Nuclear signalling by membrane protein intracellular domains: The AICD enigma

Beckett, Caroline S.; Nalivaeva, Natalia N.; Belyaev, Nikolai D.; Turner, Anthony J.

doi:10.1016/j.cellsig.2011.10.007

Cited by 73 publications

(63 citation statements)

References 109 publications

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“…␥-Secretase cleaves APP at ␥-sites within the transmembrane domain to generate A␤ peptides of varying length and also at the ⑀-site near the cytoplasmic membrane border of APP to generate the APP intracellular domain (AICD) (9). In analogy to the other membrane proteins that are subject to ␥-secretase cleavage, including the Notch receptor (10), it has been proposed that AICD can translocate to the nucleus and regulate gene transcription (11).…”

mentioning

confidence: 99%

The Role of γ-Secretase Activating Protein (GSAP) and Imatinib in the Regulation of γ-Secretase Activity and Amyloid-β Generation

Hussain

Fabrègue

Anderes

et al. 2013

Journal of Biological Chemistry

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Background: ␥-Secretase activating protein, GSAP, was identified as a novel regulator of ␥-secretase and amyloid-␤ production. Results: Reducing GSAP expression in cells decreased amyloid-␤ generation. However, overexpression of GSAP in cells and recombinant GSAP in vitro did not modulate amyloid-␤ generation. Conclusion:The relationship between GSAP and ␥-secretase is unclear. Significance: GSAP is not a validated therapeutic target for Alzheimer disease.

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mentioning

confidence: 99%

The Role of γ-Secretase Activating Protein (GSAP) and Imatinib in the Regulation of γ-Secretase Activity and Amyloid-β Generation

Hussain

Fabrègue

Anderes

et al. 2013

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

“…These metabolites include AICD, which regulates expression of numerous genes (61,62), as well as sAPP␣ and sAPP␤, whose mechanisms of action are still poorly understood (60). Of the APP fragments, AICD is by far the best characterized as a transcriptional regulator (31,(61)(62)(63). A large number of genes have been linked to AICD (64), with some consistently shown to be up-regulated, such as neprilysin (33,34), and a much smaller number to be down-regulated, such as the EGF receptor (65).…”

Section: Discussionmentioning

confidence: 99%

The Amyloid Precursor Protein Represses Expression of Acetylcholinesterase in Neuronal Cell Lines

Hicks

Makova

Gough

et al. 2013

Journal of Biological Chemistry

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Background: Acetylcholinesterase (AChE) and amyloid precursor protein (APP) are implicated in Alzheimer's disease, but their specific biological roles remain unclear. Results: Overexpression or knockdown of neuronal APP modulates AChE mRNA, protein levels, and enzyme activity. Conclusion: APP can act as a transcriptional regulator through a novel mechanism independently of ␥-secretase. Significance: Understanding the physiological functions of APP will lead to a greater understanding of Alzheimer's disease etiology.

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“…This is the case of the amyloid precursor protein, Notch and CD44 (Beckett et al, 2012;Nagano and Saya, 2004), whose intracellular domains, when released by -secretase cleavage, are targeted to the nucleus where they regulate gene expression.…”

Section: Biological Implications Of Pdpn Cleavagementioning

confidence: 99%

Podoplanin is a substrate of presenilin-1/γ-secretase

Yurrita¹,

Fernández‐Muñoz²,

Castillo³

et al. 2014

The International Journal of Biochemistry & Cell Biology

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Podoplanin (PDPN) is a mucin-like transmembrane glycoprotein that plays an important role in development and cancer. Here, we provide evidence that the intracellular domain (ICD) of podoplanin is released into the cytosol following a sequential proteolytic processing by a metalloprotease and -secretase. Western blotting and cell fractionation studies revealed that HEK293T and MDCK cells transfected with an eGFP-tagged podoplanin construct (PDPNeGFP,(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63) constitutively express two C-terminal fragments (CTFs): a ~3 3 kDa membrane-bound PCTF33, and a ~2 9 kDa cytosolic podoplanin ICD (PICD). While pharmacological inhibition of metalloproteases reduced the expression of PCTF33, treatment of cells with -secretase inhibitors resulted in enhanced PCTF33 levels. PCTF33 processing by -secretase depends on presenilin-1 (PS1) function: cells expressing a dominant negative form of PS1 (PS1 D385N), and mouse embryonic fibroblasts (MEFs) genetically deficient in PS1, but not in PS2, show higher levels of PCTF33 expression with respect to wild-type MEFs. Furthermore, transfection of PS1 deficient MEFs with wild-type PS1 (PS1 wt) decreased PCTF33 levels. N-terminal amino acid sequencing of the affinity purified PICD revealed that the -secretase cleavage site was located between valines 150 and 151, but these residues are not critical for proteolysis. We found that podoplanin CTFs are also generated in cells expressing podoplanin mutants harboring heterologous transmembrane regions. Taken together, these results indicate that podoplanin is a novel substrate for PS1/-secretase.

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Nuclear signalling by membrane protein intracellular domains: The AICD enigma

Cited by 73 publications

References 109 publications

The Role of γ-Secretase Activating Protein (GSAP) and Imatinib in the Regulation of γ-Secretase Activity and Amyloid-β Generation

The Role of γ-Secretase Activating Protein (GSAP) and Imatinib in the Regulation of γ-Secretase Activity and Amyloid-β Generation

The Amyloid Precursor Protein Represses Expression of Acetylcholinesterase in Neuronal Cell Lines

Podoplanin is a substrate of presenilin-1/γ-secretase

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