Processing of β-Secretase by Furin and Other Members of the Proprotein Convertase Family

Creemers, John W.M.; Dominguez, Diana; Plets, Evelyn; Serneels, Lutgarde; Taylor, Nick; Multhaup, Gerd; Craessaerts, Katleen; Annaert, Wim; Strooper, Bart De

doi:10.1074/jbc.m006947200

Cited by 178 publications

(217 citation statements)

References 36 publications

(55 reference statements)

Supporting

Mentioning

198

Contrasting

Order By: Relevance

“…Retrieval of furin from endosomal to TGN compartments was also shown to be dependent on phosphorylation/dephosphorylation of its cytoplasmic domain (45). Therefore, the subcellular localization of BACE is regulated in a remarkably similar fashion like furin, a protease that has recently been demonstrated to be required for propeptide cleavage of BACE (11)(12)(13).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Phosphorylation Regulates Intracellular Trafficking of β-Secretase

Walter

Fluhrer

Hartung

et al. 2001

Journal of Biological Chemistry

Self Cite

262

284

View full text Add to dashboard Cite

␤-Secretase (BACE) is a transmembrane aspartyl protease, which generates the N terminus of Alzheimer's disease amyloid ␤-peptide. Here, we report that BACE can be phosphorylated within its cytoplasmic domain at serine residue 498 by casein kinase 1. Phosphorylation exclusively occurs after full maturation of BACE by propeptide cleavage and complex N-glycosylation. Phosphorylation/dephosphorylation affects the subcellular localization of BACE. BACE wild type and an S498D mutant that mimics phosphorylated BACE are predominantly located within juxtanuclear Golgi compartments and endosomes, whereas nonphosphorylatable BACE S498A accumulates in peripheral EEA1-positive endosomes. Antibody uptake assays revealed that reinternalization of BACE from the cell surface is independent of its phosphorylation state. After reinternalization, BACE wild type as well as BACE S498D are efficiently retrieved from early endosomal compartments and further targeted to later endosomal compartments and/or the trans-Golgi network. In contrast, nonphosphorylatable BACE S498A is retained within early endosomes. Our results therefore demonstrate regulated trafficking of BACE within the secretory and endocytic pathway.

show abstract

Section: Discussionmentioning

confidence: 99%

“…BACE is cotranslationally modified by N-glycosylation and further maturates by complex glycosylation as well as proteolytic removal of its prodomain by a furin-like protease (11)(12)(13)(14). The majority of BACE molecules are localized within Golgi and endosomal compartments, where they colocalize with ␤APP (4,5,7,12,14).…”

mentioning

confidence: 99%

Phosphorylation Regulates Intracellular Trafficking of β-Secretase

Walter

Fluhrer

Hartung

et al. 2001

Journal of Biological Chemistry

Self Cite

262

284

View full text Add to dashboard Cite

show abstract

“…During maturation, BACE1 undergoes a number of post/co-translational modifications, including N-glycosylation, disulfide bridge formation, and palmitoylation (Bennett et al 2000b;Capell et al 2000;Huse et al 2000;Benjannet et al 2001). The propeptide of immature BACE1 is removed by Furin and related proteases during maturation (Capell et al 2000;Creemers et al 2001). Surprisingly, the propeptide seems not to significantly affect BACE1 proteolytic function (Creemers et al 2001).…”

Section: Subcellular Sites Of App Processingmentioning

confidence: 97%

“…The propeptide of immature BACE1 is removed by Furin and related proteases during maturation (Capell et al 2000;Creemers et al 2001). Surprisingly, the propeptide seems not to significantly affect BACE1 proteolytic function (Creemers et al 2001). BACE1 reaches the PM and becomes enriched in lipid rafts (Riddell et al 2001;Cordy et al 2003).…”

Section: Subcellular Sites Of App Processingmentioning

confidence: 99%

Trafficking and Proteolytic Processing of APP

Haass¹,

Kaether²,

Wang³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

893

892

View full text Add to dashboard Cite

Accumulations of insoluble deposits of amyloid b-peptide are major pathological hallmarks of Alzheimer disease. Amyloid b-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the b-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. b-and g-secretase liberate by sequential cleavage the neurotoxic amyloid b-peptide, whereas a-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid b-peptide generation and therefore disease onset and progression.

show abstract

“…Recent studies revealed that BACE is synthesized as an immature and inactive form in the endoplasmic reticulum [11], and undergoes maturation during its transport to cell surface along the secretory pathway [12][13][14][15][16]. The mature BACE is then internalized from cell surface to endosomes [3,12], followed by sorting to the trans golgi network (TGN) for recycling or to lysosomes for degradation [15,16].…”

Section: Introductionmentioning

confidence: 99%

Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization

et al. 2007

View full text Add to dashboard Cite

Amyloid-β (Aβ) peptide, the primary constituent of senile plaques in Alzheimer's disease (AD), is generated by β-secretase-and γ-secretase-mediated sequential proteolysis of the amyloid precursor protein (APP). The aspartic protease, β -site APP cleavage enzyme (BACE), has been identified as the main β-secretase in brain but the regulation of its activity is largely unclear. Here, we demonstrate that both BACE activity and subsequent Aβ production are enhanced after stimulation of receptor tyrosine kinases (RTKs), such as the receptors for epidermal growth factor (EGF) and nerve growth factor (NGF), in cultured cells as well as in mouse hippocampus. Furthermore, stimulation of RTKs also induces BACE internalization into endosomes and Golgi apparatus. This enhancement of BACE activity and Aβ production upon RTK activation could be specifically inhibited by Src family kinase inhibitors and by depletion of endogenous c-Src with RNAi, and could be mimicked by over-expressed c-Src. Moreover, blockage of BACE internalization by a dominant negative form of Rab5 also abolished the enhancement of BACE activity and Aβ production, indicating the requirement of BACE internalization for the enhanced activity. Taken together, our study presents evidence that BACE activity and Aβ production are under the regulation of RTKs and this is achieved via RTK-stimulated BACE internalization, and suggests that an aberration of such regulation might contribute to pathogenic Aβ production.

show abstract

Processing of β-Secretase by Furin and Other Members of the Proprotein Convertase Family

Cited by 178 publications

References 36 publications

Phosphorylation Regulates Intracellular Trafficking of β-Secretase

Phosphorylation Regulates Intracellular Trafficking of β-Secretase

Trafficking and Proteolytic Processing of APP

Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization

Contact Info

Product

Resources

About