Amyloid precursor protein and its homologues: a family of proteolysis-dependent receptors

Jacobsen, Kristin; Iverfeldt, Kerstin

doi:10.1007/s00018-009-0020-8

Cited by 112 publications

(111 citation statements)

References 180 publications

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“…Subsequently, sAPP has been found to stimulate growth in both neuronal and epithelial cells, to influence neurite outgrowth and synaptogenesis in the nervous system, and to stimulate motility in epithelial cells (26,27). As an intact integral membrane protein, the structure of APP suggests similarity to membrane receptors (28), and recent data have suggested possible roles for APP as a cell surface receptor with signaling functions activated through cell-cell and cellextracellular matrix contacts (26) and through proteolysis (29).…”

mentioning

confidence: 99%

The Amyloid Precursor Protein/Protease Nexin 2 Kunitz Inhibitor Domain Is a Highly Specific Substrate of Mesotrypsin

Salameh

Robinson

Navaneetham

et al. 2010

Journal of Biological Chemistry

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The amyloid precursor protein (APP) is a ubiquitously expressed transmembrane adhesion protein and the progenitor of amyloid-␤ peptides. The major splice isoforms of APP expressed by most tissues contain a Kunitz protease inhibitor domain; secreted APP containing this domain is also known as protease nexin 2 and potently inhibits serine proteases, including trypsin and coagulation factors. The atypical human trypsin isoform mesotrypsin is resistant to inhibition by most protein protease inhibitors and cleaves some inhibitors at a substantially accelerated rate. Here, in a proteomic screen to identify potential physiological substrates of mesotrypsin, we find that APP/protease nexin 2 is selectively cleaved by mesotrypsin within the Kunitz protease inhibitor domain. In studies employing the recombinant Kunitz domain of APP (APPI), we show that mesotrypsin cleaves selectively at the Arg 15 -Ala 16 reactive site bond, with kinetic constants approaching those of other proteases toward highly specific protein substrates. Finally, we show that cleavage of APPI compromises its inhibition of other serine proteases, including cationic trypsin and factor XIa, by 2 orders of magnitude. Because APP/protease nexin 2 and mesotrypsin are coexpressed in a number of tissues, we suggest that processing by mesotrypsin may ablate the protease inhibitory function of APP/protease nexin 2 in vivo and may also modulate other activities of APP/protease nexin 2 that involve the Kunitz domain.Mesotrypsin is a human trypsin encoded by the PRSS3 gene found on chromosome 9p13 (1). Normal expression of PRSS3 is restricted to pancreas, brain, and, to a lesser extent, small intestine and colon (2-4); additionally, PRSS3 appears to be transcriptionally up-regulated with cancer progression in epithelial cancers, including lung (5), colon (6), and prostate. Mesotrypsin exhibits substantially different specificity from other trypsins toward protein substrates. It fails to activate pancreatic zymogens and also shows reduced capacity to degrade trypsinogens (7). Compared with other trypsins, it is significantly compromised in its ability to cleave protease-activated receptors (8 -10). Despite limited activity toward these classic trypsin substrates, mesotrypsin displays enhanced catalytic activity compared with other trypsins in the cleavage of certain specific protein substrates, most notably several canonical protease inhibitors (7, 11).The "canonical" inhibitors of serine proteases, named for a protease-binding loop of highly characteristic backbone conformation (12, 13), fulfill the paradoxical function of binding to a protease in a substrate-like manner yet acting as an inhibitor rather than an ordinary substrate. These inhibitors, representing at least 18 different convergently evolved protein families (14, 15), inhibit their cognate proteases via the "Laskowski mechanism," in which inhibitors act as highly specific, limited proteolysis substrates for target enzymes (14, 16). They bind so as to position a specific peptide bond, the "reactive si...

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mentioning

confidence: 99%

The Amyloid Precursor Protein/Protease Nexin 2 Kunitz Inhibitor Domain Is a Highly Specific Substrate of Mesotrypsin

Salameh

Robinson

Navaneetham

et al. 2010

Journal of Biological Chemistry

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“…The exact biological function of APP and its paralogues is still unknown, although several different studies have shown involvement of APP in cell adhesion, neurite outgrowth, synaptogenesis, modulation of synaptic plasticity, and neuroprotection (reviewed in Ref. 2). Homo-and heterotypic cis interactions of APP family members have been detected (3).…”

mentioning

confidence: 99%

Insulin-like Growth Factor-1 (IGF-1)-induced Processing of Amyloid-β Precursor Protein (APP) and APP-like Protein 2 Is Mediated by Different Metalloproteinases

Jacobsen

Adlerz

Multhaup

et al. 2010

Journal of Biological Chemistry

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␣-Secretase cleavage of the amyloid precursor protein (APP) is of great interest because it prevents the formation of the Alzheimer-linked amyloid-␤ peptide. APP belongs to a conserved gene family including the two paralogues APP-like protein (APLP) 1 and 2. Insulin-like growth factor-1 (IGF-1) stimulates the shedding of all three proteins. IGF-1-induced shedding of both APP and APLP1 is dependent on phosphatidylinositol 3-kinase (PI3-K), whereas APLP2 shedding is independent of this signaling pathway. Here, we used human neuroblastoma SH-SY5Y cells to investigate the involvement of protein kinase C (PKC) in the proteolytic processing of endogenously expressed members of the APP family. Processing was induced by IGF-1 or retinoic acid, another known stimulator of APP ␣-secretase shedding. Our results show that stimulation of APP and APLP1 processing involves multiple signaling pathways, whereas APLP2 processing is mainly dependent on PKC. Next, we wanted to investigate whether the difference in the regulation of APLP2 shedding compared with APP shedding could be due to involvement of different processing enzymes. We focused on the two major ␣-secretase candidates ADAM10 and TACE, which both are members of the ADAM (a disintegrin and metalloprotease) family. Shedding was analyzed in the presence of the ADAM10 inhibitor GI254023X, or after transfection with small interfering RNAs targeted against TACE. The results clearly demonstrate that different ␣-secretases are involved in IGF-1-induced processing. APP is mainly cleaved by ADAM10, whereas APLP2 processing is mediated by TACE. Finally, we also show that IGF-1 induces PKC-dependent phosphorylation of TACE. Alzheimer disease (AD)2 is histopathologically characterized by the presence of amyloid plaques in the brain parenchyma. The major constituent of the plaques is the amyloid-␤ (A␤) peptide, which is derived from the A␤ precursor protein (APP) by ␤-and ␥-secretase cleavage in the amyloidogenic pathway (1). In addition to A␤, a larger secreted fragment, sAPP␤, and an intracellular fragment (APP intracellular domain) are formed. Proteolytic processing of APP occurs mainly by an alternative pathway. In this nonamyloidogenic pathway, A␤ formation is precluded because ␣-secretase cleaves APP in the middle of the A␤ region. In addition to sAPP␣, a small secreted peptide, p3, and APP intracellular domain are generated by subsequent ␥-secretase cleavage.APP belongs to a conserved gene family including the two mammalian paralogues amyloid precursor-like protein 1 and 2 (APLP1 and APLP2). The exact biological function of APP and its paralogues is still unknown, although several different studies have shown involvement of APP in cell adhesion, neurite outgrowth, synaptogenesis, modulation of synaptic plasticity, and neuroprotection (reviewed in Ref. 2). Homo-and heterotypic cis interactions of APP family members have been detected (3). APLP1 could also form trans interactions, suggesting a specific role of APLP1 in cell adhesion. Importantly, double knock-out studies in mi...

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“…Moreover, the production of soluble Appa-RFP and Aplp2-RFP fusion proteins may compensate for the loss of the full-length Appa and Aplp2 proteins, similar to studies in mice (Weyer et al, 2011). The ligand binding and adhesive activity of the extracellular domain of APP is important for its role in synaptogenesis, cell adhesion, and neurite outgrowth, but the exact biological function remains unclear (Jacobsen and Iverfeldt, 2009). The secreted App-RFP proteins expressed by the zebrafish appa is22Gt and aplp2 is23Gt gene trap alleles isolated in our study will be useful for investigating further the biological function of APP.…”

Section: Appa-rfp and Aplp2-rfp Are Localized To Blood Vessels In Thementioning

confidence: 78%

Tol2 gene trap integrations in the zebrafish amyloid precursor protein genes appa and aplp2 reveal accumulation of secreted APP at the embryonic veins

Liao

Wang

Watt

et al. 2012

Developmental Dynamics

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Background-The single spanning transmembrane amyloid precursor protein (APP) and its proteolytic product, amyloid-beta (Aβ) peptide, have been intensely studied due to their role in the pathogenesis of Alzheimer's disease. However, the biological role of the secreted ectodomain of APP, which is also generated by proteolytic cleavage, is less well understood. Here, we report Tol2 red fluorescent protein (RFP) transposon gene trap integrations in the zebrafish amyloid precursor protein a (appa) and amyloid precursor-like protein 2 (aplp2) genes. The transposon integrations are predicted to disrupt the appa and aplp2 genes to primarily produce secreted

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Amyloid precursor protein and its homologues: a family of proteolysis-dependent receptors

Cited by 112 publications

References 180 publications

The Amyloid Precursor Protein/Protease Nexin 2 Kunitz Inhibitor Domain Is a Highly Specific Substrate of Mesotrypsin

The Amyloid Precursor Protein/Protease Nexin 2 Kunitz Inhibitor Domain Is a Highly Specific Substrate of Mesotrypsin

Insulin-like Growth Factor-1 (IGF-1)-induced Processing of Amyloid-β Precursor Protein (APP) and APP-like Protein 2 Is Mediated by Different Metalloproteinases

Tol2 gene trap integrations in the zebrafish amyloid precursor protein genes appa and aplp2 reveal accumulation of secreted APP at the embryonic veins

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