Document Detail

Gamma-secretase-regulated proteolysis of the Notch receptor by mitochondrial intermediate peptidase.
MedLine Citation:
PMID:  21685396     Owner:  NLM     Status:  MEDLINE    
Notch is a transmembrane receptor that controls a diverse array of cellular processes including cell proliferation, differentiation, survival, and migration. The cellular outcome of Notch signaling is dependent on extracellular and intracellular signals, but the complexities of its regulation are not well understood. Canonical Notch signaling involves ligand association that triggers sequential and regulated proteolysis of Notch at several sites. Ligand-dependent proteolysis at the S2 site removes the bulk of the extracellular domain of Notch. Subsequent γ-secretase-mediated intramembrane proteolysis of the remaining membrane-tethered Notch fragment at the S3 site produces a nuclear-destined Notch intracellular domain (NICD). Here we show that following γ-secretase cleavage, Notch is proteolyzed at a novel S5 site. We have identified this S5 site to be eight amino acids downstream of the S3 site. Biochemical fractionation and purification resulted in the identification of the S5 site protease as the mitochondrial intermediate peptidase (MIPEP). Expression of the MIPEP-cleaved NICD (ΔNICD) results in a decrease in cell viability and mitochondria membrane potential. The sequential and regulated proteolysis by γ-secretase and MIPEP suggests a new means by which Notch function can be modulated.
Sheu-Fen Lee; Bhooma Srinivasan; Chantelle F Sephton; Daniel R Dries; Bing Wang; Cong Yu; Yun Wang; Colleen M Dewey; Sanjiv Shah; Jin Jiang; Gang Yu
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-06-17
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-08-01     Completed Date:  2011-10-10     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  27447-53     Citation Subset:  IM    
Department of Neuroscience, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
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MeSH Terms
Amyloid Precursor Protein Secretases / metabolism*
Base Sequence
HeLa Cells
Metalloendopeptidases / metabolism*
RNA Interference
RNA, Small Interfering
Receptors, Notch / metabolism*
Signal Transduction
Grant Support
Reg. No./Substance:
0/RNA, Small Interfering; 0/Receptors, Notch; EC 3.4.-/Amyloid Precursor Protein Secretases; EC 3.4.24.-/Metalloendopeptidases; EC intermediate peptidase

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