Plasminogen activator inhibitor type 2: a regulator of monocyte proliferation and differentiation

Yu, Hua; Maurer, Fabienne; Medcalf, Robert L.

doi:10.1182/blood.v99.8.2810

Cited by 58 publications

(47 citation statements)

References 42 publications

(36 reference statements)

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“…Whether these two viral SERPINlike proteins inhibit caspase-1 activity via a mechanism similar to that of PAI-2 remains to be determined. In addition, our results demonstrate that THP-1 macrophages expressing the PAI-2 A380 mutant [a residue critical for its protease inhibition (16)] failed to inhibit LPS-induced IL-1β processing. PAI-2 A380 also lost its binding to HSP90/Beclin 1, resulting in loss of autophagy induction in response to LPS.…”

Section: Discussionmentioning

confidence: 77%

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TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation

Chuang

Yang

Chou

et al. 2013

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

135

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The NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, a multiprotein complex, triggers caspase-1 activation and maturation of the proinflammatory cytokines IL-1β and IL-18 upon sensing a wide range of pathogen-and damage-associated molecules. Dysregulation of NLRP3 inflammasome activity contributes to the pathogenesis of many diseases, but its regulation remains poorly defined. Here we show that depletion of plasminogen activator inhibitor type 2 (PAI-2), a serine protease inhibitor, resulted in NLRP3-and ASC (apoptosis-associated Specklike protein containing a C-terminal caspase recruitment domain)-dependent caspase-1 activation and IL-1β secretion in macrophages upon Toll-like receptor 2 (TLR2) and TLR4 engagement. TLR2 or TLR4 agonist induced PAI-2 expression, which subsequently stabilized the autophagic protein Beclin 1 to promote autophagy, resulting in decreases in mitochondrial reactive oxygen species, NLRP3 protein level, and pro-IL-1β processing. Likewise, overexpressing Beclin 1 in PAI-2-deficient cells rescued the suppression of NLRP3 activation in response to LPS. Together, our data identify a tier of TLR signaling in controlling NLRP3 inflammasome activation and reveal a cell-autonomous mechanism which inversely regulates TLR-or Escherichia coli-induced mitochondrial dysfunction, oxidative stress, and IL-1β-driven inflammation.

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Section: Discussionmentioning

confidence: 77%

“…1D). The arginine residue at position 380 of PAI-2 is crucial for its protease inhibition (16). THP-1 macrophages expressing mutant PAI-2 containing an alanine substitution at residue 380 (A380) showed little inhibition in LPS-induced IL-1β and IL-18 production, caspase-1 activation, and ASC oligomerization ( Fig.…”

Section: Resultsmentioning

confidence: 99%

TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation

Chuang

Yang

Chou

et al. 2013

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

135

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“…Electroporations were carried out at room temperature using a Gene Pulser Xcell System (Bio-Rad Laboratories, Munich, Germany) at 300 V and 950 mF for MV4-11 cells, 300 V and 800 mF for THP-1 cells (adapted from 18 ), 250 V and 20 ms for MOLM-14 cells, 19 and 250 V, 400 mF for TF-1 cells.…”

Section: Small Interfering Rna Transfectionmentioning

confidence: 99%

FES kinases are required for oncogenic FLT3 signaling

et al. 2010

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The closely related non-receptor tyrosine kinases FEline Sarcoma (FES) and FEs Related (FER) are activated by cell surface receptors in hematopoietic cells. Despite the early description of oncogenic viral forms of fes, v-fes, and v-fps, the implication of FES and FER in human pathology is not known. We have recently shown that FES but not FER is necessary for oncogenic KIT receptor signaling. Here, we report that both FES and FER kinases are activated in primary acute myeloid leukemia (AML) blasts and in AML cell lines. FES and FER activation is dependent on FLT3 in cell lines harboring constitutively active FLT3 mutants. Moreover, both FES and FER proteins are critical for FLT3-internal tandem duplication (ITD) signaling and for cell proliferation in relevant AML cell lines. FER is required for cell cycle transitions, whereas FES seems necessary for cell survival. We concluded that FES and FER kinases mediate essential non-redundant functions downstream of FLT3-ITD.

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“…[3][4][5] Extracellular PAI-2 is a potent inhibitor of urokinase-type plasminogen activator (u-PA) and, although the intracellular targets and the molecular mechanism of PAI-2 remain undefined, different studies have indicated that PAI-2 acts as a multifunctional protein, since, it is involved in the regulation of fibrinolysis, in the regulation of keratinocytes development, in proliferation, in the invasion and metastasis of cancer cells, and in conferring resistance to apoptosis. [6][7][8] It has been reported that PAI-2 is constitutively expressed in human stratified squamous epithelia and suggested that this inhibitor could be involved in the differentiation or in the antimicrobial defense mechanisms of at least some epithelia. 5 For instance, it has been reported that PAI-2 could be a product of differentiating corneal keratinocytes, since in human corneal epithelium PAI-2 is present exclusively in the most superficial cell layers (i.e.…”

Section: Introductionmentioning

confidence: 99%

Cytoplasmic and nuclear interaction between Rb family proteins and PAI-2: a physiological crosstalk in human corneal and conjunctival epithelial cells

et al. 2006

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Extracellular plasminogen activator inhibitor type-2 (PAI-2) is a potent inhibitor of urokinase-type plasminogen activator (u-PA) and also acts as a multifunctional protein. However, the biological activity of intracellular PAI-2, as well as its intracellular targets, until now remain an enigma. Here, we show that pRb2/p130 and Rb1/p105, but not p107, interact with PAI-2 in both the cytoplasm and nucleus of normal primary human corneal and conjunctival epithelial cells. We provided the first in vivo evidence that a specific fragment of the PAI-2 promoter is bound simultaneously by pRb2/ p130, PAI-2, E2F5, histone deacetylase 1 (HDAC1), DNA methyltransferase 1 (DNMT1), and histone methyltransferase (SUV39H1), in normal primary human corneal epithelial cells, and by pRb2/p130, PAI-2, E2F5, HDAC1, and DNMT1, in normal primary human conjunctiva epithelial cells. Our results strongly indicate a physiological interaction between pRb family members and PAI-2, suggesting the hypothesis that pRb2/p130 and PAI-2 may cooperate in modulating PAI-2 gene expression by chromatin remodeling, in normal corneal and conjunctival cells.

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Plasminogen activator inhibitor type 2: a regulator of monocyte proliferation and differentiation

Cited by 58 publications

References 42 publications

TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation

TLR-induced PAI-2 expression suppresses IL-1β processing via increasing autophagy and NLRP3 degradation

FES kinases are required for oncogenic FLT3 signaling

Cytoplasmic and nuclear interaction between Rb family proteins and PAI-2: a physiological crosstalk in human corneal and conjunctival epithelial cells

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