Annexin 1 Cleavage in Activated Neutrophils

Vong, Linda; D’Acquisto, Fulvio; Pederzoli-Ribeil, Magali; Lavagno, L; Flower, Roderick J.; Witko‐Sarsat, Véronique; Perretti, Mauro

doi:10.1074/jbc.m702876200

Cited by 119 publications

(138 citation statements)

References 36 publications

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“…The AnxA1 N-terminal region is the site of attack by many proteases that may either lead to the inactivation of the protein (15) or release of peptides endowed with distinct bioactions to the parent protein (32). Thus, we assessed cleavage of AnxA1 2-50 by human PR3 and HNE, two enzymes associated with pathogenesis in vascular (33) and lung (34) diseases, but also abundant in inflammatory exudates (15,16). At variance from AnxA1, which in similar experimental settings is cleaved at positions 11, 22, and 36 (35), the shorter 50-aa-long sequence revealed a novel cleavage site at position 25.…”

Section: Discussionmentioning

confidence: 99%

“…Because the N-terminal portion of AnxA1 is a substrate for neutrophil-derived, PR-mediated cleavage and inactivation (15,16), we next assessed the cleavage of AnxA1 2-50 by HNE and PR3. This analysis demonstrated that cleavage at the C-terminal side of Val 25 was prominent and a common recognition site for both enzymes (Fig.…”

Section: Substitution Of Val 25 Yields a Cleavage-resistant Peptide Wmentioning

confidence: 99%

“…Upon calcium binding, AnxA1 undergoes conformational change with exposure of the N-terminal domain, which can then interact with FPR2/ALX. This portion of the protein is susceptible to cleavage by proteolytic enzymes, including human proteinase (PR) 3 (15) and neutrophil elastase (HNE) (16), leading to AnxA1 inactivation.…”

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confidence: 99%

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Proresolving and Tissue-Protective Actions of Annexin A1–Based Cleavage-Resistant Peptides Are Mediated by Formyl Peptide Receptor 2/Lipoxin A4 Receptor

Dalli

Consalvo²,

Ray³

et al. 2013

The Journal of Immunology

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109

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Endogenous mechanisms regulating the host response during inflammation resolution are critical in ensuring disposal of noxious stimuli and return to homeostasis. In this article, we engineered novel Annexin A1 (AnxA1)–based peptides, AnxA12–50, that displayed specific binding to the AnxA1 receptor (formyl peptide receptor 2/Lipoxin A4 receptor [FPR2/ALX]; IC50 ∼4 nM). Intravenous administration of AnxA12–50 markedly reduced (>60%) leukocyte adhesion to postcapillary venules in wild type and Fpr1−/−, but not Fpr2/Alx−/−, mice. Generation of a metabolically stable form of this peptide (CR-AnxA12–50), engineered by substituting a cleavage site shared by human proteinase 3 and neutrophil elastase, yielded an agonist that was resistant to neutrophil-mediated cleavage and displayed enhanced proresolving actions: accelerated resolution of self-limited inflammation and enhanced macrophage efferocytosis after sterile injury, when compared with AnxA12–50. These actions were retained with human primary leukocytes where CR-AnxA12–50 decreased neutrophil–endothelial interactions (∼25–45%), and stimulated neutrophil apoptosis and macrophage efferocytosis (∼45%). In murine cardiac ischemia/reperfusion injury, CR-AnxA12–50 elicited tissue-protective actions reducing infarct size (∼60%) and incidence of 24-h death. These results identify AnxA12–50 and CR-AnxA12–50 as FPR2/ALX agonists that harness the proresolving actions of AnxA1, and thus may represent therapeutic tools for treatment of inflammatory conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Substitution Of Val 25 Yields a Cleavage-resistant Peptide Wmentioning

confidence: 99%

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Proresolving and Tissue-Protective Actions of Annexin A1–Based Cleavage-Resistant Peptides Are Mediated by Formyl Peptide Receptor 2/Lipoxin A4 Receptor

Dalli

Consalvo²,

Ray³

et al. 2013

The Journal of Immunology

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109

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“…2 mg of a pcDNA3.1 plasmid with c-Myc tagged on the N terminus and FLAG tagged on the C terminus (MF-ANXA1) to over-express ANXA1 was transfected into cells. MF-ANXA1 plasmid was generated as reported previously 51 and kindly gifted by Prof. Mauro Perretti (William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK). pcDNA3.1 empty vector was used as control.…”

Section: Matrigel Invasion Assaymentioning

confidence: 99%

Hypoxia regulates ANXA1 expression to support prostate cancer cell invasion and aggressiveness

Bizzarro

Belvedere

Migliaro

et al. 2016

Cell Adhesion & Migration

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Annexin A1 (ANXA1) is a Ca 2C -binding protein overexpressed in the invasive stages of prostate cancer (PCa) development; however, its role in this tumor metastatization is largely unknown. Moreover, hypoxic conditions in solid tumors have been related to poor prognosis in PCa patients. We have previously demonstrated that ANXA1 is implicated in the acquisition of chemo-resistant features in DU145 PCa cells conferring them a mesenchymal/metastatic phenotype. In this study, we have investigated the mechanisms by which ANXA1 regulates metastatic behavior in LNCaP, DU145 and PC3 cells exposed to hypoxia. ANXA1 was differentially expressed by PCa cell lines in normoxia whereas hypoxic stimuli resulted in a significant increase of protein expression. Additionally, in low oxygen conditions ANXA1 was extensively secreted out-side the cells where its binding to formyl peptide receptors (FPRs) induced cell invasion. Loss and gain of function experiments performed by using the RNA interfering siANXA1 and an ANXA1 over-expressing plasmid (MF-ANXA1), also confirmed the leading role of the protein in modulating LNCaP, DU145 and PC3 cell invasiveness. Finally, ANXA1 played a crucial role in the regulation of cytoskeletal dynamics underlying metastatization process, such as the loss of adhesion molecules and the occurrence of the epithelial to mesenchymal transition (EMT). ANXA1 expression increased inversely to epithelial markers such as E-cadherin and cytokeratins 8 and 18 (CKs) and proportionally to mesenchymal ones such as vimentin, ezrin and moesin. Our results indicated that ANXA1 may be a key mediator of hypoxia-related metastasis-associated processes in PCa.

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“…Other aspects of host defence were also explored in the current study, namely the direct anti-microbial actions of AnxA1 and its N-terminal truncated peptides. The N-terminus of AnxA1 is reported to contain cleavage sites for elastase (Smith et al 1990) and proteinase 3 enzymes which cleave at valine and alanine residues (Vong et al, 2007). The data indicates that the majority of the imunoreactive AnxA1 protein detected in human saliva samples is in the truncated form (~33kD).…”

Section: (Insert Figure 2 Around Here) Discussionmentioning

confidence: 66%

Annexin-A1 protein and its relationship to cortisol in human saliva

Fowkes

Moradi-Bidhendi

Branceleone

et al. 2013

Psychoneuroendocrinology

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Abstract/SummarySalivary cortisol is commonly used as a clinical biomarker of endocrine status and also as a marker of psychosocial stress. Annexin-A1 (AnxA1) is an anti-inflammatory protein whose expression is modulated by glucocorticoids. Our principal objectives were to (i) detect the presence of and (ii) measure AnxA1 protein in whole human saliva and to (iii) investigate whether salivary cortisol and AnxA1 are correlated in healthy humans. A total of 37 healthy participants (male and female) were used in the study. Saliva was collected using salivette tubes. Salivary cortisol and AnxA1 protein were sampled at between 3 and 6 time points over 24 hours and measured for cortisol and AnxA1 protein using specific ELISA's. The presence of salivary AnxA1 protein was confirmed by western blotting.AnxA1 protein is detectable in whole human saliva, as detected by western blot analysis and ELISA. A diurnal rhythm was evident in both salivary cortisol (P < 0.01) and AnxA1 (P < 0.01) and was defined as a significant difference in time 0 (waking) samples compared to 'bed' (23.00 hrs) samples. AnxA1 protein did not exhibit an awakening response (P > 0.05), whereas salivary cortisol was significantly elevated between time 0 and 30 minutes post waking (P < 0.001).AnxA1 protein correlates positively with salivary cortisol, indicating that cortisol is most likely a regulator of AnxA1 in human saliva.

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Annexin 1 Cleavage in Activated Neutrophils

Cited by 119 publications

References 36 publications

Proresolving and Tissue-Protective Actions of Annexin A1–Based Cleavage-Resistant Peptides Are Mediated by Formyl Peptide Receptor 2/Lipoxin A4 Receptor

Proresolving and Tissue-Protective Actions of Annexin A1–Based Cleavage-Resistant Peptides Are Mediated by Formyl Peptide Receptor 2/Lipoxin A4 Receptor

Hypoxia regulates ANXA1 expression to support prostate cancer cell invasion and aggressiveness

Annexin-A1 protein and its relationship to cortisol in human saliva

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