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Neuron. 2002 May 16;34(4):499-502.

A RIP tide in neuronal signal transduction.

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  • 1Department of Neurology, Harvard Medical School and, Division of Neuroscience, The Children's Hospital, Enders 260, 300 Longwood Avenue, 02115, Boston, MA 02115, USA.


The generation of nuclear signaling proteins by regulated intramembrane proteolysis (RIP) is a new paradigm of signal transduction. Mammalian proteins that are processed by RIP include SREBP-1, Notch-1, amyloid precursor protein (APP), and ErbB-4. Intramembranous gamma-secretase cleavage of APP plays a central role in Alzheimer's disease by generating the amyloid beta protein. An intriguing possibility is that the cognate C-terminal fragment generated by gamma-secretase cleavage could also play a role through the regulation of nuclear signaling events. Thus, RIP may contribute to both brain development and degeneration and may provide unexpected diversity to the signaling repertoire of a cell.

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