Amyloid Precursor Protein and Presenilin1 Interact with the Adaptor GRB2 and Modulate ERK 1,2 Signaling

Nizzari, Mario; Venezia, Valentina; Repetto, Emanuela; Caorsi, Valentina; Magrassi, Raffaella; Gagliani, Maria Cristina; Carlo, Pia; Florio, Tullio; Schettini, Gennaro; Tacchetti, Carlo; Russo, Tommaso; Diaspro, Alberto; Russo, Claudio

doi:10.1074/jbc.m610146200

Cited by 86 publications

(78 citation statements)

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“…200 Interestingly, Grb2 also binds presenilin 1 (PS1), which is involved in cleavage of APP. 201 Grb2, APP and PS1 reportedly associate at the centrosome, where the complex targets extracellular signal-related kinases 1 and 2 signalling. 201 Finally, it is particularly intriguing that robust interactions between Grb2 and ErbB receptors have been demonstrated.…”

Section: Disc1 Interaction With Grb2mentioning

confidence: 99%

“…201 Grb2, APP and PS1 reportedly associate at the centrosome, where the complex targets extracellular signal-related kinases 1 and 2 signalling. 201 Finally, it is particularly intriguing that robust interactions between Grb2 and ErbB receptors have been demonstrated. ErbB receptors bind neuregulin and are thus already suspected to be involved in molecular pathways that underlie some cases of severe psychiatric illness (for a review, see Corfas et al 202 ).…”

Section: Disc1 Interaction With Grb2mentioning

confidence: 99%

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The DISC locus in psychiatric illness

et al. 2007

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The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention. Molecular Psychiatry (2008) 13, 36-64; doi:10.1038/sj.mp.4002106; published online 2 October 2007 Keywords: schizophrenia; bipolar disorder; depression; DISC1; DISC2; mouse models Genetics of DISC1 discoverySt Clair et al. 1 first reported a Scottish family with a high loading of major mental illness, which cosegregates with a t(1;11) translocation. Long-term follow-up of this family over a period of 30 years has reported 87 family members, of whom 37 carry the translocation. 2 Of 29 individuals carrying the translocation, for whom psychiatric assessment was possible, 7 have a diagnosis of schizophrenia, 1 has a diagnosis of bipolar disorder and 10 cases of recurrent major depression were also reported. 2 Thus, 18 of 29 translocation carriers are diagnosed with major mental illness whereas none of...

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Section: Disc1 Interaction With Grb2mentioning

confidence: 99%

Section: Disc1 Interaction With Grb2mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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“…The only exception to this is Shc, which requires the phosphorylation of Tyr682 for binding to APP [21,29]. Tyr682 phosphorylation is also necessary for the binding of APP to the SH2 domains of Abl and Grb2, and might regulate downstream signal transduction cascades [29,30]. Structural studies have revealed that the binding interface of APP and the PTB domain of X11 involves residues within the GYENPTY motif [31].…”

Section: The Cytoplasmic Domain Of App and Its Binding Proteinsmentioning

confidence: 99%

Regulation of the Physiological Function and Metabolism of AβPP by AβPP Binding Proteins

Taru

Suzuki

2009

JAD

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“…2E). Previous studies have suggested that APP can influence ERK and/or Akt activation (Nizzari et al, 2007; Lee et al, 2009). We observed decreased ERK‐1 and ‐2 phosphorylation at 24, 48, and 72 h after siRNA‐mediated knockdown of APP in NSCLC cell lines A549 and H1299 (Fig.…”

Section: Resultsmentioning

confidence: 98%

Amyloid Precursor Protein (APP) Affects Global Protein Synthesis in Dividing Human Cells

Sobol¹,

Galluzzo²,

Liang³

et al. 2015

Journal Cellular Physiology

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Hypoxic non‐small cell lung cancer (NSCLC) is dependent on Notch‐1 signaling for survival. Targeting Notch‐1 by means of γ‐secretase inhibitors (GSI) proved effective in killing hypoxic NSCLC. Post‐mortem analysis of GSI‐treated, NSCLC‐burdened mice suggested enhanced phosphorylation of 4E‐BP1 at threonines 37/46 in hypoxic tumor tissues. In vitro dissection of this phenomenon revealed that Amyloid Precursor Protein (APP) inhibition was responsible for a non‐canonical 4E‐BP1 phosphorylation pattern rearrangement—a process, in part, mediated by APP regulation of the pseudophosphatase Styx. Upon APP depletion we observed modifications of eIF‐4F composition indicating increased recruitment of eIF‐4A to the mRNA cap. This phenomenon was supported by the observation that cells with depleted APP were partially resistant to silvestrol, an antibiotic that interferes with eIF‐4A assembly into eIF‐4F complexes. APP downregulation in dividing human cells increased the rate of global protein synthesis, both cap‐ and IRES‐dependent. Such an increase seemed independent of mTOR inhibition. After administration of Torin‐1, APP downregulation and Mechanistic Target of Rapamycin Complex 1 (mTORC‐1) inhibition affected 4E‐BP1 phosphorylation and global protein synthesis in opposite fashions. Additional investigations indicated that APP operates independently of mTORC‐1. Key phenomena described in this study were reversed by overexpression of the APP C‐terminal domain. The presented data suggest that APP may be a novel regulator of protein synthesis in dividing human cells, both cancerous and primary. Furthermore, APP appears to affect translation initiation using mechanisms seemingly dissimilar to mTORC‐1 regulation of cap‐dependent protein synthesis. J. Cell. Physiol. 230: 1064–1074, 2015. © 2014 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

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Amyloid Precursor Protein and Presenilin1 Interact with the Adaptor GRB2 and Modulate ERK 1,2 Signaling

Cited by 86 publications

References 78 publications

The DISC locus in psychiatric illness

The DISC locus in psychiatric illness

Regulation of the Physiological Function and Metabolism of AβPP by AβPP Binding Proteins

Amyloid Precursor Protein (APP) Affects Global Protein Synthesis in Dividing Human Cells

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