Presenilin 1 is involved in maturation and trafficking of N‐cadherin to the plasma membrane

Uemura, Kazunori; Kitagawa, Naoyuki; Kohno, Ryuichi; Kuzuya, Akira; Kageyama, Takashi; Chonabayashi, Kazuhisa; Shibasaki, Hiroshi; Shimohama, Shun

doi:10.1002/jnr.10753

Cited by 43 publications

(28 citation statements)

References 44 publications

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“…These include proteins that are substrates for ␥-secretase activity (APP, cadherins, tyrosinase, ErbB4, and others) (17,41,43,44) and those that are not ␥-secretase substrates (TrkB, telencephalin, ␣-synuclein, ␤-catenin, EGFR, and others) (8, 14 -16). Although the precise manner in which PS1 regulates the trafficking and turnover of each of these proteins may not be uniform, PS1 appears to function as a hub that modulates multiple and disparate signaling and trafficking events via both intramembrane proteolysis and other mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Presenilin 1 Regulates Epidermal Growth Factor Receptor Turnover and Signaling in the Endosomal-Lysosomal Pathway

Repetto

Yoon

Zheng

et al. 2007

Journal of Biological Chemistry

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Mutations in the gene encoding presenilin 1 (PS1) cause the most aggressive form of early-onset familial Alzheimer disease. In addition to its well established role in A␤ production and Notch proteolysis, PS1 has been shown to mediate other physiological activities, such as regulation of the Wnt/␤-catenin signaling pathway, modulation of phosphatidylinositol 3-kinase/ Akt and MEK/ERK signaling, and trafficking of select membrane proteins and/or intracellular vesicles. In this study, we present evidence that PS1 is a critical regulator of a key signaling receptor tyrosine kinase, epidermal growth factor receptor (EGFR). Specifically, EGFR levels were robustly increased in fibroblasts deficient in both PS1 and PS2 (PS ؊/؊ ) due to delayed turnover of EGFR protein. Stable transfection of wild-type PS1 but not PS2 corrected EGFR to levels comparable to PS ؉/؉ cells, while FAD PS1 mutations showed partial loss of activity. The C-terminal fragment of PS1 was sufficient to fully reduce EGFR levels. In addition, the rapid ligand-induced degradation of EGFR was markedly delayed in PS ؊/؊ cells, resulting in prolonged signal activation. Despite the defective turnover of EGFR, ligand-induced autophosphorylation, ubiquitination, and endocytosis of EGFR were not affected by the lack of PS1. Instead, the trafficking of EGFR from early endosomes to lysosomes was severely delayed by PS1 deficiency. Elevation of EGFR was also seen in brains of adult mice conditionally ablated in PS1 and in skin tumors associated with the loss of PS1. These findings demonstrate a critical role of PS1 in the trafficking and turnover of EGFR and suggest potential pathogenic effects of elevated EGFR as well as perturbed endosomal-lysosomal trafficking in cell cycle control and Alzheimer disease.Mutations in genes encoding presenilin 1 (PS1) 2 and presenilin 2 (PS2) account for the vast majority of early onset familial Alzheimer disease (FAD) (1, 2). Presenilins are multipass transmembrane proteins that form the core enzymatic activity of the ␥-secretase complex together with nicastrin, pen-2, and aph-1. These four proteins are required for regulated intramembrane proteolysis of multiple type I transmembrane proteins, including APP and Notch, such that the loss of any one of these four proteins destabilizes the complex and abrogates ␥-secretase activity (3). Accordingly, null mice for any one of these components display embryonic lethality associated with severe malformations of the axial skeleton and cerebral hemorrhage, resembling that of Notch deficiency (3). As expected, this activity is conserved in Caenorhabditis elegans and Drosophila where the presenilin complex functions to facilitate Notch signaling (4, 5).FAD mutations in PS1 and PS2 alter the activity of the ␥-secretase complex, leading to the change in the ratio of A␤ to that favoring A␤42 generation and accelerated amyloid deposition in brain (6). Although the amyloid hypothesis is the leading model for AD pathogenesis, the aggressive early age of disease onset by PS1 FAD mutations have...

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Section: Discussionmentioning

confidence: 99%

Presenilin 1 Regulates Epidermal Growth Factor Receptor Turnover and Signaling in the Endosomal-Lysosomal Pathway

Repetto

Yoon

Zheng

et al. 2007

Journal of Biological Chemistry

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“…PS/␥-secretase-mediated release of E-cadherin ICD has been shown to result in the disassembly of adherens junctions (19). On the other hand, PS1 was demonstrated to complex with cadherins and ␤-and ␣-catenins, localize to intercellular contacts and synaptic adhesions in vivo, and enhance cell adhesion, while the PS1/D385A mutant suppressed cell adhesion (61,62). Therefore, PS function and PS-dependent ␥-secretase activity may differentially regulate cell adhesion.…”

Section: Discussionmentioning

confidence: 99%

Presenilin/γ-Secretase-mediated Cleavage Regulates Association of Leukocyte-Common Antigen-related (LAR) Receptor Tyrosine Phosphatase with β-Catenin

Haapasalo

Kim

Carey

et al. 2007

Journal of Biological Chemistry

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Leukocyte-common antigen-related (LAR) receptor tyrosine phosphatase regulates cell adhesion and formation of functional synapses and neuronal networks. Here we report that LAR is sequentially cleaved by ␣-and presenilin (PS)/␥-secretases, which also affect signaling and/or degradation of type-I membrane proteins including the Alzheimer disease-related ␤-amyloid precursor protein. Similar to the previously characterized PS/␥-secretase substrates, inhibition of ␥-secretase activity resulted in elevated LAR C-terminal fragment (LAR-CTF) levels in stably LAR-overexpressing Chinese hamster ovary (CHO) cells, human neuroglioma cells, and mouse cortical neurons endogenously expressing LAR. Furthermore, LAR-CTF levels increased in cells lacking functional PS, indicating that ␥-secretase-mediated cleavage of LAR was PS-dependent. Inhibition of ␣-secretase activity by TAPI-1 treatment blocked LAR-CTF accumulation, demonstrating that prior ectodomain shedding was prerequisite for PS/␥-secretase-mediated cleavage of LAR. Moreover, we identified the product of PS/␥-secretase cleavage, LAR intracellular domain (LICD), both in vitro and in cells overexpressing full-length (FL) LAR or LAR-CTFs. LAR localizes to cadherin-␤-catenin-based cellular junctions. Assembly and disassembly of these junctions are regulated by tyrosine phosphorylation. We found that endogenous tyrosine-phosphorylated ␤-catenin coimmunoprecipitated with LAR in CHO cells. However, when PS/␥-secretase activity was inhibited, the association between LAR and ␤-catenin significantly diminished. In addition to cell adhesion, ␤-catenin is involved in transcriptional regulation. We observed that LICD significantly decreased transcription of cyclin D1, one of the ␤-catenin target genes. Thus, our results show that PS/␥-secretase-mediated cleavage of LAR controls LAR-␤-catenin interaction, suggesting an essential role for PS/␥-secretase in the regulation of LAR signaling. Presenilin (PS)2 /␥-secretase is a high molecular weight enzymatic complex composed of PS1 or PS2, nicastrin, Aph-1, and Pen-2 (1-5). PS/␥-secretase plays a key role in the pathogenesis of Alzheimer disease (AD) by cleaving ␤-amyloid precursor protein (APP) by regulated intramembraneous processing (RIP) at two adjacent sites (6 -8). Following ectodomain shedding of APP, the ␥-cleavage generates the A␤-peptide, the major constituent of amyloid plaques in AD brain, and a small p3 fragment. The product of the ⑀-cleavage is the APP intracellular domain (AICD) (9 -11). APP ectodomain shedding is mediated by either ␣-secretases of the ADAM family metalloproteases (12, 13) or BACE (␤-site APP cleaving enzyme) (14 -17), producing membrane-bound APP C-terminal fragments (CTFs). In addition to APP, other type-I membrane proteins are known to undergo PS/␥-secretase-mediated RIP (18). Among these are Notch (8), cadherins (19), nectin-1␣ (20), and voltagegated sodium channel ␤2-subunit (21, 22). Similar to APP, these proteins undergo ectodomain shedding prior to ␥-secretase-mediated cleavage and release intrace...

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“…Western Blot and Immunoprecipitation-Preparation of protein samples, the Western blot, and immunoprecipitation analysis were carried out as described elsewhere (25). For some experiments, cells were fractionated as previously described (25).…”

Section: Methodsmentioning

confidence: 99%

“…Immunostaining-The samples for immunostaining were prepared as described elsewhere (25). Samples were examined using a laser scanning confocal microscopy, LSM 510 META (Zeiss), or a fluorescence microscopy, Axiovert 200 (Zeiss).…”

Section: Methodsmentioning

confidence: 99%

GSK3β Activity Modifies the Localization and Function of Presenilin 1

Uemura

Kuzuya

Shimozono

et al. 2007

Journal of Biological Chemistry

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Presenilin 1 is involved in maturation and trafficking of N‐cadherin to the plasma membrane

Cited by 43 publications

References 44 publications

Presenilin 1 Regulates Epidermal Growth Factor Receptor Turnover and Signaling in the Endosomal-Lysosomal Pathway

Presenilin 1 Regulates Epidermal Growth Factor Receptor Turnover and Signaling in the Endosomal-Lysosomal Pathway

Presenilin/γ-Secretase-mediated Cleavage Regulates Association of Leukocyte-Common Antigen-related (LAR) Receptor Tyrosine Phosphatase with β-Catenin

GSK3β Activity Modifies the Localization and Function of Presenilin 1

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