Current Biology.