P1-273 Nuclear translocation of the APP intracellular domain (AICD) and its role in cellular toxicity

2004 ◽  
Vol 25 ◽  
pp. S174
Author(s):  
Ellen Kilger ◽  
Gabriele Vacun ◽  
Monika Palchaudhuri ◽  
Bernd Sommer ◽  
Mathias Jucker ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Intracellular Domain ◽  
Cellular Toxicity

scholarly journals NUMB enhances Notch signaling by repressing ubiquitination of NOTCH1 intracellular domain

2019 ◽  
Vol 12 (5) ◽  
pp. 345-358 ◽  
Author(s):  
Zhiyuan Luo ◽  
Lili Mu ◽  
Yue Zheng ◽  
Wenchen Shen ◽  
Jiali Li ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Posttranslational Modifications ◽  
Transcriptional Activation ◽  
Neural Progenitor Cells ◽  
Nuclear Translocation ◽  
Notch Receptor ◽  
Deubiquitinating Enzyme ◽  
Intracellular Domain ◽  
Ubiquitin Proteasome ◽  
Notch1 Receptor

Abstract The release and nuclear translocation of the intracellular domain of Notch receptor (NICD) is the prerequisite for Notch signaling-mediated transcriptional activation. NICD is subjected to various posttranslational modifications including ubiquitination. Here, we surprisingly found that NUMB proteins stabilize the intracellular domain of NOTCH1 receptor (N1ICD) by regulating the ubiquitin–proteasome machinery, which is independent of NUMB’s role in modulating endocytosis. BAP1, a deubiquitinating enzyme (DUB), was further identified as a positive N1ICD regulator, and NUMB facilitates the association between N1ICD and BAP1 to stabilize N1ICD. Intriguingly, BAP1 stabilizes N1ICD independent of its DUB activity but relying on the BRCA1-inhibiting function. BAP1 strengthens Notch signaling and maintains stem-like properties of cortical neural progenitor cells. Thus, NUMB enhances Notch signaling by regulating the ubiquitinating activity of the BAP1–BRCA1 complex.

scholarly journals The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone

2004 ◽  
Vol 167 (3) ◽  
pp. 469-478 ◽  
Author(s):  
Christopher C. Williams ◽  
June G. Allison ◽  
Gregory A. Vidal ◽  
Matthew E. Burow ◽  
Barbara S. Beckman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Transcription Factor ◽  
Nuclear Translocation ◽  
Cancer Cell Line ◽  
Nuclear Accumulation ◽  
Intracellular Domain ◽  
Receptor Signal ◽  
Transcription Factor Target ◽  
Lactating Breast

In the lactating breast, ERBB4 localizes to the nuclei of secretory epithelium while regulating activities of the signal transducer and activator of transcription (STAT) 5A transcription factor essential for milk-gene expression. We have identified an intrinsic ERBB4 NLS (residues 676–684) within the ERBB4 intracellular domain (4ICD) that is essential for nuclear accumulation of 4ICD. To determine the functional significance of 4ICD nuclear translocation in a physiologically relevant system, we have demonstrated that cotransfection of ERBB4 and STAT5A in a human breast cancer cell line stimulates β-casein promoter activity. Significantly, nuclear localization of STAT5A and subsequent stimulation of the β-casein promoter requires nuclear translocation of 4ICD. Moreover, 4ICD and STAT5A colocalize within nuclei of heregulin β1 (HRG)-stimulated cells and both proteins bind to the endogenous β-casein promoter in T47D breast cancer cells. Together, our results establish a novel molecular mechanism of transmembrane receptor signal transduction involving nuclear cotranslocation of the receptor intracellular domain and associated transcription factor. Subsequent binding of the two proteins at transcription factor target promoters results in activation of gene expression.

scholarly journals The Neogenin Intracellular Domain Regulates Gene Transcription via Nuclear Translocation

2008 ◽  
Vol 28 (12) ◽  
pp. 4068-4079 ◽  
Author(s):  
David Goldschneider ◽  
Nicolas Rama ◽  
Catherine Guix ◽  
Patrick Mehlen
Keyword(s):  
Cell Death ◽  
Transcriptional Regulation ◽  
Neuronal Differentiation ◽  
Nuclear Import ◽  
Nuclear Translocation ◽  
Notch Receptor ◽  
Nuclear Proteins ◽  
Nuclear Chromatin ◽  
Intracellular Domain ◽  
Import And Export

ABSTRACT Neogenin is a multifunctional receptor implicated in axon navigation, neuronal differentiation, morphogenesis, and cell death. Very little is known about signaling downstream of neogenin. Because we found that the neogenin intracellular domain (NeICD) interacts with nuclear proteins implicated in transcription regulation, we investigated further whether neogenin signals similarly to the Notch receptor. We show here that neogenin is cleaved by γ-secretase, an event that releases the complete NeICD. We also describe that NeICD is located at the nucleus, a feature regulated through a balance between nuclear import and export. NeICD triggers gene reporter transactivation and associates with nuclear chromatin. Direct transcriptional targets of NeICD were determined and were shown to be up-regulated in the presence of neogenin ligand. Together, we reveal here a novel aspect of neogenin signaling that relies on the direct implication of its intracellular domain in transcriptional regulation.

scholarly journals Phosphorylation of Amyloid Precursor Protein (APP) at Thr668 Regulates the Nuclear Translocation of the APP Intracellular Domain and Induces Neurodegeneration

2006 ◽  
Vol 26 (11) ◽  
pp. 4327-4338 ◽  
Author(s):  
Keun-A Chang ◽  
Hye-Sun Kim ◽  
Tae-Young Ha ◽  
Ji-Won Ha ◽  
Ki Young Shin ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Nuclear Translocation ◽  
Glycogen Synthase ◽  
Neuronal Degeneration ◽  
Specific Inhibitor ◽  
Precursor Protein ◽  
Intracellular Domain ◽  
Neuronal Functions ◽  
The Brain ◽  
Constitutive Phosphorylation

ABSTRACT Amyloid precursor protein (APP) has eight potential phosphorylation sites in its cytoplasmic domain. Recently, it has demonstrated that the constitutive phosphorylation of APP at T668 (APP695 isoform numbering) was observed specifically in the brain. Neuron-specific phosphorylation of APP at T668 is thought to be important for neuronal functions of APP, although its exact physiological significance remains to be clarified. In this study, we show that the phosphorylation of the APP intracellular domain (AICD) at T668 is essential for its binding to Fe65 and its nuclear translocation and affects the resultant neurotoxicity, possibly mediated through the induction of glycogen synthase kinase 3β and tau phosphorylation by enhancing the formation of a ternary complex with Fe65 and CP2 transcription factor. Taken together, these results suggest that the phosphorylation of AICD at T668 contributes to the neuronal degeneration in Alzheimer's disease (AD) by regulating its translocation into the nucleus and then affects neurodegeneration; therefore, the specific inhibitor of T668 phosphorylation might be the target of AD therapy.

scholarly journals Novel Notch signaling inhibitor NSI‑1 suppresses nuclear translocation of the Notch intracellular domain

2019 ◽  
Author(s):  
Takaya Shiraishi ◽  
Masahiro Sakaitani ◽  
Satoko Otsuguro ◽  
Katsumi Maenaka ◽  
Toshiharu Suzuki ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Nuclear Translocation ◽  
Intracellular Domain ◽  
Notch Intracellular Domain
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