Platelet Coagulation Factor XI
            <sub>a</sub>
            -Inhibitor, a Form of Alzheimer Amyloid Precursor Protein

Smith, Raymond P.; Higuchi, Darryl A.; Broze, George J.

doi:10.1126/science.2111585

Cited by 310 publications

(174 citation statements)

References 28 publications

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“…PNII is a protease inhibitor that forms SDS-resistant inhibitory complexes with epidermal growth factor-binding protein, the ␥-subunit of nerve growth factor, and trypsin. Smith et al (25) reported that an inhibitor of coagulation factor XIa purified from the serumfree conditioned medium of HepG2 liver cells is also a secreted form of APP. Truncated forms of APP are derived from their cognate membrane-associated forms by proteolysis and have apparently lost the cytoplasmic and the transmembrane domains (26).…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte Growth Factor Activator Inhibitor, a Novel Kunitz-type Serine Protease Inhibitor

Shimomura

Denda

Kitamura

et al. 1997

Journal of Biological Chemistry

250

264

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Hepatocyte growth factor (HGF) activator is a serine protease that is produced and secreted by the liver and circulates in the blood as an inactive zymogen. In response to tissue injury, the HGF activator zymogen is converted to the active form by limited proteolysis. The activated HGF activator converts an inactive single chain precursor of HGF to a biologically active heterodimer in injured tissue. The activated HGF may be involved in the regeneration of the injured tissue. In this study, we purified an inhibitor of HGF activator from the conditioned medium of a human MKN45 stomach carcinoma cell line and molecularly cloned its cDNA. The sequence of the cDNA revealed that the inhibitor has two well defined Kunitz domains, suggesting that the inhibitor is a member of the Kunitz family of serine protease inhibitors. The sequence also showed that the primary translation product of the inhibitor has a hydrophobic sequence at the COOH-terminal region. Inhibitory activity toward HGF activator was detected in the membrane fraction as well as in the conditioned medium of MKN45 cells. These results suggest that the inhibitor may be produced as a membrane-associated form and secreted by the producing cells as a proteolytically truncated form.

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Section: Discussionmentioning

confidence: 99%

Hepatocyte Growth Factor Activator Inhibitor, a Novel Kunitz-type Serine Protease Inhibitor

Shimomura

Denda

Kitamura

et al. 1997

Journal of Biological Chemistry

250

264

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“…This enzyme cleaves the /IAPP intracellularly (for review, see Checler, 1995) or nearby the external membrane (Sisodia, 1992), thereby liberating APPa, the putative physiological role of which has been well documented (Oltersdorf et al, 1989;Saitoh et al, 1989;Smith et al, 1990;Mattson et al, 1993;Qiu et a!., 1995). Most important is the observation that the site of a-secretase cleavage on /IAPP occurs in the middle of the A/I sequence and therefore likely precludes the formation of this amyloidogenic product.…”

Section: Discussionmentioning

confidence: 99%

Constitutive and Protein Kinase C‐Regulated Secretory Cleavage of Alzheimer's β‐Amyloid Precursor Protein: Different Control of Early and Late Events by the Proteasome

Marambaud

Lopez-Perez

Wilk

et al. 1997

Journal of Neurochemistry

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Abstract:The physiological processing of the /3-amyloid precursor protein (/3APP) by a protease called a-secretase gives rise to APPa, a C-terminally truncated fragment of /3APP with known neurotrophic and cytoprotective properties. Several lines of evidence indicate that protein kinase C (PKC)-mediated events regulate this physiological pathway. We show here that the proteasome multicatalytic complex modulates the phorbol 12,1 3-dibutyrate-stimulated APPr secretion at several levels in human kidney 293 (HK293) cells. Two blocking agents of the proteasome, namely, Z-IE(Ot-Bu)A-leucinal and lactacystin, elicit a dual effect on PKC-regulated APPa secretion by metabolically labeled HK293 cells.

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“…This protein, also known as protease nexin 2, contains a Kunitz serine protease inhibitor domain (sequence shown in red in Fig. 1B), which has been found to strongly inhibit trypsin as well as several enzymes of the coagulation system (23,24). In the mesotrypsin-treated sample, the 120 kDa band is depleted, whereas two newly appearing bands with apparent molecular mass of ϳ40 and ϳ65 kDa were found by trypsin digestion and nanoLC-MS/MS to represent cleavage fragments of APP.…”

Section: Identification Of App As a Mesotrypsinmentioning

confidence: 99%

“…In normal biology, a variety of functions for APP have been implicated. The earliest to be described was the function of the secreted ectodomain of APP (sAPP) as protease nexin 2, a serine protease inhibitor that targets coagulation factor XIa (FXIa) with high specificity (23,24). This inhibitory activity has been localized to the Kunitz domain of sAPP (25).…”

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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Platelet Coagulation Factor XI _a -Inhibitor, a Form of Alzheimer Amyloid Precursor Protein

Cited by 310 publications

References 28 publications

Hepatocyte Growth Factor Activator Inhibitor, a Novel Kunitz-type Serine Protease Inhibitor

Hepatocyte Growth Factor Activator Inhibitor, a Novel Kunitz-type Serine Protease Inhibitor

Constitutive and Protein Kinase C‐Regulated Secretory Cleavage of Alzheimer's β‐Amyloid Precursor Protein: Different Control of Early and Late Events by the Proteasome

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

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Platelet Coagulation Factor XI a -Inhibitor, a Form of Alzheimer Amyloid Precursor Protein

Cited by 310 publications

References 28 publications

Hepatocyte Growth Factor Activator Inhibitor, a Novel Kunitz-type Serine Protease Inhibitor

Hepatocyte Growth Factor Activator Inhibitor, a Novel Kunitz-type Serine Protease Inhibitor

Constitutive and Protein Kinase C‐Regulated Secretory Cleavage of Alzheimer's β‐Amyloid Precursor Protein: Different Control of Early and Late Events by the Proteasome

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

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Platelet Coagulation Factor XI _a -Inhibitor, a Form of Alzheimer Amyloid Precursor Protein