Key Points
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The presenilin–γ-secretase complex mediates the intramembrane proteolysis of the Notch receptor and the amyloid precursor protein (APP).
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Several lines of evidence indicate that presenilin is likely to function as the catalytic core of the γ-secretase proteolytic activity.
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APP and Notch have alternate intramembrane cleavage sites that depend on γ-secretase activity.
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Intramembrane cleavage of γ-secretase substrates is preceded by ectodomain shedding that is mediated by extracellular cleavage events.
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Several new putative γ-secretase substrates have recently been identified, including the ErbB4 receptor tyrosine kinase, the CD44 cell-surface protein, E-cadherin, and the low-density lipoprotein-receptor-related protein (LRP).
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For APP, ErbB4, CD44 and LRP, intramembrane proteolysis apparently liberates a signalling fragment of the molecule, which is similar to the role of this cleavage event in the Notch pathway.
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A newly characterized type of intramembrane proteolysis generates secreted ligands that activate the epidermal growth factor receptor (EGFR).
Abstract
Many cell-surface receptors transmit signals to the nucleus through complex protein cascades. By contrast, the Notch signalling pathway uses a relatively direct mechanism, in which the intracellular domain of the receptor is liberated by intramembrane cleavage and translocates to the nucleus. This critical cleavage is mediated by the γ-secretase complex, and new findings reveal that this mechanism is used by various receptors, although many questions remain about the biochemical details.
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Acknowledgements
I am grateful to members of my lab for helpful discussions, and to J. Nye and D. Curtis for sharing their results before publication. This work was supported by a grant from the National Institutes of Health and intramural funding from the National Cancer Institute.
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Glossary
- TYPE I INTEGRAL MEMBRANE PROTEIN
-
A protein that is tightly associated with the membrane, has at most one hydrophobic region that completely or partially resides in the lipid bilayer, and is oriented with its amino-terminal segment inserted into the extracellular/lumenal space (as opposed to type II proteins, which have a carboxy-terminal extracellular/lumenal orientation).
- HOLOPROTEIN
-
The entire protein in its intact form, before post-translational modifications, that remove portions of the polypeptide chain or cleave the polypeptide into smaller fragments.
- ENDOPROTEOLYTIC CLEAVAGE
-
A proteolytic cleavage event that occurs at an internal site of a protease, as opposed to the proteolytic cleavage of a different substrate molecule.
- BACTERIAL TYPE 4 PREPILIN PROTEASES
-
A family of polytopic aspartyl proteases that are needed for the cleavage of precursor proteins, which are assembled into certain filamentous cell-surface structures, termed type 4 pili, and which are important for motility, antigenicity and other contact-dependent processes of many Gram-negative bacteria.
- FURIN-LIKE CONVERTASE
-
A type of protease that belongs to the family of subtilisin/kexin-like, calcium-dependent enzymes that process proproteins in the secretory pathway.
- FAST ANTEROGRADE TRANSPORT
-
Rapid energy-dependent movement of material in a proximal-to-distal direction in a cell or organelle (for example, from the cell body towards the axon terminus of a neuron).
- RETROGRADE TRANSPORT
-
Movement of material in a distal-to-proximal direction in a cell or organelle (for example, from peripheral regions towards the cell body of a neuron).
- PROTEASOME
-
A large multiprotein complex that is responsible for the proteolytic degradation of many intracellular proteins that have been targeted for destruction by the covalent addition of ubiquitin.
- AXONOGENESIS
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The formation and growth of thin thread-like neuronal extensions that conduct signals from the neuronal cell body to the specialized cellular sites where the neuron contacts other neurons.
- DENDRITIC ARBORIZATION
-
The formation of finely branched tree-like structures on dendrites, which are long extensions of the neuronal cell body that receive signals from other neurons.
- SYNAPTIC DIFFERENTIATION
-
The process by which a morphologically and biologically distinct junction between the axon of one neuron and the dendrite of another forms during development and becomes specialized for the transmission of signals between neurons.
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Fortini, M. γ-Secretase-mediated proteolysis in cell-surface-receptor signalling. Nat Rev Mol Cell Biol 3, 673–684 (2002). https://doi.org/10.1038/nrm910
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DOI: https://doi.org/10.1038/nrm910
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