The Intracellular Domain of the β-Amyloid Precursor Protein Is Stabilized by Fe65 and Translocates to the Nucleus in a Notch-like Manner

Kimberly, W. Taylor; Zheng, Jessica B.; Guénette, Suzanne Y.; Selkoe, Dennis J.

doi:10.1074/jbc.c100447200

Cited by 416 publications

(357 citation statements)

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“…Proteolytically released ICDs of many other transmembrane proteins are short-lived and removed by the proteasome. [28][29][30] Indeed, treatment of FasL-expressing 293T cells with the proteasome inhibitor lactacystin facilitated detection of soluble SPA generated by endogenous SPPL2a activity ( Figure 3b, lane 2). The use of (Z-LL) 2 ketone abolished SPA production, again confirming the dependence of SPA generation on SPPL2a (Figure 3b, lane 3).…”

Section: Resultsmentioning

confidence: 99%

“…Proteolytically released ICD of many other transmembrane proteins are typically short-lived and rapidly degraded by the proteasome, [28][29][30] which may represent an effective way to downregulate any (nuclear) signal provided by the released peptides. The Deltex protein, for example, has been proposed to act as an E3 ligase responsible for ubiquitination of the Notch ICD ((N)ICD).…”

Section: Discussionmentioning

confidence: 99%

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The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells

Cahuzac²,

et al. 2007

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Fas ligand (FasL) is a type II transmembrane protein belonging to the tumor necrosis factor family. Its binding to the cognate Fas receptor triggers the apoptosis that plays a pivotal role in the maintenance of immune system homeostasis. The cell deathinducing property of FasL has been associated with its extracellular domain, which can be cleaved off by metalloprotease activity to produce soluble FasL. The fate of the remaining membrane-anchored N-terminal part of the FasL molecule has not been determined. Here we show that post-translational processing of overexpressed and endogenous FasL in T-cells by the disintegrin and metalloprotease ADAM10 generates a 17-kDa N-terminal fragment, which lacks the receptor-binding extracellular domain. This FasL remnant is membrane anchored and further processed by SPPL2a, a member of the signal peptide peptidaselike family of intramembrane-cleaving proteases. SPPL2a cleavage liberates a smaller and highly unstable fragment mainly containing the intracellular FasL domain (FasL ICD). We show that this fragment translocates to the nucleus and is capable of inhibiting gene transcription. With ADAM10 and SPPL2a we have identified two proteases implicated in FasL processing and release of the FasL ICD, which has been shown to be important for retrograde FasL signaling.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells

Cahuzac²,

et al. 2007

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“…Expression of exogenous AICD in baby hamster kidney, COS cells, or in primary neurons also demonstrates a predominant nuclear localization (Cupers et al, 2001;Gao and Pimplikar, 2001; Kimberly et al, 2001;Walsh et al, 2003). The function of AICD as a signaling protein has been suggested to be dependent on the interaction of AICD with several transcriptional coactivators.…”

Section: Introductionmentioning

confidence: 99%

Modulation of Gene Expression and Cytoskeletal Dynamics by the Amyloid Precursor Protein Intracellular Domain (AICD)

Müller

Concannon

Ward

et al. 2007

MBoC

123

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Amyloidogenic processing of the amyloid precursor protein (APP) results in the generation of ␤-amyloid, the main constituent of Alzheimer plaques, and the APP intracellular domain (AICD).Recently, it has been demonstrated that AICD has transactivation potential; however, the targets of AICD-dependent gene regulation and hence the physiological role of AICD remain largely unknown. We analyzed transcriptome changes during AICD-dependent gene regulation by using a human neural cell culture system inducible for expression of AICD, its coactivator FE65, or the combination of both. Induction of AICD was associated with increased expression of genes with known function in the organization and dynamics of the actin cytoskeleton, including ␣2-Actin and Transgelin (SM22). AICD target genes were also found to be differentially regulated in the frontal cortex of Alzheimer's disease patients compared with controls as well as in AICD/FE65 transiently transfected murine cortical neurons. Confocal image analysis of neural cells and cortical neurons expressing both AICD and FE65 confirmed pronounced changes in the organization of the actin cytoskeleton, including the destabilization of actin fibers and clumping of actin at the sites of cellular outgrowth. Our data point to a role of AICD in developmental and injury-related cytoskeletal dynamics in the nervous system. INTRODUCTIONThe amyloid precursor protein (APP) is a type-1 transmembrane protein composed of a large extracellular and a small intracellular domain and has been widely implicated in the pathogenesis of Alzheimer's disease (AD). APP can undergo proteolytic cleavage by ␤-and ␥-secretase activities, resulting in the production of ␤-amyloid (A␤) (Selkoe, 1994). A␤ is the main constituent of amyloid plaques and is thought to be neurotoxic by inducing oxidative stress, inflammation, and neurodegeneration (Mattson, 2004). The intraneuronal accumulation of A␤ protofibrils is thought to cause progressive neurotoxicity in cortical neurons (Hartley et al., 1999). In addition, the secretion of soluble A␤ oligomers inhibits hippocampal long-term potentiation and alters the memory of complex learned behavior (Walsh et al., 2005).The APP intracellular domain (AICD), a small 6-kDa protein, originates from APP cleavage mediated by ␥-secretase activity (Octave et al., 2000). This cleavage can occur after Val636 (AICD59), Ala638 (AICD57), or Leu645 (AICD50) corresponding to the ␥-or -cleavage site ( Figure 1A) of the ␥-secretase complex (Sastre et al., 2001;Yu et al., 2001). More recently, AICD was shown to have transactivation potential (Cao and Sudhof, 2001). AICD levels are detectable in membrane fractions of murine total brain homogenates, and they increase significantly in mice overexpressing the Swedish mutation of human APP (Ryan and Pimplikar, 2005). Moreover, Hirano bodies found in the degenerating neurons of Alzheimer's patients stain positive with antisera raised against the cytoplasmic domain of APP (Munoz et al., 1993), suggesting an accumulation of AICD during Alzheimer...

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“…4 As a transmembrane cell surface glycoprotein, APP is a receptor that may transduce signals within the cell in response to an extracellular ligand. 5 For example, following the action of the g-secretase that cleaves APP in the plane of the membrane, the intracellular domain of APP reaches the cell nucleus to modulate gene expression regulating apoptosis. However, neither a ligand nor downstream signaling cascades for APP has been clearly established.…”

Section: Introductionmentioning

confidence: 99%

Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

et al. 2007

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Amyloid precursor protein (APP) and amyloid b-peptide (Ab) have been implicated in a variety of physiological and pathological processes underlying nervous system functions. APP shares many features with adhesion molecules in that it is involved in neurite outgrowth, neuronal survival and synaptic plasticity. It is, thus, of interest to identify binding partners of APP that influence its functions. Using biochemical cross-linking techniques we have identified ATP synthase subunit a as a binding partner of the extracellular domain of APP and Ab. APP and ATP synthase colocalize at the cell surface of cultured hippocampal neurons and astrocytes. ATP synthase subunit a reaches the cell surface via the secretory pathway and is N-glycosylated during this process. Transfection of APP-deficient neuroblastoma cells with APP results in increased surface localization of ATP synthase subunit a. The extracellular domain of APP and Ab partially inhibit the extracellular generation of ATP by the ATP synthase complex. Interestingly, the binding sequence of APP and Ab is similar in structure to the ATP synthase-binding sequence of the inhibitor of F1 (IF 1 ), a naturally occurring inhibitor of the ATP synthase complex in mitochondria. In hippocampal slices, Ab and IF 1 similarly impair both short-and long-term potentiation via a mechanism that could be suppressed by blockade of GABAergic transmission. These observations indicate that APP and Ab regulate extracellular ATP levels in the brain, thus suggesting a novel mechanism in Ab-mediated Alzheimer's disease pathology.

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The Intracellular Domain of the β-Amyloid Precursor Protein Is Stabilized by Fe65 and Translocates to the Nucleus in a Notch-like Manner

Cited by 416 publications

References 33 publications

The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells

The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells

Modulation of Gene Expression and Cytoskeletal Dynamics by the Amyloid Precursor Protein Intracellular Domain (AICD)

Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

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