The Notch1 receptor is cleaved constitutively by a furin-like convertase

被引:597
作者
Logeat, F
Bessia, C
Brou, C
LeBail, O
Jarriault, S
Seidah, NG
Israël, A
机构
[1] Inst Pasteur, CNRS, URA 1773, Unite Biol Mol Express Gen, F-75724 Paris 15, France
[2] Clin Res Inst Montreal, JA DeSeve Lab Biochem Neuroendocrinol, Montreal, PQ H2W 1R7, Canada
关键词
D O I
10.1073/pnas.95.14.8108
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The Notch receptor, which is involved in numerous cell fate decisions in invertebrates and vertebrates, is synthesized as a 300-kDa precursor molecule (p300), We show here that proteolytic processing of p300 is an essential step in the formation of the biologically active receptor because only the cleaved fragments are present at the cell surface. Our results confirm and extend recent reports indicating that the Notch receptor exists at the plasma membrane as a heterodimeric molecule, but disagree as to the nature of the protease that is responsible for the cleavage that takes place in the extracellular region. We report here that constitutive processing of murine Notch1 involves a furin-like convertase. We show that the calcium ionophore A23187 and the alpha 1-antitrypsin variant, alpha 1-PDX, a known inhibitor of furin-like convertases, inhibit p300 processing. When expressed in the furin-deficient Love cell line, p300 is not processed. In vitro digestion of a recombinant Notch-derived substrate with purified furin allowed mapping of the processing site to the carboxyl side of the sequence RQRR (amino acids 1651-1654), Mutation of these four amino acids (and of two secondary dibasic furin sites located nearby) completely abolished processing of the Notch1 receptor.
引用
收藏
页码:8108 / 8112
页数:5
相关论文
共 23 条
  • [1] ANDERSON ED, 1993, J BIOL CHEM, V268, P24887
  • [2] NOTCH SIGNALING
    ARTAVANISTSAKONAS, S
    MATSUNO, K
    FORTINI, ME
    [J]. SCIENCE, 1995, 268 (5208) : 225 - 232
  • [3] FUNCTIONAL-ANALYSIS OF THE TAN-1 GENE, A HUMAN HOMOLOG OF DROSOPHILA NOTCH
    ASTER, J
    PEAR, W
    HASSERJIAN, R
    ERBA, H
    DAVI, F
    LUO, B
    SCOTT, M
    BALTIMORE, D
    SKLAR, J
    [J]. COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY, 1994, 59 : 125 - 136
  • [4] alpha 1-antitrypsin portland inhibits processing of precursors mediated by proprotein convertases primarily within the constitutive secretory pathway
    Benjannet, S
    Savaria, D
    Laslop, A
    Munzer, JS
    Chretien, M
    Marcinkiewicz, M
    Seidah, NG
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (42) : 26210 - 26218
  • [5] Intracellular cleavage of notch leads to a heterodimeric receptor on the plasma membrane
    Blaumueller, CM
    Qi, HL
    Zagouras, P
    ArtavanisTsakonas, S
    [J]. CELL, 1997, 90 (02) : 281 - 291
  • [6] Identification of the paired basic convertases implicated in HIV gp160 processing based on in vitro assays and expression in CD4(+) cell lines
    Decroly, E
    Wouters, S
    DiBello, C
    Lazure, C
    Ruysschaert, JM
    Seidah, NG
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (48) : 30442 - 30450
  • [7] The NOTCH receptor and its ligands
    Fleming, RJ
    Purcell, K
    ArtavanisTsakonas, S
    [J]. TRENDS IN CELL BIOLOGY, 1997, 7 (11) : 437 - 441
  • [8] SIGNALING DOWNSTREAM OF ACTIVATED MAMMALIAN NOTCH
    JARRIAULT, S
    BROU, C
    LOGEAT, F
    SCHROETER, EH
    KOPAN, R
    ISRAEL, A
    [J]. NATURE, 1995, 377 (6547) : 355 - 358
  • [9] BREFELDIN-A - INSIGHTS INTO THE CONTROL OF MEMBRANE TRAFFIC AND ORGANELLE STRUCTURE
    KLAUSNER, RD
    DONALDSON, JG
    LIPPINCOTTSCHWARTZ, J
    [J]. JOURNAL OF CELL BIOLOGY, 1992, 116 (05) : 1071 - 1080
  • [10] INHIBITION OF PROTEOLYTIC CLEAVAGE OF THE HEMAGGLUTININ OF INFLUENZA-VIRUS BY THE CALCIUM-SPECIFIC IONOPHORE A23187
    KLENK, HD
    GARTEN, W
    ROTT, R
    [J]. EMBO JOURNAL, 1984, 3 (12) : 2911 - 2915