Characterization of an Atypical γ-Secretase Complex from Hematopoietic Origin

被引：16
作者：
Placanica, Lisa [1 ,2 ]
Chien, Jennifer W. [1 ,2 ]
Li, Yue-Ming [1 ,2 ]
机构：
[1] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10065 USA
[2] Cornell Univ, Dept Pharmacol, Joan Weill Grad Sch Med Sci, New York, NY 10021 USA
来源：
BIOCHEMISTRY | 2010年 / 49卷 / 13期
关键词：
AMYLOID PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; PRESENILIN ENDOPROTEOLYSIS; NOTCH; APH-1; PEN-2; INHIBITORS; EXPRESSION; NICASTRIN; MODULATION;
D O I：
10.1021/bi901388t
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：
gamma-Secretase is a widely expressed multisubunit enzyme complex which is involved in the pathogenesis of Alzheimer disease and hematopoietic malignancies through its aberrant processing of the amyloid precursor protein (APP) and Notch1, respectively. While gamma-secretase has been extensively studied, there is a dearth of information surrounding the activity, composition, and function of gamma-secretase expressed in distinct cellular populations. Here we show that endogenous gamma-secretase complexes of hematopoietic origin are distinct from epithelial derived gamma-secretase complexes. Hematopoietic gamma-secretase has reduced activity for APP and Notch I processing compared to epithelial gamma-secretase. Characterization of the active complexes with small molecule affinity probes reveals that hematopoietic gamma-secretase has an atypical subunit composition with significantly altered subunit stoichiometry. Furthermore, we demonstrate that these discrete complexes exhibit cell-line specific substrate selectivity suggesting a possible mechanism of substrate regulation. These data underscore the need for studying endogenous gamma-secretase to fully understand of the biology of gamma-secretase and its complexity as a molecular target for the development of disease therapeutics.
引用
收藏
页码：2796 / 2804
页数：9
相关论文
共 54 条
[1]   Notch signaling in hematopoiesis and early lymphocyte development [J].
Allman, D ;
Aster, JC ;
Pear, WS .
IMMUNOLOGICAL REVIEWS, 2002, 187 :75-86
[2]   In vitro characterization of the presenilin-dependent γ-secretase complex using a novel affinity ligand [J].
Beher, D ;
Fricker, M ;
Nadin, A ;
Clarke, EE ;
Wrigley, JDJ ;
Li, YM ;
Culvenor, JG ;
Masters, CL ;
Harrison, T ;
Shearman, MS .
BIOCHEMISTRY, 2003, 42 (27) :8133-8142
[3]   Notch signaling in development and cancer [J].
Bolos, Victoria ;
Grego-Bessa, Joaquin ;
de la Pompa, Jose Luis .
ENDOCRINE REVIEWS, 2007, 28 (03) :339-363
[4]   Presenilin endoproteolysis is an intrarnolecular cleavage [J].
Brunkan, AL ;
Martinez, M ;
Walker, ES ;
Goate, AM .
MOLECULAR AND CELLULAR NEUROSCIENCE, 2005, 29 (01) :65-73
[5]   Presenilin function and γ-secretase activity [J].
Brunkan, AL ;
Goate, AM .
JOURNAL OF NEUROCHEMISTRY, 2005, 93 (04) :769-792
[6]   TMP21 is a presenilin complex component that modulates γ-secretase but not ε-secretase activity [J].
Chen, FS ;
Hasegawa, H ;
Schmitt-Ulms, G ;
Kawarai, T ;
Bohm, C ;
Katayama, T ;
Gu, YJ ;
Sanjo, N ;
Glista, M ;
Rogaeva, E ;
Wakutani, Y ;
Pardossi-Piquard, R ;
Ruan, XY ;
Tandon, A ;
Checler, F ;
Marambaud, P ;
Hansen, K ;
Westaway, D ;
St George-Hyslop, P ;
Fraser, P .
NATURE, 2006, 440 (7088) :1208-1212
[7]   Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1 [J].
Esler, WP ;
Kimberly, WT ;
Ostaszewski, BL ;
Diehl, TS ;
Moore, CL ;
Tsai, JY ;
Rahmati, T ;
Xia, WM ;
Selkoe, DJ ;
Wolfe, MS .
NATURE CELL BIOLOGY, 2000, 2 (07) :428-434
[8]   Inhibition of γ-secretase as a therapeutic intervention for Alzheimer's disease -: Prospects, limitations and strategies [J].
Evin, Genevieve ;
Sernee, Marijke Fleur ;
Masters, Colin L. .
CNS DRUGS, 2006, 20 (05) :351-372
[9]   aph-1 and pen-2 are required for notch pathway signaling, γ-secretase cleavage of βAPP, and presenilin protein accumulation [J].
Francis, R ;
McGrath, G ;
Zhang, JH ;
Ruddy, DA ;
Sym, M ;
Apfeld, J ;
Nicoll, M ;
Maxwell, M ;
Hai, B ;
Ellis, MC ;
Parks, AL ;
Xu, W ;
Li, JH ;
Gurney, M ;
Myers, RL ;
Himes, CS ;
Hiebsch, R ;
Ruble, C ;
Nye, JS ;
Curtis, D .
DEVELOPMENTAL CELL, 2002, 3 (01) :85-97
[10]   The presenilin proteins are components of multiple membrane-bound complexes that have different biological activities [J].
Gu, YJ ;
Sanjo, N ;
Chen, FS ;
Hasegawa, H ;
Petit, A ;
Ruan, XY ;
Li, WP ;
Shier, C ;
Kawarai, T ;
Schmitt-Ulms, G ;
Westaway, D ;
St George-Hyslop, P ;
Fraser, PE .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (30) :31329-31336
123456