Got RIP? Presenilin-dependent intramembrane proteolysis in growth factor receptor signaling

Cytokine Growth Factor Rev. 2004 Oct;15(5):337-51. doi: 10.1016/j.cytogfr.2004.04.001.


A number of cell surface growth factor receptors are subject to presenilin-dependent regulated intramembrane proteolysis (PS-RIP) after ligand binding and/or ectodomain cleavage. PS-RIP is mediated by a highly conserved multi-component membrane-bound protease, termed gamma-secretase, responsible for generating Alzheimer's disease (AD)-associated Abeta peptide from its membrane-bound beta-amyloid precursor protein (APP), as well as for cleaving a number of other type-I membrane receptors. PS-RIP is a conserved cellular process by which cells transmit signals from one compartment to another, including the liberation of membrane-bound transcription factors. Recent studies indicate that PS-RIP also mediates the proteolytic inactivation of heteromeric receptor complexes by removing the transmembrane domains required for receptor-receptor interaction. Thus, PS-RIP appears to regulate diverse cellular pathways either by generating soluble effectors from membrane-bound precursors, or by removing the transmembrane domain of a membrane-tethered signaling component.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amyloid Precursor Protein Secretases
  • Animals
  • Aspartic Acid Endopeptidases
  • Cell Membrane / metabolism*
  • Endopeptidases / metabolism
  • Humans
  • Membrane Proteins / metabolism*
  • Nuclear Envelope / metabolism*
  • Presenilin-1
  • Receptors, Growth Factor / metabolism*
  • Signal Transduction / physiology*


  • Membrane Proteins
  • PSEN1 protein, human
  • Presenilin-1
  • Receptors, Growth Factor
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human