Inhibition of Glycosphingolipid Biosynthesis Reduces Secretion of the β-Amyloid Precursor Protein and Amyloid β-Peptide*[boxs]

Tamboli, Irfan Y.; Prager, Kai; Barth, Esther; Heneka, Michael T.; Sandhoff, Konrad; Walter, Jochen

doi:10.1074/jbc.m414525200

Cited by 122 publications

(120 citation statements)

References 56 publications

(47 reference statements)

Supporting

Mentioning

113

Contrasting

Unclassified

Order By: Relevance

“…It could be involved in transferring GlcCer to the cellular site, where GlcCer can be translocated across the membrane to function as a precursor luminally for complex glycolipid synthesis either at the TGN or in the ER as suggested previously (7,8). However, whether the membrane trafficking function could be explained solely by the glycolipid-transfer activity of FAPP2 seems unlikely because reduction of glycolipid biosynthesis has not previously been demonstrated to have such inhibitory effects on TGN to plasma membrane transport (22)(23)(24). It is also possible that FAPP2 functions as a sensor for regulating glycolipid levels in the cell.…”

Section: Discussionmentioning

confidence: 84%

Golgi protein FAPP2 tubulates membranes

Cao

Coskun

Rößle

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The Golgi-associated four-phosphate adaptor protein 2 (FAPP2) has been shown to possess transfer activity for glucosylceramide both in vitro and in cells. We have previously shown that FAPP2 is involved in apical transport from the Golgi complex in epithelial MDCK cells. In this paper we assign an unknown activity for the protein as well as providing structural insight into protein assembly and a low-resolution envelope structure. By applying analytical ultracentrifugation and small-angle x-ray scattering, we show that FAPP2 is a dimeric protein in solution, having a curved shape 30 nm in length. The purified FAPP2 protein has the capability to form tubules from membrane sheets in vitro. This activity is dependent on the phosphoinositide-binding activity of the PH domain of FAPP2. These data suggest that FAPP2 functions directly in the formation of apical carriers in the trans-Golgi network.membrane tubulation ͉ PH domain ͉ phosphatidylinositol 4-phosphate ͉ trans-Golgi network ͉ small-angle x-ray scattering (SAXS)

show abstract

Section: Discussionmentioning

confidence: 84%

Golgi protein FAPP2 tubulates membranes

Cao

Coskun

Rößle

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The constructs encoding C99-EGFP, LC3-GFP, and LC3-RFP have been described earlier (Kabeya et al, 2000;Kaether et al, 2006). Anti-APP-CT (140), , and anti-A␤ (2964) (Tamboli et al, 2005), anti-APP-CT (C1/6.1) (Mathews et al, 2002), and anti-cathepsin CT (generous gift from Dr. S. Höning, Cologne, Germany) antibodies have been described before. Antibodies against LC3 and 82E1 (Cell Signaling Technology), P70S6 kinase and phospho-P70S6 kinase (pP70S6K) (Abcam), lamp-2 (Iowa Hybridoma Bank), rab-7, beclin-1, and Ser 70 phospho-Bcl-2 (Santa Cruz Biotechnology), Bcl-2 (BD Transduction), and p62 (Sigma) were obtained from the respective companies listed.…”

Section: Methodsmentioning

confidence: 99%

Sphingolipid Storage Affects Autophagic Metabolism of the Amyloid Precursor Protein and Promotes Aβ Generation

Tamboli¹,

Hampel²,

Tiên³

et al. 2011

J. Neurosci.

View full text Add to dashboard Cite

“…Reagents and Antibodies-The following antibodies were used: monoclonal APP/A␤ antibody W0-2 (1:5000, The Genetics Co.), APP (1:250 of monoclonal antibody 22C11, Chemicon; 1:500 of polyclonal antibody 23850, generous gift from Gerd Multhaup), polyclonal APP antibody 5313 (27), anti-acetyl histone H4 (1:2000, Millipore), EGFR (1:200, Santa Cruz Biotechnology), APLP2 (1:5000, Calbiochem), GRP78 (1:1000, Cell Signaling Technology), and monoclonal mouse anti-actin (1:5000, Sigma). VPA (Sigma) was prepared in sterile water as concentrated stock solution and added to the final concentrations as indicated.…”

Section: Methodsmentioning

confidence: 99%

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Venkataramani

Roßner

Iffland

et al. 2010

Journal of Biological Chemistry

Self Cite

110

View full text Add to dashboard Cite

The ␤-amyloid precursor protein (APP) represents a type I transmembrane glycoprotein that is ubiquitously expressed. In the brain, it is a key player in the molecular pathogenesis of Alzheimer disease. Its physiological function is however less well understood. Previous studies showed that APP is up-regulated in prostate, colon, pancreatic tumor, and oral squamous cell carcinoma. In this study, we show that APP has an essential role in growth control of pancreatic and colon cancer. Abundant APP staining was found in human pancreatic adenocarcinoma and colon cancer tissue. Interestingly, treating pancreatic and colon cancer cells with valproic acid (VPA, 2-propylpentanoic acid), a known histone deacetylase (HDAC) inhibitor, leads to up-regulation of GRP78, an endoplasmic reticulum chaperone immunoglobulin-binding protein. GRP78 is involved in APP maturation and inhibition of tumor cell growth by down-regulation of APP and secreted soluble APP␣. Trichostatin A, a pan-HDAC inhibitor, also lowered APP and increased GRP78 levels. In contrast, treating cells with valpromide, a VPA derivative lacking HDAC inhibitory properties, had no effect on APP levels. VPA did not modify the level of epidermal growth factor receptor, another type I transmembrane protein, and APLP2, a member of the APP family, demonstrating the specificity of the VPA effect on APP. Small interfering RNA-mediated knockdown of APP also resulted in significantly decreased cell growth. Based on these observations, the data suggest that APP downregulation via HDAC inhibition provides a novel mechanism for pancreatic and colon cancer therapy. ␤-Amyloid precursor protein (APP)2 is a highly conserved single transmembrane protein (type I) with a receptor-like structure and consists of a heterogeneous group of proteins migrating between 110 and 135 kDa (1, 2). The heterogeneity is due to alternative splicing, leading to eight distinct isoforms (namely APP677, APP695, APP696, APP714, APP733, APP751, APP752, and APP770), as well as by a variety of post-translational modifications, including O-and N-glycosylation, sulfation, and phosphorylation. APP isoforms exist as immature (N-glycosylated) and mature (N-and O-glycosylated, tyrosylsulfated) species. Immature APP localizes in the endoplasmic reticulum and cis-Golgi, and the mature APP form preferentially localizes in the trans-Golgi network, secretory and endocytic vesicles, and at the plasma membrane (3, 4).APP695 is the most common isoform in the central nervous system, whereas APP751 and APP770 are predominantly expressed in non-neuronal cells (5). The key event in the pathogenic cascade in Alzheimer disease is the amyloidogenic pathway characterized by subsequent cleavage of APP by the enzyme ␤-secretase and further processing by ␥-secretase, which finally leads to the generation of A␤ peptides. However, the predominant route of APP processing consists of successive cleavages by ␣-and ␥-secretases in non-neuronal cells (6, 7). The cleavage of APP at Lys 16 -Leu 17 bond by ␣-secretase within the A␤ sequence ...

show abstract

Inhibition of Glycosphingolipid Biosynthesis Reduces Secretion of the β-Amyloid Precursor Protein and Amyloid β-Peptide*[boxs]

Cited by 122 publications

References 56 publications

Golgi protein FAPP2 tubulates membranes

Golgi protein FAPP2 tubulates membranes

Sphingolipid Storage Affects Autophagic Metabolism of the Amyloid Precursor Protein and Promotes Aβ Generation

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

Contact Info

Product

Resources

About