Requirements for Presenilin-Dependent Cleavage of Notch and Other Transmembrane Proteins

Struhl, Gary; Adachi, Atsuko

doi:10.1016/s1097-2765(00)00061-7

Cited by 401 publications

(360 citation statements)

References 64 publications

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“…Furthermore, a 50-amino acid stretch of the Met extracellular juxtamembrane domain, added to the TRK-Met chimera, is necessary and sufficient to initiate ectodomain shedding and further ␥-secretase cleavage. This is consistent with the observation that ␥-secretase cleavage depends on prior ectodomain shedding (Struhl and Adachi, 2000). Presenilin is the catalytic core of the ␥-secretase complex (De Strooper, 2003).…”

Section: Discussionsupporting

confidence: 91%

Down-Regulation of the Met Receptor Tyrosine Kinase by Presenilin-dependent Regulated Intramembrane Proteolysis

Foveau

Ancot

Leroy

et al. 2009

MBoC

100

113

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Section: Discussionsupporting

confidence: 91%

Down-Regulation of the Met Receptor Tyrosine Kinase by Presenilin-dependent Regulated Intramembrane Proteolysis

Foveau

Ancot

Leroy

et al. 2009

MBoC

100

113

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“…Thus, accumulating evidence suggests that PS/g-secretase cleavage of adhesion molecules is a key mechanism for their functional regulation. Of note, one determination of whether a protein is a substrate for presenilin-dependent cleavage appears to be the size of extracellular domain rather than the recognition of specific target sequences (Struhl and Adachi, 2000). Since several other adhesion molecules, similarly to CD44 and E-cadherin, are found to be cleaved at the ectodomain (Hooper et al, 1997;Egeblad and Werb, 2002), they may be also targeted for PS/g-secretase intramembranous cleavage.…”

Section: Figure 1 Continuedmentioning

confidence: 99%

Presenilin-dependent γ-secretase activity mediates the intramembranous cleavage of CD44

et al. 2003

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CD44 is the major adhesion molecule for the extracellular matrix components and is implicated in a wide variety of physiological and pathological processes including the regulation of tumor cell growth and metastasis. Our previous studies have shown that CD44 undergoes sequential proteolytic cleavages in the extracellular and transmembrane domains and the cleavage product derived from CD44 intramembranous cleavage acts as a signal transduction molecule. However, the underlying mechanism of the intramembranous cleavage of CD44 remains to be elucidated. In the present study, we report for the first time that CD44 is a substrate of the presenilin (PS)-dependent c-secretase. We demonstrate that the intramembranous cleavage of CD44 induced by 12-Otetradecanoylphorbol 13-acetate (TPA) treatment or mechanical scraping is blocked by c-secretase inhibitors in U251MG cells and that this cleavage is also inhibited in PS-deficient mouse embryonic fibroblasts. Furthermore, we showed that PS1 is redistributed to ruffling areas of the plasma membrane similarly to CD44 after TPA treatment, supporting our biochemical observation that PS1 is involved in the intramembranous cleavage of CD44. Our present findings suggest important implications for understanding CD44-dependent signal transduction and a potential role of PS/c-secretase activity in the functional regulation of adhesion molecules.

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“…The function of nicastrin within the γ-secretase complex is beginning to emerge. Ectodomain shedding is a prerequisite for γ-secretase cleavage of substrates [47]. The extracellular domain of nicastrin binds to C-terminal stubs generated by ectodomain shedding of type I membrane protein substrates, thus recruiting substrates for cleavage by the γ-secretase [43].…”

Section: Introductionmentioning

confidence: 99%

Cellular distribution of γ-secretase subunit nicastrin in the developing and adult rat brains

Kodam

Vetrivel

Wang

et al. 2008

Neurobiology of Aging

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Nicastrin and presenilin 1 are integral components of the high molecular weight γ-secretase complexes that regulate proteolytic processing of various type I membrane proteins including amyloid precursor protein and Notch. At present, there is little information regarding the cellular distribution of nicastrin in the developing or adult rat brain. We report here, using immunoblotting and immunohistochemical methods, that nicastrin in the adult rat brain is widely expressed and colocalized with presenilin 1 in select neuronal populations within all major areas, including the basal forebrain, striatum, cortex, hippocampus, amygdala, thalamus, hypothalamus, cerebellum and brainstem. We also observed dense neuropil labeling in many regions in the brain, suggesting that nicastrin gets transported to dendrites and/or axon terminals in the central nervous system. The levels of nicastrin are found to be relatively high at the early stages of postnatal development and then declined gradually to reach the adult profile. At the cellular level, nicastrin is localized predominantly in neuronal cell bodies at early postanatal stages, but is apparent both in cell bodies and dendrites/ neuropil in all brain regions at the later stages. The regulation of nicastrin expression and localization during development and its distribution in a wide spectrum of neurons in the postnatal and adult rat brains provide an anatomical basis to suggest a multifunctional role for the γ-secretase complex in the developing and adult rat brains.

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Requirements for Presenilin-Dependent Cleavage of Notch and Other Transmembrane Proteins

Cited by 401 publications

References 64 publications

Down-Regulation of the Met Receptor Tyrosine Kinase by Presenilin-dependent Regulated Intramembrane Proteolysis

Down-Regulation of the Met Receptor Tyrosine Kinase by Presenilin-dependent Regulated Intramembrane Proteolysis

Presenilin-dependent γ-secretase activity mediates the intramembranous cleavage of CD44

Cellular distribution of γ-secretase subunit nicastrin in the developing and adult rat brains

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