Two Receptor Systems Are Involved in the Plasma Clearance of Tissue Factor Pathway Inhibitor in Vivo

Narita, Masaaki; Bu, Guojun; Olins, Gillian M.; Higuchi, Darryl A.; Herz, Joachim; Broze, George J.; Schwartz, Alan L.

doi:10.1074/jbc.270.42.24800

Cited by 78 publications

(67 citation statements)

References 22 publications

(41 reference statements)

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“…Because exogenously added TFPI-1 partitions throughout detergent-insoluble and -soluble fractions, we suggest that the internalization pathway of exogenously added inhibitor involves binding of TFPI-1 to the detergent-soluble proteogly- cans. This would facilitate the cooperation 20,36 with endocytotic receptors, such as LRP, which was detected in the same membrane environment. As an additional difference from the degradative pathway described for exogenous TFPI-1, we find that the inhibitory function of endogenous TFPI-1 is restored after prolonged incubation, which allowed for the dissociation of the quaternary complex.…”

Section: Ott Et Al Tf Regulation By Gpi-anchored Tfpi 879mentioning

confidence: 99%

Reversible Regulation of Tissue Factor–Induced Coagulation by Glycosyl Phosphatidylinositol–Anchored Tissue Factor Pathway Inhibitor

Ott

Miyagi

Miyazaki

et al. 2000

ATVB

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Abstract-Endothelial and tumor cells synthesize tissue factor pathway inhibitor (TFPI-1), which regulates tissue factor (TF) function by TF ⅐ VIIa ⅐ Xa ⅐ TFPI-1 quaternary complex formation (where VIIa and Xa are coagulation factors) and by translocation of these complexes into glycosphingolipid-rich microdomains of the cell membrane. Recombinant TFPI-1 added exogenously to cells is targeted to a degradation pathway. This study analyzes whether quaternary complex formation with endogenous TFPI-1 results also in internalization and degradation. We demonstrate that endogenous TFPI-1 and recombinant TFPI-1 differ in their distribution on the cell surface. Recombinant TFPI-1 is found in phospholipid-and glycosphingolipid-rich membrane domains, whereas endogenous TFPI-1 preferentially localizes to glycosphingolipid-rich microdomains. On quaternary complex formation, endogenous TFPI-1 remains protease sensitive and accessible for antibodies on intact cells, demonstrating that it is not appreciably internalized. Rather, regulation of TF by TFPI-1 is restored within 12 hours, consistent with dissociation of quaternary complexes on the cell surface. Endogenous TFPI-1 can be released from the cell surface by phospholipase treatment, indicating that TFPI-1 either is a glycosyl phosphatidylinositol (GPI)-anchored protein or binds to a GPI-linked receptor. We demonstrate that expression of a recombinant GPI-anchored form of TFPI-1 targets TF ⅐ VIIa complexes to glycosphingolipid-rich membrane fractions. Thus, GPI anchoring of TFPI-1 is sufficient for regulation of TF ⅐ VIIa complex function by a pathway of reversible inhibition rather than internalization and degradation.

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Section: Ott Et Al Tf Regulation By Gpi-anchored Tfpi 879mentioning

confidence: 99%

Reversible Regulation of Tissue Factor–Induced Coagulation by Glycosyl Phosphatidylinositol–Anchored Tissue Factor Pathway Inhibitor

Ott

Miyagi

Miyazaki

et al. 2000

ATVB

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“…To determine whether HSPGs are necessary for liposome endocytosis by LRP, we incubated neurons with AL-Cy3ONs along with 100 g/ml heparin or protamine sulfate. Heparin is a specific inhibitor of HSPGs, and protamine competes with LRP ligands for HSPG-binding sites (19). Neither heparin (Figs.…”

Section: Neuronal Uptake Of Anionic Liposomes Occurs By Clathrinmediamentioning

confidence: 99%

Low-density Lipoprotein Receptor-related Protein Mediates the Endocytosis of Anionic Liposomes in Neurons

Lakkaraju¹,

Rahman²,

Dubinsky³

2002

Journal of Biological Chemistry

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We have recently demonstrated that anionic liposomes efficiently introduce foreign DNA into postmitotic neurons and other cell types (Lakkaraju, A., Dubinsky, J. M., Low, W. C., and Rahman, Y.-E. (2001) J. Biol. Chem. 276, 32000 -32007). To investigate the mechanism of liposome uptake, we followed the internalization of anionic liposome-encapsulated Cy3-labeled oligonucleotides (AL-Cy3ONs) by hippocampal neurons using confocal microscopy. Uptake of ALCy3ONs was widespread and time-and temperature-dependent, indicative of receptor-mediated endocytosis. The low-density lipoprotein receptor-related protein (LRP) was crucial for anionic liposome endocytosis because the receptor-associated protein or an anti-LRP antibody inhibited internalization, and fibroblasts lacking LRP did not internalize AL-Cy3ONs. Using selective endocytosis inhibitors, we found that liposome endocytosis and intracellular transport required clathrin, dynamin, an intact cytoskeletal network, and phosphatidylinositol 3-kinase activity. Cy3ONs did not significantly colocalize with recycling endosomal/ lysosomal markers and entered neuronal nuclei within 1-3 h of incubation. Approximately 50% of the internalized liposomal phospholipids were recycled back to the cell surface, in keeping with the fluidity of their acyl chains. Liposome endocytosis did not require heparan sulfate proteoglycans or cause calcium influx into neurons. Thus, constitutive endocytosis of anionic liposomes by LRP utilizes only one component, in contrast to the more involved heparan sulfate proteoglycan-LRP pathway implicated in the pathogenesis of Alzheimer's disease.Endocytosis in neurons has mainly been studied in the context of synaptic vesicle recycling (1) and the regulation of neurotransmitter receptor numbers in the post-synaptic membrane (2). Constitutive endocytosis also occurs in neurons, albeit at a slower rate than in non-polarized or mitotically active cells. Growth factors and hormones modulate the rate of constitutive endocytosis of neurotransmitter receptors as well as receptors involved in nutrient acquisition and metabolism. Neurotrophins such as nerve growth factor and bone-derived neurotrophic factor increase both the recruitment of clathrin to the plasma membrane and the rate of constitutive endocytosis of transferrin in hippocampal neurons (3).Little is known, however, about the mechanisms of internalization of exogenous macromolecules such as phospholipids and nucleic acids in neurons. Insight into the interactions between neurons and these molecules would further our understanding of lipid and DNA transport pathways and provide potential therapeutic advantages. We have recently designed and developed an anionic liposome vector (composed of the anionic phospholipid dioleoylphosphatidylglycerol and the zwitterionic phospholipid dioleoylphosphatidylcholine) for oligonucleotide delivery to neurons. Antisense oligonucleotides targeted to the p53 tumor suppressor mRNA, delivered to neurons via anionic liposomes, efficiently protected hippocampal neurons fr...

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Section: Introductionmentioning

confidence: 99%

“…26,27 Moreover, intravenously administered [ 125 I]-TFPI-1 is rapidly cleared from the circulation, a process that seems to involve both LRP and HSPG. 28 However, there is no direct evidence to support a role for proteoglycans (PGs) in the regulation of TF-dependent PAR signaling by TFPI.The function of TFPI-1 as the physiologic inhibitor of TFinitiated coagulation has prompted interest in applying recombinant TFPI-1 (rTFPI-1) as a substitution therapy to counterbalance exacerbated coagulant responses in severe inflammation. Although TFPI-1 showed positive effects in several animal sepsis models, 29-31 no effect on 28-day mortality in septic patients could be established in a phase 3 clinical study.…”

mentioning

confidence: 99%

Regulation of tissue factor–induced signaling by endogenous and recombinant tissue factor pathway inhibitor 1

Ahamed

Belting

Ruf

2005

Blood

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Tissue factor (TF) triggers upstream coagulation signaling via the activation of protease-activated receptors (PARs) of relevance for inflammation and angiogenesis. TF pathway inhibitor 1 (TFPI-1) is the physiologic inhibitor of TF-initiated coagulation, but its role in regulating TF signaling is poorly understood. Here, we demonstrate that endogenous, endothelial cell-expressed TFPI-1 controls TFmediated signaling through PARs. In en IntroductionActivation of coagulation and cell signaling are interconnected by multiple pathways. Coagulation proteases signal via cleavage of protease-activated receptors (PARs), a family of G protein-coupled receptors with 4 known members (PAR1-PAR4). [1][2][3] The overlap in PAR signaling induced by different coagulation proteases, the partial redundancy between PARs, as well as possible intracellular cross-talk between PARs, make it challenging to distinguish the pathophysiologic significance of these signaling pathways. 4 Activation of coagulation by the tissue factor (TF) pathway is common in systemic and local inflammation. 5 In vivo, PAR signaling has generally been attributed to activation by thrombin. 1 However, our recent study has provided clear evidence for relevant thrombinindependent, TF-mediated PAR2 signaling in angiogenesis in vivo. 6 TF-dependent signaling is either by the TF-VIIa protease complex specifically through PAR2 7,8 or by the nascent product Xa in the ternary TF-VIIa-Xa complex that signals through PAR2 9,10 as well as PAR1, [8][9][10][11] the first recognized thrombin receptor.Tissue factor pathway inhibitor 1 (TFPI-1) is the central endogenous regulator of coagulation activation by TF. [12][13][14][15] Although purified TFPI-1 at high concentrations can inhibit TFVIIa, 16 efficient inhibition by TFPI-1 is dependent on Xa that is generated during TF-dependent initiation of coagulation. TFPI-1 contains 3 Kunitz-type protease inhibitor domains and a C-terminal polybasic region. The second domain binds and inhibits Xa, and TFPI-1 can thus act as a direct protease inhibitor of Xa. Kunitz domain 1 inhibits VIIa in complex with TF. 12,14,15 Endogenous TFPI-1 is directly or indirectly anchored by glycosylphosphatidylinositol (GPI) on cell surfaces. [17][18][19][20][21][22][23] Lipoprotein receptor-related protein (LRP) and heparan sulfate proteoglycan (HSPG) have been implicated in the binding and internalization of recombinant forms of TFPI-1, depending on their C-terminal polybasic portions. 24,25 Endothelial cells, which are normally deficient in LRP, may bind TFPI-1 via HSPG and the very-low-density lipoprotein receptor. 26,27 Moreover, intravenously administered [ 125 I]-TFPI-1 is rapidly cleared from the circulation, a process that seems to involve both LRP and HSPG. 28 However, there is no direct evidence to support a role for proteoglycans (PGs) in the regulation of TF-dependent PAR signaling by TFPI.The function of TFPI-1 as the physiologic inhibitor of TFinitiated coagulation has prompted interest in applying recombinant TFPI-1 (rTFPI-1) as a subs...

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Two Receptor Systems Are Involved in the Plasma Clearance of Tissue Factor Pathway Inhibitor in Vivo

Cited by 78 publications

References 22 publications

Reversible Regulation of Tissue Factor–Induced Coagulation by Glycosyl Phosphatidylinositol–Anchored Tissue Factor Pathway Inhibitor

Reversible Regulation of Tissue Factor–Induced Coagulation by Glycosyl Phosphatidylinositol–Anchored Tissue Factor Pathway Inhibitor

Low-density Lipoprotein Receptor-related Protein Mediates the Endocytosis of Anionic Liposomes in Neurons

Regulation of tissue factor–induced signaling by endogenous and recombinant tissue factor pathway inhibitor 1

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