| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.97293267 |
| Activated Notch 1 associates with a presenilin 1 / gamma secretase docking site . 0.97293267^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| Recent studies have implicated presenilin 1 ( PS 1 ) in the processing of the amyloid precursor protein and Notch 1 . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| Presenilin 1 is required for Notch 1 and DII 1 expression in the paraxial mesoderm . ^^^ Moreover , expression of mRNA encoding Notch 1 and Dll 1 ( delta like gene 1 ) , a vertebrate Notch ligand , is markedly reduced in the presomitic mesoderm of PS 1 / embryos compared to controls . ^^^ Hence , PS 1 is required for the spatiotemporal expression of Notch 1 and Dll 1 , which are essential for somite segmentation and maintenance of somite borders . . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| We reasoned that , if Notch1 / PS 1 interaction is relevant in Alzheimer disease , Notch 1 would also need to be expressed in neurons in adult brain and colocalized with PS 1 . ^^^ Double immunofluorescent staining demonstrates neuronal colocalization of Notch 1 with PS 1 . ^^^ These results support the hypothesis that Notch 1 continues to play a role in terminally differentiated neurons , and that Notch1 / PS 1 interactions may occur in adult mammalian brain . ^^^ The alteration in Notch 1 expression in sporadic Alzheimer disease raises the possibility that disruption of Notch1 / PS 1 functional interactions may occur in Alzheimer disease . . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| To gain insight into the biochemical basis of this genetic interaction , we tested the possibility that presenilin 1 ( PS 1 ) physically associates with the Notch 1 receptor in mammalian cells . ^^^ Notch 1 and PS 1 coimmunoprecipitated from transiently transfected human embryonic kidney 293 cell lysates in a detergent sensitive manner , consistent with a noncovalent physical association between the two proteins . ^^^ The interaction predominantly occurred early in the secretory pathway prior to Notch cleavage in the Golgi , because PS 1 immunoprecipitation preferentially recovered the full length Notch 1 precursor . ^^^ When PS 1 was immunoprecipitated from 293 cells that had been metabolically labeled with [ 35S ] methionine and [ 35S ] cysteine , Notch 1 was the primary protein detected in PS 1 immunoprecipitates , suggesting that this interaction is specific . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| Proteolytic release and nuclear translocation of Notch 1 are induced by presenilin 1 and impaired by pathogenic presenilin 1 mutations . ^^^ Here we show that proteolytic release of the Notch 1 intracellular domain ( NICD ) , an essential step in the activation of Notch signaling , is markedly reduced in presenilin 1 ( PS 1 ) deficient cells and is restored by PS 1 expression . ^^^ These results suggest that PS 1 plays a central role in the proteolytic activation of the Notch 1 signaling pathway and that this function is impaired by pathogenic PS 1 mutations . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| The Alzheimer related gene presenilin 1 facilitates notch 1 in primary mammalian neurons . ^^^ To better understand the potential role of Notch 1 in mammalian postmitotic neurons and to test the hypothesis that Notch and PS 1 interact , we studied the effect of Notch 1 transfection on neurite outgrowth in primary cultures of hippocampal / cortical neurons . ^^^ Furthermore , we present evidence demonstrating that there is a functional interaction between PS 1 and Notch 1 in mammalian neurons , analogous to the sel 12 / lin 12 interaction in vulval development in C . elegans [ D . ^^^ The inhibitory effect of Notch 1 on neurite outgrowth is markedly attenuated in neurons from PS 1 knockout mice , and enhanced in neurons from transgenic mice overexpressing wild type PS 1 , but not mutant PS 1 . ^^^ These data suggest that PS 1 facilitates Notch 1 function in mammalian neurons , and support the hypothesis that a functional interaction exists between PS 1 and Notch 1 in postmitotic mammalian neurons . . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| Presenilin 1 ( PS 1 ) facilitates gamma secretase cleavage of the beta amyloid precursor protein and the intramembraneous cleavage of Notch 1 . ^^^ Presenilin 1 ( PS 1 ) facilitates gamma secretase cleavage of the beta amyloid precursor protein and the intramembraneous cleavage of Notch 1 . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| Although PS 1 ( + / ) PS 2 ( / ) mice survive in relatively good health , complete deletion of both PS 2 and PS 1 genes causes a phenotype closely resembling full Notch 1 deficiency . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| We show here that these aspartates are required for Notch processing , since mutation of these residues prevents PS 1 from inducing the gamma secretase like proteolysis of a Notch 1 derivative . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| Lack of requirement for presenilin 1 in Notch 1 signaling . ^^^ Here , we report that Notch 1 signaling elicited by the ligand Delta 1 was quantitatively unchanged in PS 1 deficient primary embryonic fibroblasts ( PEFs ) . ^^^ Although signaling through Notch 1 persisted in PS 1 deficient cells , we found a marked reduction in the appearance of a complex of a cleaved , intracellular Notch fragment ( NICD ) and a CSL protein , as previously reported [ 6 ] [ 10 ] . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| In the ventricular zone of PS 1 ( / ) mice , expression of the Notch 1 downstream effector gene Hes 5 is reduced and expression of the Notch 1 ligand Dll 1 is elevated , whereas expression of Notch 1 is unchanged . ^^^ The level of Dll 1 transcripts is also increased in the presomitic mesoderm of PS 1 ( / ) embryos , while the level of Notch 1 transcripts is unchanged , in contrast to a previous report ( Wong et al . , 1997 , Nature 387 , 288 292 ) . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| It has been hypothesized that a presenilin 1 ( PS 1 ) related enzymatic activity is responsible for proteolytic cleavage of the C terminal intracellular protein of Notch 1 , in addition to its role in beta amyloid protein ( Abeta ) formation from the amyloid precursor protein ( APP ) . ^^^ Using this assay , we now confirm and extend the observation that PS 1 is involved in Notch 1 nuclear translocation and signaling in mammalian cells . ^^^ We demonstrate that the D257A and the D385A PS 1 mutations , which had been shown previously to block APP gamma secretase activity , also prevent Notch 1 cleavage and translocation to the nucleus but do not alter Notch 1 trafficking to the cell surface . ^^^ Notch 1 signaling , assessed by measuring the activity of CBF 1 , a downstream transcription factor , was impaired but not abolished by the PS 1 aspartate mutations or gamma secretase inhibitors . ^^^ Our results support the hypotheses that ( a ) PS 1 dependent APP gamma secretase like enzymatic activity is critical for both APP and Notch processing and ( b ) the Notch 1 signaling pathway remains partially activated even when Notch 1 proteolytic processing and nuclear translocation are markedly inhibited . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| The loss of function of sel 12 in C . elegans is not associated with a dominant negative activity in human cells , because SEL 12 C60S and the corresponding PS 1 C92S mutation do not interfere with Notch 1 cleavage . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| Notch 1 activation by familial Alzheimer ' s disease ( FAD ) linked mutant forms of presenilin 1 . ^^^ To assess Notch 1 processing and its nuclear localization in familial Alzheimer ' s disease ( FAD ) linked presenilin 1 ( PS 1 ) mutants , we overexpressed wild type , M146V , A246E , C410Y , or deltaE 9 PS 1 mutant with a membrane bound Notch 1 in a PS 1 deficient cell line . ^^^ On Western blot and immunocytochemical analyses using the NICD specific antibody , M146V and A246E mutants showed the comparable levels of Notch 1 processing and nuclear localizing activities to wild type PS 1 whereas C410Y and deltaE 9 mutants failed to show these activities . ^^^ These results suggest that the loss or partial loss of PS 1 activities in Notch 1 proteolysis and its nuclear translocation may be irrelevant for the neuropathology of Alzheimer ' s disease . . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| Previous work in non neuronal cells indicates that presenilin 1 ( PS 1 ) associates with cytoskeletal elements and that it facilitates Notch 1 signaling . ^^^ Because Notch 1 participates in the control of neurite growth , cultured hippocampal neurons were used to investigate the cytoskeletal association of PS 1 and its potential role during neuronal development . ^^^ In differentiated neurons , PS 1 mutations reduced the interaction of PS 1 with cytoskeletal elements , diminished the nuclear translocation of the Notch 1 intracellular domain ( NICD ) , and promoted a marked increase in total neurite length . ^^^ In the Alzheimer ' s brain PS 1 mutations may promote neuritic dystrophy and tangle formation by interfering with Notch 1 signaling and enhancing pathological changes in tau . . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| In the ventricular zone of PS 1 / mice , expression of the Notch 1 downstream effector gene Hes 5 is reduced , and expression of the Notch 1 ligand Dll 1 is elevated , indicating reduced Notch signaling . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| Recent data suggest an intimate relationship between the familial Alzheimer disease gene presenilin 1 ( PS 1 ) and proteolytic processing of both the amyloid precursor protein ( APP ) and the important cell signaling molecule , Notch 1 . ^^^ Using this assay , we demonstrate that the same aspartate mutations in PS 1 that block APP processing also prevent Notch 1 cleavage and translocation to the nucleus . ^^^ Our results support the hypothesis that similar PS 1 related enzymatic activity is necessary for both APP and Notch 1 processing , yet suggest that Notch signaling may remain relatively preserved with moderate levels of gamma secretase inhibition . . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| Presenilin 1 ( PS 1 ) has been implicated in normal Notch 1 processing and signaling in several experimental systems . ^^^ Effect of PS 1 deficiency and an APP gamma secretase inhibitor on Notch 1 signaling in primary mammalian neurons . ^^^ Presenilin 1 ( PS 1 ) has been implicated in normal Notch 1 processing and signaling in several experimental systems . ^^^ In the present study , the relationship between PS 1 and Notch 1 in mammalian neurons is studied by analyzing Notch 1 cleavage and C terminal nuclear translocation as well as Notch 1 signaling via the transactivation of a CBF 1 luciferase reporter construct . ^^^ PS 1 deficient neurons show normal Notch 1 insertion into the cellular membrane , yet lack Notch 1 activation resulting in markedly inhibited nuclear translocation of the C terminal Notch fragment ( NICD ) . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| In Psen 1 deficient mice , proteolytic activation of Notch 1 was significantly affected and the expression of several genes involved in the Notch signalling pathway was altered , including Delta like 3 , Hes 5 , lunatic fringe ( Lfng ) and Mesp 2 . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| Requirement for presenilin 1 in facilitating lagged 2 mediated endoproteolysis and signaling of notch 1 . ^^^ Moreover , in a ligand independent , Ca2+ depletion paradigm , we demonstrate that PS 1 facilitates endoproteolysis of a plasma membrane associated , Notch 1 GFP derivative . ^^^ These findings strongly suggest that intramembranous processing of APP and Notch 1 are mediated by similar , if not identical , proteases that require PS 1 for their activation . . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| The cytoplasmic portion of Notch 1 DeltaE was released from the membrane upon incubation at 37 degrees C , which was inhibited by the specific gamma secretase inhibitor , MW 167 , or by overexpression of dominant negative presenilin 1 . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| In addition , the inhibitory response of the cells to the FGFs could be overcome by downregulating Notch 1 expression and by disrupting Notch cleavage and signaling by the ablation of the Presenilin 1 gene . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| Western blot analysis revealed the expression of three Notch receptors ( Notch 1 , Notch 2 , and Notch 3 ) , Notch ligands ( Jagged 1 , Jagged 2 , and Delta 1 ) , and presenilin 1 ( PS 1 ) in neonatal mouse testis . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| PSEN 1 and PSEN 2 encode polytopic membrane proteins , termed presenilin 1 ( PS 1 ) and presenilin 2 ( PS 2 ) that play an essential role in intramembranous ( `` gamma secretase ' ' ) proteolysis of selected type 1 membrane proteins , that include Notch 1 and beta amyloid precursor protein ( APP ) . ^^^ Moreover , S3 / NICD production is neither detected in detergent solubilized membrane preparations from PS 1 deficient cells , nor in reactions containing PS 1 containing membranes that were co solubilized with membranes from PS / cells expressing a chimeric Notch 1 species . ^^^ PSEN 1 and PSEN 2 encode polytopic membrane proteins , termed presenilin 1 ( PS 1 ) and presenilin 2 ( PS 2 ) that play an essential role in intramembranous ( `` gamma secretase ' ' ) proteolysis of selected type 1 membrane proteins , that include Notch 1 and beta amyloid precursor protein ( APP ) . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| Oncogenic Ras increases levels and activity of the intracellular form of wild type Notch 1 , and upregulates Notch ligand Delta 1 and also presenilin 1 , a protein involved in Notch processing , through a p 38 mediated pathway . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| Presenilin 1 ( PS 1 ) and presenilin 2 play a critical role in the gamma secretase processing of amyloid precursor protein ( APP ) and Notch 1 . ^^^ Presenilin 1 ( PS 1 ) and presenilin 2 play a critical role in the gamma secretase processing of amyloid precursor protein ( APP ) and Notch 1 . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| Presenilin 1 ( PS 1 ) plays an essential role in intramembranous `` gamma secretase ' ' processing of several type 1 membrane proteins , including the beta amyloid precursor proteins ( APP ) and Notch 1 . ^^^ Presenilin 1 ( PS 1 ) plays an essential role in intramembranous `` gamma secretase ' ' processing of several type 1 membrane proteins , including the beta amyloid precursor proteins ( APP ) and Notch 1 . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| Notch 1 competes with the amyloid precursor protein for gamma secretase and down regulates presenilin 1 gene expression . ^^^ Presenilin 1 ( PS 1 ) is a critical component of the gamma secretase complex , which is involved in the cleavage of several substrates including the amyloid precursor protein ( APP ) and Notch 1 . ^^^ Presenilin 1 ( PS 1 ) is a critical component of the gamma secretase complex , which is involved in the cleavage of several substrates including the amyloid precursor protein ( APP ) and Notch 1 . ^^^ In this report , we examined the interactions between APP , Notch , and PS 1 using the direct gamma secretase substrates , Notch 1 Delta extracellular domain ( N1DeltaEC ) and APP carboxyl terminal fragment of 99 amino acids , and measured the effects on amyloid beta protein production and Notch signaling , respectively . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| Presenilin 1 is indirectly implicated in Notch 1 cleavage . ^^^ SUMMARY : It has been previously demonstrated that the Notch 1 signalling pathway is impaired in presenilin 1 null cells . ^^^ This observation suggests a role for presenilin 1 in the Notch 1 developmental pathway , possibly through physical interaction . ^^^ Here , we show that presenilin 1 and Notch 1 do not interact directly with each other but are associated in the cell . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| Expressing PS 1 or PS 2 but not the intracellular form of Notch 1 in PS1 / 2 null cells restored normal caveolin 1 localization , demonstrating that presenilins are required for the subcellular trafficking of caveolin 1 independently from Notch activity . ^^^ |
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| Interacting proteins: P46531 and P49768 |
Pubmed |
SVM Score :0.0 |
| In embryonic brain , the majority of PS 1 and nicastrin is present in Lubrol WX soluble membranes , wherein the CTFs derived from APP , Notch 1 , DCC , and N cadherin also reside . ^^^ |
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