Murine Notch Homologs (N1–4) Undergo Presenilin-dependent Proteolysis*

Oncogenic forms of Notch1, Notch2, and Notch4 appear to mimic signaling intermediates of Notch1 and suggest that the role of proteolysis in Notch signaling has been conserved. Here we demonstrate that extracellularly truncated Notch homologs are substrates for a presenilin-dependent γ-secretase activity. Despite minimal conservation within the transmembrane domain, the requirement for a specific amino acid (P1′ valine) and its position at the cleavage site relative to the cytosolic border of the transmembrane domain are preserved. Cleaved, untethered Notch intracellular domains from each receptor translocate to the nucleus and interact with the transcriptional regulatory protein CSL. All four Notch proteins display presenilin-dependent transactivating potential on a minimal promoter reporter. Thus, this study increases the number of biochemically characterized γ-secretase substrates from two to five. Despite a high degree of structural homology and the presenilin-dependent activity of truncated Notch proteins, the extent that this reflects functional redundancy is unknown.

• Publication year

  2001

• Venue

  Journal of Biological Chemistry

• Publication date

  2001-10-26

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/JBC.M107234200PMID 11518718
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• All four murine Notch proteins show presenilin-dependent transactivating potential on a minimal promoter reporter.

  Confidence 0.95

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAK (4715169a40) review
• Cleaved Notch intracellular domains from each receptor translocate to the nucleus and interact with CSL.

  Confidence 0.97

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAK (4715169a40) review
• The requirement for a P1′ valine at the cleavage site, and its position relative to the cytosolic border of the transmembrane domain, is preserved across the Notch homologs examined.

  Confidence 0.94

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAK (4715169a40) review
• Extracellularly truncated Notch homologs are substrates for a presenilin-dependent gamma-secretase activity.

  Confidence 0.98

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAK (4715169a40) review

• csl

  protein, transcription factor

  A transcriptional regulatory protein that binds Notch intracellular domains in the nucleus.

  Aliases: CBF1, Su(H), Lag-1

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAK (4715169a40) review
• cytosolic border of the transmembrane domain

  protein region, membrane region

  The intracellular boundary of the membrane-spanning segment where the Notch cleavage position is mapped.

  Aliases: cytoplasmic border of the transmembrane domain, intracellular border of the transmembrane domain

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAK (4715169a40) review
• extracellularly truncated notch homologs

  protein, substrate

  Notch receptor homologs lacking their extracellular portion and therefore retaining the membrane-tethered signaling fragment studied here.

  Aliases: truncated Notch homologs, extracellularly truncated Notch proteins

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAK (4715169a40) review
• minimal promoter reporter

  reporter, assay system

  A reporter construct with a minimal promoter used to assay Notch-dependent transcriptional activation.

  Aliases: minimal promoter construct, reporter assay

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAK (4715169a40) review
• murine notch homologs n1–4

  protein family, receptor family

  The four murine Notch receptor homologs Notch1, Notch2, Notch3, and Notch4 examined in this paper.

  Aliases: Notch1-4, N1-4, Notch proteins

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAK (4715169a40) review
• notch intracellular domain

  protein fragment, signaling domain

  The cleaved intracellular fragment of Notch that is released from the membrane-tethered receptor.

  Aliases: NICD, Notch IC domain

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAK (4715169a40) review
• p1′ valine

  amino acid, cleavage-site residue

  The valine residue immediately C-terminal to the Notch cleavage site examined in the transmembrane region.

  Aliases: P1 prime valine, P1-prime valine

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAK (4715169a40) review
• presenilin-dependent gamma-secretase

  enzyme activity, protease activity

  A presenilin-requiring intramembrane protease activity implicated in cleavage of membrane-tethered Notch proteins.

  Aliases: gamma-secretase activity, presenilin-dependent proteolysis

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewKiller Whale (322360f1c1) reviewAK (4715169a40) review

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