PMID- 14527950
OWN - NLM
STAT- MEDLINE
DCOM- 20040130
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 278
IP  - 51
DP  - 2003 Dec 19
TI  - Generation of the beta-amyloid peptide and the amyloid precursor protein 
      C-terminal fragment gamma are potentiated by FE65L1.
PG  - 51100-7
AB  - Members of the FE65 family of adaptor proteins, FE65, FE65L1, and FE65L2, bind 
      the C-terminal region of the amyloid precursor protein (APP). Overexpression of 
      FE65 and FE65L1 was previously reported to increase the levels of 
      alpha-secretase-derived APP (APPs alpha). Increased beta-amyloid (A beta) 
      generation was also observed in cells showing the FE65-dependent increase in APPs 
      alpha. To understand the mechanism for the observed increase in both A beta and 
      APPs alpha given that alpha-secretase cleavage of a single APP molecule precludes 
      A beta generation, we examined the effects of FE65L1 overexpression on APP 
      C-terminal fragments (APP CTFs). Our data show that FE65L1 potentiates 
      gamma-secretase processing of APP CTFs, including the amyloidogenic CTF C99, 
      accounting for the ability of FE65L1 to increase generation of APP C-terminal 
      domain and A beta 40. The FE65L1 modulation of these processing events requires 
      binding of FE65L1 to APP and APP CTFs and is not because of a direct effect on 
      gamma-secretase activity, because Notch intracellular domain generation is not 
      altered by FE65L1. Furthermore, enhanced APP CTF processing can be detected in 
      early endosome vesicles but not in endoplasmic reticulum or Golgi membranes, 
      suggesting that the effects of FE65L1 occur at or near the plasma membrane. 
      Finally, although FE65L1 increases APP C-terminal domain production, it does not 
      mediate the APP-dependent transcriptional activation observed with FE65.
FAU - Chang, Yang
AU  - Chang Y
AD  - Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative 
      Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, 
      Massachusetts 02129-4404, USA.
FAU - Tesco, Giuseppina
AU  - Tesco G
FAU - Jeong, William J
AU  - Jeong WJ
FAU - Lindsley, Loren
AU  - Lindsley L
FAU - Eckman, Elizabeth A
AU  - Eckman EA
FAU - Eckman, Christopher B
AU  - Eckman CB
FAU - Tanzi, Rudolph E
AU  - Tanzi RE
FAU - Guenette, Suzanne Y
AU  - Guenette SY
LA  - eng
GR  - AG/NS14713/AG/NIA NIH HHS/United States
GR  - AG15903/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20031003
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (APBB2 protein, human)
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Carrier Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Receptors, Notch)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
RN  - EC 3.4.- (Endopeptidases)
RN  - EC 3.4.23.- (Aspartic Acid Endopeptidases)
RN  - EC 3.4.23.46 (BACE1 protein, human)
SB  - IM
MH  - *Adaptor Proteins, Signal Transducing
MH  - Amino Acid Sequence
MH  - Amyloid Precursor Protein Secretases
MH  - Amyloid beta-Peptides/*biosynthesis
MH  - Amyloid beta-Protein Precursor/*biosynthesis/metabolism
MH  - Aspartic Acid Endopeptidases
MH  - Carrier Proteins/metabolism/*physiology
MH  - Cell Line, Tumor
MH  - Endopeptidases/metabolism
MH  - Endosomes/metabolism
MH  - Humans
MH  - Membrane Proteins/biosynthesis
MH  - Organelles/metabolism
MH  - Protein Binding
MH  - Protein Processing, Post-Translational
MH  - Receptors, Notch
EDAT- 2003/10/07 05:00
MHDA- 2004/01/31 05:00
CRDT- 2003/10/07 05:00
PHST- 2003/10/07 05:00 [pubmed]
PHST- 2004/01/31 05:00 [medline]
PHST- 2003/10/07 05:00 [entrez]
AID - S0021-9258(20)75366-4 [pii]
AID - 10.1074/jbc.M309561200 [doi]
PST - ppublish
SO  - J Biol Chem. 2003 Dec 19;278(51):51100-7. doi: 10.1074/jbc.M309561200. Epub 2003 
      Oct 3.