Characterization of sequential N-cadherin cleavage by ADAM10 and PS1

Uemura, Kazunori; Kihara, Takeshi; Kuzuya, Akira; Okawa, Katsuya; Nishimoto, Takaaki; Ninomiya, Haruaki; Sugimoto, Hachiro; Kinoshita, Ayae; Shimohama, Shun

doi:10.1016/j.neulet.2006.04.018

Cited by 108 publications

(116 citation statements)

References 22 publications

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“…5A). As reported previously (15), N-cadherin is sequentially cleaved by ADAM10 , top), whereas the expression in the endoplasmic reticulum fraction (bottom) was comparable. B, either wtPS1 or one of the pseudo-phosphorylation mutants (S353D or S357D PS1) was transfected into MEF PS Ϫ/Ϫ cells.…”

Section: Ps1⅐n-cadherin⅐␤-catenin Complex Formation Is Required For Csupporting

confidence: 79%

“…receptor stimulation (14,15). Thus, the subcellular distribution of PS1/␥-secretase in neurons would be altered dynamically in the course of synaptic remodeling, which would also change processing of various adhesion and receptor molecules.…”

Section: Discussionmentioning

confidence: 99%

“…Actually, in neurons, PS1 binds to ␤-catenin and N-(and E-) cadherin through a large hydrophilic loop region (13) at the synapse. Moreover, N-cadherin is cleaved by PS1/␥-secretase in response to N-methyl-D-aspartic acid-type receptor stimulation (14,15). N-cadherin is essential for synaptic contact (16) and regulates synaptogenesis and dendritic spine morphology (17,18).…”

Section: Pathological Features Of Alzheimer Disease (Ad)mentioning

confidence: 99%

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GSK3β Activity Modifies the Localization and Function of Presenilin 1

Uemura

Kuzuya

Shimozono

et al. 2007

Journal of Biological Chemistry

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Section: Ps1⅐n-cadherin⅐␤-catenin Complex Formation Is Required For Csupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Pathological Features Of Alzheimer Disease (Ad)mentioning

confidence: 99%

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GSK3β Activity Modifies the Localization and Function of Presenilin 1

Uemura

Kuzuya

Shimozono

et al. 2007

Journal of Biological Chemistry

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“…The proteolytic cleavage by ADAM10 -as well as by PS1/g-secretase -is critically important for the roles of CDH2 in cell adhesion and cell signaling. 42,43 In addition, a prior study showed that induced single aminoacid changes that disrupted self-assembly of the transmembrame region reduced E-cadherin cell-cell adhesiveness. 41 Thus, N706S, found in one OCD proband, an unrelated TD proband, and an unrelated TD proband's sibling with chronic tics, and in none of the 447 healthy controls in this study, may represent a very rare variant related to the complex OCD, TD as well as perhaps bipolar and other neuropsychiatric disorder phenotypes found in these individuals and at least one of their relatives.…”

Section: Resultsmentioning

confidence: 99%

Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes

et al. 2013

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The recent finding that the neuronal cadherin gene CDH2 confers a highly significant risk for canine compulsive disorder led us to investigate whether missense variants within the human ortholog CDH2 are associated with altered susceptibility to obsessive-compulsive disorder (OCD), Tourette disorder (TD) and related disorders. Exon resequencing of CDH2 in 320 individuals identified four non-synonymous single-nucleotide variants, which were subsequently genotyped in OCD probands, Tourette disorder probands and relatives, and healthy controls (total N ¼ 1161). None of the four variants was significantly associated with either OCD or TD. One variant, N706S, was found only in the OCD/TD groups, but not in controls. By examining clinical data, we found there were significant TD-related phenotype differences between those OCD probands with and without the N845S variant with regard to the co-occurrence of TD (Fisher's exact test P ¼ 0.014, OR ¼ 6.03). Both N706S and N845S variants conferred reduced CDH2 protein expression in transfected cells. Although our data provide no overall support for association of CDH2 rare variants in these disorders considered as single entities, the clinical features and severity of probands carrying the uncommon non-synonymous variants suggest that CDH2, along with other cadherin and cell adhesion genes, is an interesting gene to pursue as a plausible contributor to OCD, TD and related disorders with repetitive behaviors, including autism spectrum disorders.

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“…This unusual proteolytic complex indeed has an important role in cell signalling pathways by processing different type-I transmembrane cell receptors including the Notch receptors, the Insulin receptor and the Growth hormone receptor 6 . In the brain, it maintains synaptic contacts by regulating cleavage of neuronal adhesion molecules like Cadherins and Neurexins 7,8 . With the continuously growing number of substrates the need for understanding the exact molecular mechanism of this particular proteolytic processing arises.…”

mentioning

confidence: 99%

Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

et al. 2013

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Pathological amino-acid substitutions in the amyloid precursor protein (APP) and chemical g-secretase modulators affect the processing of APP by the g-secretase complex and the production of the amyloid-beta peptide Ab42, the accumulation of which is considered causative of Alzheimer's disease. Here we demonstrate that mutations in the transmembrane domain of APP causing aggressive early-onset familial Alzheimer's disease affect both g-and e-cleavage sites, by raising the Ab42/40 ratio and inhibiting the production of AICD50-99, one of the two physiological APP intracellular domains (ICDs). This is in sharp contrast to g-secretase modulators, which shift Ab42 production towards the shorter Ab38, but unequivocally spare the e-site and APP-and Notch-ICDs production. Molecular simulations suggest that familial Alzheimer's disease mutations modulate the flexibility of the APP transmembrane domain and the presentation of its g-site, modifying at the same time, the solvation of the e-site.

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Characterization of sequential N-cadherin cleavage by ADAM10 and PS1

Cited by 108 publications

References 22 publications

GSK3β Activity Modifies the Localization and Function of Presenilin 1

GSK3β Activity Modifies the Localization and Function of Presenilin 1

Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes

Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

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