Protease Nexin-II(amyloid β-protein Precursor): a Platelet α-Granule Protein

Nostrand, W. Van; Schmaier, AH; Farrow, J S; Cunningham, Dennis D.

doi:10.1126/science.2110384

Cited by 309 publications

(170 citation statements)

References 32 publications

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“…It has been surmised from the amino acid sequence of exon 7 of ␤APP and from studies of its function in cultured cells that this region acts as a serine protease inhibitor of the Kunitz family. ␣-APP s molecules derived from ␤APP 751 and ␤APP 770 (which contain this alternatively spliced exon) have been shown to inhibit several different serine proteases in vitro (66) and to occur in human plasma as an inhibitor of factor XIa of the coagulation cascade (67,68). Other functions of ␣-APP s and/or cell surface holo-␤APP that have been postulated on the basis of cell culture experiments include as a trophic (69) or neuroprotective (70) molecule and as a mediator of cell-cell (71) and cell-substrate (72,73) interactions.…”

Section: ␤App Function and Dysfunctionmentioning

confidence: 99%

Amyloid β-Protein and the Genetics of Alzheimer's Disease

Selkoe

1996

Journal of Biological Chemistry

776

550

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The effort to decipher the mechanism of Alzheimer's disease (AD) 1 has attracted the interest of investigators from diverse biological disciplines, including biochemistry, cell biology, molecular genetics, neuroscience, and structural biology. The eclectic nature of research approaches to AD and the intensity of scientific interest in the problem have made it increasingly likely that AD will become a premier example of the successful application of biological chemistry to the identification of rational therapeutic targets in a major human disease. Much of the recent progress in elucidating the pathogenesis of AD has centered on the apparent role of the 40 -42-residue amyloid ␤-protein (A␤) (1) as a unifying pathological feature of the genetically diverse forms of this complex disorder. Biochemistry of Cerebral ␤-Amyloidosis, a Route toGenetic Insights It has been known since the time of Alzheimer (2) that insidiously progressive loss of memory, cognition, and behavioral stability in older humans can be associated with the development of innumerable intraneuronal and extracellular filamentous lesions in the limbic and cerebral cortices. Inside neurons, bundles of abnormal ϳ20-nm cytoplasmic fibers (paired helical filaments) occur both in neuronal cell bodies (comprising neurofibrillary tangles) and in axons and dendrites (referred to collectively as dystrophic neurites). In addition to this filamentous degeneration of selected neurons and their processes, AD is characterized by abundant extracellular masses of ϳ8-nm filaments composed of A␤. These spherical deposits of A␤ fibrils (amyloid plaques) are often intimately associated with dystrophic axons and dendrites (some of which contain paired helical filaments) as well as with activated microglia and reactive astrocytes. The presence of such "neuritic plaques," together with numerous neurofibrillary tangles, in the hippocampus, amygdala, cerebral cortex, and certain other brain regions serves as the basis for a definitive pathological diagnosis of AD. It should be noted that the amyloid ␤-protein of AD is only one of several different proteins that can accumulate excessively in the extracellular spaces of various tissues and produce distinct human diseases (collectively called amyloidoses).Although arguments were once raised that studying the biochemistry of the plaques and tangles would be unlikely to lead to insights into critical events in AD pathogenesis, this has not turned out to be the case. Immunocytochemical and biochemical analyses of the intraneuronal neurofibrillary tangles conducted during the last decade have led to the conclusion that the microtubule-associated phosphoprotein, tau, is the major or, more likely, the sole subunit of the paired helical filaments found in both the tangles and in many of the dystrophic neurites observed in AD cortex (3,4). Intensive studies by numerous laboratories have shown that tau protein, which normally enhances the polymerization of tubulin into microtubules and stabilizes these organelles in neurons, becomes e...

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Section: ␤App Function and Dysfunctionmentioning

confidence: 99%

Amyloid β-Protein and the Genetics of Alzheimer's Disease

Selkoe

1996

Journal of Biological Chemistry

776

550

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“…The additional inhibition observed in the case of PRP (Fig. 7B) could stem from protease nexin-2 released from platelets (43,77,78). Although only ϳ25% inhibition of FXIa was observed during the first 5 min of the experiment (Fig.…”

Section: Discussionmentioning

confidence: 92%

“…In conclusion, platelet TFPI-2 plays an important role in the hemostatic process and adds to the list of other platelet factors, including polyphosphate (79), FV (80), protease nexin 1 and 2 (77,78,81), TFPI-1 (56), and plasminogen activator inhibitor-1 (72), that act as coagulant, anticoagulant, and antifibrinolytic agents. The effect of TFPI-2 on fibrinolysis is large and agrees with the K i for plasmin being lower than for FXIa and pKLK.…”

Section: Discussionmentioning

confidence: 99%

Platelets Contain Tissue Factor Pathway Inhibitor-2 Derived from Megakaryocytes and Inhibits Fibrinolysis

Vadivel

Ponnuraj

Kumar

et al. 2014

Journal of Biological Chemistry

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Background: TFPI-2 inhibits plasma kallikrein, FXIa, and plasmin, but its concentration in normal plasma is insufficient to inhibit clotting or fibrinolysis. Results: Platelets contain TFPI-2 derived from megakaryocytes and binds to platelet FV/Va and circulating FV in late pregnancy when plasma TFPI-2 is ϳ7 nM. Conclusion: Platelet-derived TFPI-2 regulates intrinsic coagulation and tPA-induced fibrinolysis. Significance: Platelet-derived TFPI-2 promotes clot stabilization while attenuating intrinsic clotting.

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“…The NH 2 ; chymotrypsin numbering system, which will be used throughout this paper) (7). During cleavage of FXI, a new NH 2 -terminal sequence, Ile 16 -Val 17 -Gly 18 -Gly 19 , is formed, which is characteristic of serine proteases. The NH 2 -terminal Ile 16 inserts into the protease domain of FXIa, and the NH 2 group forms a salt bridge with the COOH group of Asp 194 .…”

mentioning

confidence: 99%

“…Protease nexin 2 (PN2) is a Kunitz-type protease inhibitor (KPI) secreted by activated platelets (17)(18)(19) that has been shown to have high affinity and specificity for FXIa. The interaction between PN2 and FXIa has previously been shown to involve interactions that occur exclusively between the KPI domain of PN2 (PN2KPI) and the catalytic domain of FXIa (FXIac) (20).…”

mentioning

confidence: 99%