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Cytokine Growth Factor Rev. 2004 Oct;15(5):337-51.

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

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Department of Pathology, Center for Neurobiology and Behavior, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.


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.

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