The Low Density Lipoprotein Receptor-related Protein Is a Motogenic Receptor for Plasminogen Activator Inhibitor-1

Degryse, Bernard; Neels, Jaap G.; Czekay, Ralf-Peter; Aertgeerts, K.; Kamikubo, Yu-ichi; Loskutoff, David J.

doi:10.1074/jbc.m313004200

Cited by 182 publications

(215 citation statements)

References 57 publications

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“…Because apoptotic cell clearance is critical to the resolution of inflammation, our data suggest that PAI-1 may exacerbate inflammatory responses by blocking the clearance of apoptotic neutrophils, thereby allowing such neutrophils to become necrotic and to release their intracellular contents into the extracellular milieu. Our findings, together with previous studies demonstrating that PAI-1 enhances LPS induced neutrophil activation (22) and promotes the migration and infiltration of lymphocytes and neutrophils into inflammatory sites (19)(20)(21)27), demonstrate that PAI-1 has multiple proinflammatory roles that are independent of its participation in coagulation and microvascular thrombosis. We found that the enhanced neutrophil phagocytosis associated with PAI-1 deficiency can be abrogated by blocking LRP on macrophages with anti-LRP antibodies or the LRP-specific blocking peptide RAP, indicating that LRP participates in PAI-1 mediated modulation of efferocytosis.…”

Section: Discussionmentioning

confidence: 78%

“…Elevated serum and tissue levels of PAI-1 have been found in a number of inflammatory diseases, including myocardial infarction, sepsis, and acute lung injury, with increased circulating PAI-1 levels being associated with unfavorable outcomes (15)(16)(17)(18). Previous studies suggested that microvascular thrombosis associated with inhibition of fibrinolytic processes by PAI-1 and the role of PAI-1 as a chemotactic factor promoting the migration of lymphocytes and neutrophils into inflammatory sites contributed to its inflammatory effects (19)(20)(21). In addition, PAI-1 also appears to have intrinsic proinflammatory properties by potentiating Toll-like receptor 4 (TLR4) mediated activation of neutrophils (22).…”

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confidence: 99%

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PAI-1 inhibits neutrophil efferocytosis

Park

Liu²,

Lorne³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

103

105

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Phagocytosis of apoptotic cells, also called efferocytosis, is an essential feature of immune responses and critical for the resolution of inflammation. Plasma and tissue levels of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, are elevated in inflammatory conditions, including sepsis and acute lung injury, in which activated neutrophils accumulate in tissues and contribute to organ dysfunction. In this study, we explored the potential involvement of PAI-1 in modulating neutrophil efferocytosis. We found enhanced phagocytosis of viable PAI-1 deficient (PAI-1 ؊/؊ ) and of wild-type neutrophils treated with anti-PAI-1 antibodies. PAI-1 levels were decreased on the surface of apoptotic neutrophils and the enhanced phagocytosis of apoptotic wild-type neutrophils or of viable PAI-1 ؊/؊ neutrophils was diminished by preincubation with PAI-1. The increased phagocytosis associated with PAI-1 deficiency or blockade depended on both the lipoprotein receptor-related protein (LRP) and its ligand, calreticulin (CRT), because the LRP-mediated increase in phagocytosis of viable neutrophils induced by blockade of CD 47 was abrogated by PAI-1. CRT levels are increased on viable PAI-1 ؊/؊ neutrophils. While CRT colocalizes with PAI-1 on viable neutrophils, markedly diminished colocalization of PAI-1 and CRT was present on apoptotic neutrophils. Our data therefore indicate that PAI-1 serves as a novel ''don't eat me'' signal for viable and apoptotic neutrophils.calreticulin ͉ phagocytosis ͉ plasminogen activator inhibitor-1

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Section: Discussionmentioning

confidence: 78%

mentioning

confidence: 99%

PAI-1 inhibits neutrophil efferocytosis

Park

Liu²,

Lorne³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

103

105

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“…Given this, it was unnecessary to investigate the impact of uPA-SerpinB2 KYK (or other SerpinB2 mutants generated with incomplete LDLR-binding motifs) on mitogenic signaling, because the VLDLR binding affinity of this complex was indistinguishable from that of uPASerpinB2 YK . Direct binding of SerpinE1 to LRP1 has also been demonstrated to activate the JAK/STAT pathway, leading to increased cell motility (34). However, because the prognostic data for SerpinE1 is only significant in tumors also expressing uPA (1)(2)(3)35), the impact of complementing SerpinB2 with LRP1 binding on the activation of this pathway was not investigated in this study.…”

Section: Discussionmentioning

confidence: 98%

Dependence on Endocytic Receptor Binding via a Minimal Binding Motif Underlies the Differential Prognostic Profiles of SerpinE1 and SerpinB2 in Cancer

Cochran

Croucher

Lobov

et al. 2011

Journal of Biological Chemistry

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Tumor overexpression of urokinase-type plasminogen activator (uPA) and its specific inhibitor SerpinE1 (plasminogen activator inhibitor type-1) correlates with poor prognosis and increased metastatic potential. Conversely, tumor expression of uPA and another specific inhibitor, SerpinB2 (plasminogen activator inhibitor type-2), are associated with favorable outcome and relapse-free survival. It is not known how overexpression of these uPA inhibitors results in such disparate outcomes. A possible explanation may be related to the presence of a proposed low density lipoprotein receptor (LDLR)-binding motif in SerpinE1 responsible for mitogenic signaling via ERK that is absent in SerpinB2. We now show that complementation of such a LDLR-binding motif in SerpinB2 by mutagenesis of two key residues enabled high affinity binding to very LDLR (VLDLR). Furthermore, the VLDLR-binding SerpinB2 form behaved in a manner indistinguishable from SerpinE1 in terms of enhanced uPA-SerpinB2 complex endocytosis and subsequent ERK phosphorylation and cell proliferation; that is, the introduction of the LDLR-binding motif to SerpinB2 was necessary and sufficient to allow it to acquire characteristics of SerpinE1 associated with malignancy. In conclusion, this study defines the structural elements underlying the distinct interactions of SerpinE1 versus SerpinB2 with endocytic receptors and how differential VLDLR binding impacts on downstream cellular behavior. This has clear relevance to understanding the paradoxical disease outcomes associated with overexpression of these serpins in cancer.SerpinE1 (plasminogen activator inhibitor type-1, PAI-1) 4 and SerpinB2 (plasminogen activator inhibitor type-2, PAI-2) are both efficient inhibitors of the urokinase-type plasminogen activator (uPA), a key enzyme in the tissue remodeling process. Combined tumor overexpression of uPA, its receptor (uPAR), and SerpinE1 (serine protease inhibitor E1) is strongly correlated with poor patient prognosis (1-3) and metastatic potential (4 -8). Consequently, uPA and SerpinE1 expression is recommended as an independent prognostic indicator in node-negative breast cancer (9). On the contrary, tumor expression of SerpinB2 is correlated with increased relapse-free survival in breast cancer (and possibly other cancer types) (10). Further, the relationship between outcome and high SerpinB2 levels in node-negative breast cancer is only relevant if uPA levels are also elevated (1, 11), suggesting that the inhibitory relationship between uPA and SerpinB2 mediates this functionality.Binding of uPA to uPAR has been reported to induce the activation of numerous cell type-specific signaling pathways, such as MAPK/ERK, JAK/STAT, Src, focal adhesion kinase, and Rac, thereby affecting cell adhesion, migration, differentiation, and apoptosis (12). Because uPAR is not a transmembrane protein, being linked to the cell surface by a glycosylphosphatidylinositol anchor, uPA/uPAR signaling is mediated by integrins and several other adaptor molecules, including members of the lo...

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“…Although both are efficient uPA inhibitors, PAI-1 and PAI-2 are structurally and functionally quite distinct serpins, as recognized by their grouping into different serpin subfamily groups (6). For example, PAI-1 also has alternative non-uPA inhibitory activities that affect cell adhesion, intracellular signaling, and cell migration (8) that have not been demonstrated for PAI-2.…”

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confidence: 99%

The Urokinase/PAI-2 Complex

Croucher

Saunders

Ranson

2006

Journal of Biological Chemistry

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The efficient inactivation of urokinase plasminogen activator (uPA) by plasminogen activator inhibitor type 2 (PAI-2) at the surface of carcinoma cells is followed by rapid endocytosis of the uPA-PAI-2 complex. We now show that one pathway of this receptormediated endocytosis is mediated via the low density lipoprotein receptor-related protein (LRP) in prostate cancer cells. Detailed biochemical analyses using ligand binding assays and surface plasmon resonance revealed a novel and distinct interaction mechanism between native, human LRP and uPA-PAI-2. As reported previously for PAI-1, inhibition of uPA by PAI-2 significantly increased the affinity of the complex for LRP (K D of 36 nM for uPA-PAI-2 versus 200 nM for uPA). This interaction was maintained in the presence of uPAR, confirming the validity of this interaction at the cell surface. However, unlike PAI-1, no interaction was observed between LRP and PAI-2 in either the stressed or the relaxed conformation. This suggests that the uPA-PAI-2-LRP interaction is mediated by site(s) within the uPA molecule alone. Thus, as inhibition of uPA by PAI-2 resulted in accelerated clearance of uPA from the cell surface possibly via its increased affinity for LRP, this represents a mechanism through which PAI-2 can clear proteolytic activity from the cell surface. Furthermore, lack of a direct interaction between PAI-2 and LRP implies that downstream signaling events initiated by PAI-1 may not be activated by PAI-2.Inhibition of urokinase plasminogen activator (uPA) 4 proteolytic activity at the cell surface is an important step in the regulation of pericellular plasminogen activation (1-4). This process is facilitated by members of the serpin (serine protease inhibitor) superfamily, most notably by plasminogen activator inhibitors 1 (PAI-1) and 2 (PAI-2) (SerpinE1 and SerpinB2, respectively) (5-7). Although both are efficient uPA inhibitors, PAI-1 and PAI-2 are structurally and functionally quite distinct serpins, as recognized by their grouping into different serpin subfamily groups (6). For example, PAI-1 also has alternative non-uPA inhibitory activities that affect cell adhesion, intracellular signaling, and cell migration (8) that have not been demonstrated for PAI-2.In their classical inhibitory role, serpins interact with their target protease through an exposed peptide loop, the reactive center loop (6, 9). This acts as bait for the active site of the protease, leading to formation of an equimolar covalent complex. The formation of this complex results in extensive deformation of both the protease and the serpin (9), resulting in the conversion of the serpin from a "stressed" to a "relaxed" form. The relaxed conformation of PAI-2 and other serpins can also be induced by the insertion of a peptide that mimics the reactive center loop (10).uPA is a potent marker of metastatic capacity in multiple human tumors and makes an attractive therapeutic target (11-13). Recent work has shown that cytotoxins attached to the PAI-2 molecule can be specifically delivered to ...

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The Low Density Lipoprotein Receptor-related Protein Is a Motogenic Receptor for Plasminogen Activator Inhibitor-1

Cited by 182 publications

References 57 publications

PAI-1 inhibits neutrophil efferocytosis

PAI-1 inhibits neutrophil efferocytosis

Dependence on Endocytic Receptor Binding via a Minimal Binding Motif Underlies the Differential Prognostic Profiles of SerpinE1 and SerpinB2 in Cancer

The Urokinase/PAI-2 Complex

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