Interactions between cells and the extracellular matrix are integral to tissue development, remodelling and pathogenesis. This is underlined by bi-directional flow of information signalling, referred to as dynamic reciprocity. Annexin A2 is a complex and multifunctional protein that belongs to a large family of Ca 2+ -dependent anionic phospholipid and membrane-binding proteins. It has been implicated in diverse cellular processes at the nuclear, cytoplasmic and extracellular compartments including Ca 2+ -dependent regulation of endocytosis and exocytosis, focal adhesion dynamics, transcription and translation, cell proliferation, oxidative stress and apoptosis. Most of these functions are mediated by the annexin A2-S100A10 heterotetramer (AIIt) via its ability to simultaneously interact with cytoskeletal, membrane and extracellular matrix components, thereby mediating regulatory effects of extracellular matrix adhesion on cell behaviour and vice versa. While Src kinase-mediated phosphorylation of filamentous actin-bound AIIt results in membrane-cytoskeletal remodelling events which control cell polarity, cell morphology and cell migration, AIIt at the cell surface can bind to a number of extracellular matrix proteins and catalyse the activation of serine and cysteine proteases which are important in facilitating tissue remodelling during tissue repair, neoangiogenesis and pathological situations. This review will focus on the role of annexin A2 in regulating tissue integrity through intercellular and cell-extracellular matrix interaction. Annexin A2 is differentially expressed in various tissue types as well as in many pathologies, particularly in several types of cancer. These together suggest that annexin A2 acts as a central player during dynamic reciprocity in tissue homeostasis.
ScopeGarlic (Allium sativum) has been used for centuries as a prophylactic and therapeutic medicinal agent to control inflammation‐associated pathologies. To investigate the underlying mechanisms, an in vitro inflammatory model is established using RAW264.7 murine macrophages exposed to low‐doses of lipopolysaccharide (LPS) in the presence of garlic compounds allicin and Z‐ajoene (ZA), mimicking regular garlic consumption.Methods and ResultsBoth allicin and Z‐ajoene dampen both transcript and protein expression of the pro‐inflammatory cytokines IL1β, IL6, and IL12β, and upregulate the expression of the anti‐inflammatory cytokine IL10. Protein arrays of selected secreted inflammatory mediators confirm that Z‐ajoene has a pronounced down‐regulatory effect on LPS‐induced inflammatory cytokines and chemokines. Many of these proteins are known targets of the transcription factor signal transducer and activator of transcription 3 (STAT3); and indeed, Z‐ajoene or its analogue dansyl‐ajoene is found to decrease phosphorylation and nuclear translocation of STAT3, and to covalently modify the protein by S‐thiolation at Cys108, Cys367, and Cys687. Z‐Ajoene dose‐dependently and non‐competitively inhibit the activity of cyclooxygenase 2 (COX2), possibly attributed to S‐thiolation at Cys9 and Cys299.ConclusionThe characterization of Z‐ajoene's activity of targeting and covalently modifying STAT3 and COX2, both important regulators of inflammation, may contribute to the health benefits of regular dietary garlic consumption.
The fibrillar collagen scaffold of the extracellular matrix provides a structural framework for cells in tissues and regulates intercellular communication; its disregulation has been associated with tumour development and progression. Previous work has shown that expression of type I collagen, the most abundant mammalian extracellular matrix protein, is decreased in chemically or virally transformed cells. This negative regulation could be mapped to a proximal COL1A2 promoter element spanning a CME (Collagen Modulating Element) site in SV40‐transformed human fibroblasts (SV‐WI38) that binds an unknown repressing protein. By magnetic bead pull‐down, we observed a multi‐protein complex bound to the CME with preference for single‐stranded over conventional double‐stranded DNA. MALDI‐TOF mass spectrometry of the CME‐binding protein complex revealed involvement of nuclear annexin A2 (AnxA2) which was increased in SV40‐transformed cells. Further EMSA analysis demonstrated that AnxA2 did not directly bind to the DNA but stabilised the complex and led to an increase in protein binding to the CME in SV‐WI38 but not untransformed WI38 cells. Knockdown of AnxA2 by siRNA increased type I collagen production in both WI38 and SV‐WI38 cells; however, these effects were not mediated at the transcriptional level. Rather, our data indicate a novel functional role of AnxA2 in the negative post‐transcriptional regulation of type I collagen synthesis in human fibroblasts. In SV40‐transformed cells, AnxA2 is accumulated at the proximal COL1A2 promoter region, suggesting close association with the transcriptional machinery that possibly facilitates binding to the emerging mRNA, eventually contributing to overall repression of type I collagen protein synthesis. J. Cell. Biochem. 116: 408–417, 2015. © 2014 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals, Inc.
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