Presenilin-dependent processing and nuclear function of γ-protocadherins

被引:116
作者
Haas, IG [1 ]
Frank, M [1 ]
Véron, N [1 ]
Kemler, R [1 ]
机构
[1] Max Planck Inst Immunobiol, Dept Mol Embryol, D-79108 Freiburg, Germany
关键词
D O I
10.1074/jbc.M412909200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The recently described protocadherin gene clusters encode cadherin-related proteins, which are highly expressed in the vertebrate nervous system. Here, we report biochemical studies addressing proteolytic processing of gamma-protocadherins. These type-I transmembrane proteins are cleaved by a metalloproteinase in vivo, generating a soluble extracellular fragment and a carboxyl-terminal fragment associated with the cellular membrane. In addition, we show that the carboxyl-terminal fragment is a substrate for further cleavage mediated by presenilin. Consequently, accumulation of the fragment is found when gamma-secretase is inactivated either by the specific presenilin- inhibitor L685,458 or in double mutant murine embryonic fibroblasts lacking both presenilin genes. The gamma-secretase- generated carboxyl-terminal fragment is largely unstable but accumulates when proteasomal degradation is inhibited. Interestingly, the proteolytic fragment generated by gamma-secretase can localize to the nucleus. This is the first report providing experimental evidence for a cell surface receptor signaling function of protocadherins regulated by proteolytic events.
引用
收藏
页码:9313 / 9319
页数:7
相关论文
共 41 条
  • [1] Aberle H, 1996, J CELL BIOCHEM, V61, P514, DOI 10.1002/(SICI)1097-4644(19960616)61:4<514::AID-JCB4>3.3.CO
  • [2] 2-D
  • [3] Angst BD, 2001, J CELL SCI, V114, P625
  • [4] Presenilins: molecular switches between proteolysis and signal transduction
    Annaert, W
    De Strooper, B
    [J]. TRENDS IN NEUROSCIENCES, 1999, 22 (10) : 439 - 443
  • [5] Presenilin-1 binds cytoplasmic epithelial cadherin, inhibits cadherin/p120 association, and regulates stability and function of the cadherin/catenin adhesion complex
    Baki, L
    Marambaud, P
    Efthimiopoulos, S
    Georgakopoulos, A
    Wen, P
    Cui, W
    Shioi, J
    Koo, E
    Ozawa, M
    Friedrich, VL
    Robakis, NK
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (05) : 2381 - 2386
  • [6] Presenilins, processing of β-amyloid precursor protein, and Notch signaling
    Chan, YM
    Jan, YN
    [J]. NEURON, 1999, 23 (02) : 201 - 204
  • [7] The amyloid precursor protein (APP)-cytoplasmic fragment generated by γ-secretase is rapidly degraded but distributes partially in a nuclear fraction of neurones in culture
    Cupers, P
    Orlans, I
    Craessaerts, K
    Annaert, W
    De Strooper, B
    [J]. JOURNAL OF NEUROCHEMISTRY, 2001, 78 (05) : 1168 - 1178
  • [8] A core function for p120-catenin in cadherin turnover
    Davis, MA
    Ireton, RC
    Reynolds, AB
    [J]. JOURNAL OF CELL BIOLOGY, 2003, 163 (03) : 525 - 534
  • [9] DE SB, 1999, NATURE, V398, P518
  • [10] Reconstitution of γ-secretase activity
    Edbauer, D
    Winkler, E
    Regula, JT
    Pesold, B
    Steiner, H
    Haass, C
    [J]. NATURE CELL BIOLOGY, 2003, 5 (05) : 486 - 488