Phosphorylation, Subcellular Localization, and Membrane Orientation of the Alzheimer's Disease-associated Presenilins

Strooper, Bart De; Beullens, Monique; Contreras, Bart; Lévesque, Lyne; Craessaerts, Katleen; Cordell, Barbara; Moechars, Dieder; Bollen, Mathieu; Fraser, Paul E.; George-Hyslop, Peter St; Leuven, Fred Van

doi:10.1074/jbc.272.6.3590

Cited by 272 publications

(215 citation statements)

References 51 publications

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“…Confocal microscopic analysis of cells without any treatment showed that CD44 was mainly localized to filopodia of the plasma membrane (Figure 3a). PS1 was abundant in the perinuclear region (Figure 3b) as previously reported (De Strooper et al, 1997). However, a small amount of PS1 was detected at the plasma membrane ( Figure 3b) and colocalized with CD44 partially (Figure 3c).…”

Section: Figure 1 Continuedsupporting

confidence: 54%

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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Section: Figure 1 Continuedsupporting

confidence: 54%

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

et al. 2003

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“…g-Secretase is thought to be an internal protease that cleaves within the membrane-spanning domain of all its substrate proteins. g-Secretase (PS1/NTF) is localized at the plasma membrane in cells with extensive cell-cell contacts (36)(37)(38)(39)(40)(41). On the basis of this g-secretase distribution, it did not seem that g-secretase would naturally favor Notch over E-cadherin cleavage in the well-formed spheroids.…”

Section: Discussionmentioning

confidence: 99%

Early to Intermediate Steps of Tumor Embolic Formation Involve Specific Proteolytic Processing of E-Cadherin Regulated by Rab7

Yin

Gao

Tian

et al. 2012

Molecular Cancer Research

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The lymphovascular embolus is an enigmatic entity adept at metastatic dissemination and chemotherapy resistance. Using MARY-X, a human breast cancer xenograft that exhibits florid lymphovascular emboli in mice and spheroids in vitro, we established a model where the in vitro transition stages from minced tumoral aggregates to well-formed spheroids served as a surrogate for in vivo emboli formation. MARY-X well-formed spheroids and emboli exhibited strong similarity of expression. The aggregate-to-spheroid transition stages were characterized by increased ExoC5, decreased Hgs and Rab7, increased calpains, increased full-length E-cadherin (E-cad/FL), and the transient appearance of E-cad/NTF2, a 95 kDa E-cadherin fragment and increased Notch3icd (N3icd), the latter two fragments produced by increased g-secretase. Both transient and permanent knockdowns of Rab7 in MCF-7 cells increased protein but not transcription of E-cad/FL and resulted in the de novo appearance of E-cad/NTF2, the presence of nuclear E-cad/CTF2, and increased Notch1icd (N1icd). Overexpression of Rab7 conversely decreased E-cad/FL, g-secretase (PS1/NTF), and E-cad/NTF2. Overexpression of calpains did not alter PS1/NTF but decreased E-cad/FL and E-cad/NTF2 and increased N1icd. Well-formed spheroids showed increased Rab7, absent E-cad/NTF2, decreased PS1/NTF, increased E-cad/NTF1, and increased N3icd, the latter two fragments being the direct and indirect consequences, respectively, of increased calpains (calpain 1 and calpain 2). Inhibition of calpains decreased E-cad/NTF1 but increased E-cad/NTF2 showing that calpains compete with g-secretase (PS1) for closely located cleavage/binding sites on E-cadherin and that increased calpains can shuttle even decreased

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“…Similarly, stable cells transfected with the first series of mutant cDNAs (K306A, K306E, KL/AP, and MAK/3A cells) showed increased amounts of the full-length polypeptides, NTF and CTF ( Fig. 2A, top and bottom panels, lanes [5][6][7][8][9][10][11][12], and decreased levels of endogenous PS1NTF and CTF (Fig. 2B, lanes 5-12).…”

Section: Endoproteolytic Processing Of Ps2 With Cleavagementioning

confidence: 99%

Mutational Analysis of Intrinsic Regions of Presenilin 2 That Determine Its Endoproteolytic Cleavage and Pathological Function

Shirotani¹,

Takahashi²,

Araki³

et al. 2000

Journal of Biological Chemistry

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To investigate the significance of endoproteolytic processing of presenilin 2 (PS2) on its pathological function, we constructed PS2 cDNAs causing amino acid substitutions or deletions around the cleavage site. We found that a PS2 mutant (Del3) with a 20-amino acid deletion was not endoproteolytically processed, while other PS2s with amino acid substitutions and short deletions were cleaved. Overproduction of all the mutant proteins led to a compensatory decrease of endogenous PS1 fragments, but did not affect the amyloid ␤ peptide X-42/A␤ X-40 ratio without the familial Alzheimer's disease mutation. The Del3 mutant did not exhibit significant deficits in ␥-secretase activity. The turnover rate of the Del3 holoprotein was the same as that of full-length PS2. These data suggest that the determinants of the PS2 cleavage site reside within a large region and that the pathological function of PS2 is exerted by familial Alzheimer's disease mutations not related to the cleavage of holoproteins. We also found that PS2 with an 18-amino acid deletion at the C-terminal end was not processed. Its overexpression led neither to diminished accumulation of endogenous PS1 fragments nor to increased production of amyloid ␤ peptide X-42. The Cterminal end of PS2 seems to possess the signal for entry into the processing pathway.Mutations in homologous presenilin 1 and 2 (PS1 1 and PS2) genes are associated with early-onset autosomal dominant familial Alzheimer's disease (FAD) (1-3). To date, more than 50 different pathogenic missense mutations and one splice site mutation (loss of exon 10, designated as PS1⌬E10) have been found in PS1, and two missense mutations have been identified in PS2. The gene products of PS1 and PS2 are thought to contain six or eight transmembrane (TM) domains, and the N and C termini and a large hydrophilic loop region following the sixth TM domain are located within the cytoplasm (4 -6). PS1 proteins are involved in cell fate decisions by facilitating Notch signaling pathway (7-9). Recently, PS1 proteins have been shown to have a role in the endoproteolytic processing of ␤-amyloid precursor protein (APP) (10, 11) and , and trafficking of proteins including APP (15) and Notch (12, 13), while the physiological function of PS2 proteins is poorly understood. The amount of highly amyloidogenic A␤42 (amyloid ␤ peptide 42) increases in cells and transgenic mice with the PS1 and PS2 mutant genes (16 -20), supporting a hypothesis that mutations in PS lead to Alzheimer's disease by increasing the extracellular levels of A␤42.The PS proteins are proteolytically cleaved at the hydrophilic loop region and detected predominantly as N-terminal fragments (NTF) and C-terminal fragments (CTF) in culture cells and tissues (19,(21)(22)(23). The formation of PS fragments is highly regulated in a saturable and stoichiometric manner, since overproduction of full-length PS in transfected cells and transgenic mice does not yield a linear increase of fragments (21) and causes a compensatory decrease of the endogenous PS fragments...

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Phosphorylation, Subcellular Localization, and Membrane Orientation of the Alzheimer's Disease-associated Presenilins

Cited by 272 publications

References 51 publications

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

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

Early to Intermediate Steps of Tumor Embolic Formation Involve Specific Proteolytic Processing of E-Cadherin Regulated by Rab7

Mutational Analysis of Intrinsic Regions of Presenilin 2 That Determine Its Endoproteolytic Cleavage and Pathological Function

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