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The Annexin A2/S100A10 Complex: The Mutualistic Symbiosis of Two Distinct Proteins.
Bharadwaj, A, Kempster, E, Waisman, DM
Biomolecules. 2021;(12)
Abstract
Mutualistic symbiosis refers to the symbiotic relationship between individuals of different species in which both individuals benefit from the association. S100A10, a member of the S100 family of Ca2+-binding proteins, exists as a tight dimer and binds two annexin A2 molecules. This association forms the annexin A2/S100A10 complex known as AIIt, and modifies the distinct functions of both proteins. Annexin A2 is a Ca2+-binding protein that binds F-actin, phospholipid, RNA, and specific polysaccharides such as heparin. S100A10 does not bind Ca2+, but binds tPA, plasminogen, certain plasma membrane ion channels, neurotransmitter receptors, and the structural scaffold protein, AHNAK. S100A10 relies on annexin A2 for its intracellular survival: in the absence of annexin A2, it is rapidly destroyed by ubiquitin-dependent and independent proteasomal degradation. Annexin A2 requires S100A10 to increase its affinity for Ca2+, facilitating its participation in Ca2+-dependent processes such as membrane binding. S100A10 binds tissue plasminogen activator and plasminogen, and promotes plasminogen activation to plasmin, which is a process stimulated by annexin A2. In contrast, annexin A2 acts as a plasmin reductase and facilitates the autoproteolytic destruction of plasmin. This review examines the relationship between annexin A2 and S100A10, and how their mutualistic symbiosis affects the function of both proteins.
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Modulation of Ion Channels and Receptors by p11 (S100A10).
Seo, JS, Svenningsson, P
Trends in pharmacological sciences. 2020;(7):487-497
Abstract
p11 (S100A10, annexin II light chain, calpactin I light chain) is a multifunctional protein that forms a heterotetrameric complex with Annexin A2, particularly at cell membranes. p11, alone or together with Annexin A2, interacts with several ion channels and receptors and regulates their cellular localization and function. Altered levels of p11 are implicated in the pathophysiology of several forms of cancer, psychiatric disorders, and neurodegeneration. Via interactions with ion channels and receptors, p11 modulates therapeutic actions of drugs targeting brain disorders. By serving as a plasminogen receptor, p11 plays an important role in plasmin generation, fibrinolysis, angiogenesis, tumor progression, and metastasis. Here, we review mechanisms whereby p11 regulates functions of ion channels and receptors in health and disease states.
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Impact of S100A4 Expression on Clinicopathological Characteristics and Prognosis in Pancreatic Cancer: A Meta-Analysis.
Huang, S, Zheng, J, Huang, Y, Song, L, Yin, Y, Ou, D, He, S, Chen, X, Ouyang, X
Disease markers. 2016;:8137378
Abstract
BACKGROUND The small Ca(2+)-binding protein S100A4 is identified as a metastasis-associated or metastasis-inducing protein in various types of cancer. The goal of this meta-analysis was to evaluate the relationship between S100A4 expression and clinicopathological characteristics and prognosis of patients with pancreatic cancer. METHODS A comprehensive literature search was carried out in the electronic databases PubMed and Chinese CNKI. Only the studies reporting the correlation between S100A4 expression and clinicopathological characteristics or overall survival (OS) of patients with pancreatic cancer are enrolled. Extracted data was analyzed using the RevMan 5.3 software to calculate the pooled relative risks (95% confidence interval, CI) for statistical analyses. RESULTS Seven studies including a total of 474 patients were enrolled into this meta-analysis. Negative expression of S100A4 was significantly associated with higher 3-year OS rate (RR = 3.92, 95% CI = 2.24-6.87, P < 0.0001), compared to S100A4-positive cases. Moreover, negative expression of S100A4 was also related to N0 stage for lymph node metastasis (RR = 2.15, 95% CI = 1.60-2.88, P < 0.0001). However, S100A4 expression was not significantly correlated with histological types and distant metastasis status. CONCLUSION S100A4 expression represents a potential marker for lymph node metastasis of pancreatic cancer and a potential unfavorable factor for prognosis of patients with this disease.
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Cardiomyocytes, endothelial cells and cardiac fibroblasts: S100A1's triple action in cardiovascular pathophysiology.
Rohde, D, Busch, M, Volkert, A, Ritterhoff, J, Katus, HA, Peppel, K, Most, P
Future cardiology. 2015;(3):309-21
Abstract
Over the past decade, basic and translational research delivered comprehensive evidence for the relevance of the Ca(2+)-binding protein S100A1 in cardiovascular diseases. Aberrant expression levels of S100A1 surfaced as molecular key defects, driving the pathogenesis of chronic heart failure, arterial and pulmonary hypertension, peripheral artery disease and disturbed myocardial infarction healing. Loss of intracellular S100A1 renders entire Ca(2+)-controlled networks dysfunctional, thereby leading to cardiomyocyte failure and endothelial dysfunction. Lack of S100A1 release in ischemic myocardium compromises cardiac fibroblast function, entailing impaired damage healing. This review focuses on molecular pathways and signaling cascades regulated by S100A1 in cardiomyocytes, endothelial cells and cardiac fibroblasts in order to provide an overview of our current mechanistic understanding of S100A1's action in cardiovascular pathophysiology.
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Clinicopathological and prognostic value of S100A4 expression in gastric cancer: a meta-analysis.
Ling, Z, Li, R
The International journal of biological markers. 2014;(2):e99-e111
Abstract
PURPOSES For several years S100A4 has been implicated in tumor progression and prognosis. However, the prognostic value of S100A4 overexpression in patients with gastric cancer remains unknown. Therefore, we performed a meta-analysis to assess the relationship between S100A4 overexpression and clinical outcome of gastric cancer. METHODS AND RESULTS Candidate studies were searched from PubMed, Embase, Cochrane Library, and ISI Web of Science. We included studies that evaluated the prognostic value of S100A4 expression in gastric cancer patients with regard to survival and a series of clinicopathological parameters. The pooled hazard ratios (HR) and odds ratios (OR) with 95% confidence intervals (CI) were used to estimate the effects. Ten studies, all from Asia, were included in the meta-analysis. The pooled analysis showed that S100A4 overexpression was significantly associated with worse overall survival (OS) (HR=1.86, 95% CI: 1.45-2.38, p<0.00001) without heterogeneity in the data (I2=43.6%, p=0.131). Furthermore, our results showed that S100A4 overexpression was significantly correlated with some clinicopathological parameters such as tumor grade, stage, metastasis, invasion, and relapse. CONCLUSIONS The results of our meta-analysis indicate that S100A4 overexpression correlates with more adverse clinical features and a poor prognosis of gastric cancer patients in Asia, thus suggesting that S100A4 could be a useful marker to evaluate progression and prognosis of Asian gastric cancer patients. More studies from Western countries with a larger number of tumors and standardized methods are required before significant conclusions can be drawn.
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Clinicopathological and prognostic significance of S100A4 overexpression in colorectal cancer: a meta-analysis.
Liu, Y, Tang, W, Wang, J, Xie, L, Li, T, He, Y, Qin, X, Li, S
Diagnostic pathology. 2013;:181
Abstract
BACKGROUND Accumulated evidence has indicated a correlation between S100A4 expression and colorectal cancer (CRC) progression. However, its prognostic significance for patients with CRC remains inconclusive. To clarify their relationship, a meta-analysis of the relevant published studies was performed. METHOD PubMed, Cochrane Library, and Web of Science databases were electronically searched. All studies evaluating the prognostic value of S100A4 expression in CRC patients regarding survival and a series of clinicopathological parameters were included. The effect of S100A4 expression on the overall survival (OS) and disease-free survival (DFS) were measured by pooled hazard ratios (HRs) and 95% confidence intervals (CIs), while the effect of S100A4 expression on the clinicopathological parameters were measured by the pooled odds ratios (ORs) and their 95% CIs. RESULTS Eleven studies (2,824 patients in total) were included in the meta-analysis. Overall, S100A4 overexpression was significantly associated with worse OS (HR = 1.90, 95% CI: 1.58-2.29, P <0.001), and worse DFS (HR = 2.16, 95% CI: 1.53-3.05, P <0.001) in patients with CRC. Subgroup analyses showed that S100A4 overexpression was significantly correlated with poor OS in Asian, European, and Australian patients and patients treated with surgery or chemotherapy. Additionally, there were significant associations between S100A4 expression and several clinicopathological parameters (tumour location, lymph node metastasis, nodal status, TNM stage, and tumour depth). CONCLUSIONS This meta-analysis indicates that S100A4 overexpression seems to correlate with tumour progression and poor prognosis of CRC patients. It may be a useful marker to predict progression and prognosis of CRC. VIRTUAL SLIDES The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8643820431072915.
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Predictive value of S-100β protein for prognosis in patients with moderate and severe traumatic brain injury: systematic review and meta-analysis.
Mercier, E, Boutin, A, Lauzier, F, Fergusson, DA, Simard, JF, Zarychanski, R, Moore, L, McIntyre, LA, Archambault, P, Lamontagne, F, et al
BMJ (Clinical research ed.). 2013;:f1757
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Abstract
OBJECTIVES To determine the ability and accuracy of the S-100β protein in predicting prognosis after a moderate or severe traumatic brain injury. DESIGN Systematic review and meta-analysis of randomised controlled trials and observational studies. DATA SOURCES Medline, Embase, Cochrane Central Register of Controlled Trials, BIOSIS (from their inception to April 2012), conference abstracts, bibliographies of eligible articles, and relevant narrative reviews. STUDY SELECTION Two reviewers independently reviewed citations and selected eligible studies, defined as cohort studies or randomised control trials including patients with moderate or severe traumatic brain injury and evaluating the prognostic value of S-100β protein. Outcomes evaluated were mortality, score on the Glasgow outcome scale, or brain death. DATA EXTRACTION Two independent reviewers extracted data using a standardised form and evaluated the methodological quality of included studies. Pooled results were presented with geometric means ratios and analysed with random effect models. Prespecified sensitivity analyses were performed to explain heterogeneity. RESULTS The search strategy yielded 9228 citations. Two randomised controlled trials and 39 cohort studies were considered eligible (1862 patients). Most studies (n=23) considered Glasgow outcome score ≤ 3 as an unfavourable outcome. All studies reported at least one measurement of S-100β within 24 hours after traumatic brain injury. There was a significant positive association between S-100β protein concentrations and mortality (12 studies: geometric mean ratio 2.55, 95% confidence interval 2.02 to 3.21, I(2)=56%) and score ≤ 3 (18 studies: 2.62, 2.01 to 3.42, I(2)=79%). Sensitivity analysis based on sampling time, sampling type, blinding of outcome assessors, and timing of outcome assessment yielded similar results. Thresholds for serum S-100β protein values with 100% specificity ranged from 1.38 to 10.50 µg/L for mortality (six studies) and from 2.16 to 14.00 µg/L for unfavourable neurological prognosis as defined by the Glasgow outcome score. CONCLUSIONS After moderate or severe traumatic brain injury, serum S-100β protein concentrations are significantly associated with unfavourable prognosis in the short, mid, or long term. Optimal thresholds for discrimination remain unclear. Measuring the S-100β protein could be useful in evaluating the severity of traumatic brain injury and in the determination of long term prognosis in patients with moderate and severe injury.
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The evolution of S100B inhibitors for the treatment of malignant melanoma.
Hartman, KG, McKnight, LE, Liriano, MA, Weber, DJ
Future medicinal chemistry. 2013;(1):97-109
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Abstract
Malignant melanoma continues to be an extremely fatal cancer due to a lack of viable treatment options for patients. The calcium-binding protein S100B has long been used as a clinical biomarker, aiding in malignant melanoma staging and patient prognosis. However, the discovery of p53 as a S100B target and the consequent impact on cell apoptosis redirected research efforts towards the development of inhibitors of this S100B-p53 interaction. Several approaches, including computer-aided drug design, fluorescence polarization competition assays, NMR, x-ray crystallography and cell-based screens have been performed to identify compounds that block the S100B-p53 association, reactivate p53 transcriptional activities and induce cancer cell death. Eight promising compounds, including pentamidine, are presented in this review and the potential for future modifications is discussed. Synthesis of compound derivatives will likely exhibit increased S100B affinity and mimic important S100B-target dynamic properties that will result in high specificity.
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The S100B protein in biological fluids: more than a lifelong biomarker of brain distress.
Michetti, F, Corvino, V, Geloso, MC, Lattanzi, W, Bernardini, C, Serpero, L, Gazzolo, D
Journal of neurochemistry. 2012;(5):644-59
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S100B is a calcium-binding protein concentrated in glial cells, although it has also been detected in definite extra-neural cell types. Its biological role is still debated. When secreted, S100B is believed to have paracrine/autocrine trophic effects at physiological concentrations, but toxic effects at higher concentrations. Elevated S100B levels in biological fluids (CSF, blood, urine, saliva, amniotic fluid) are thus regarded as a biomarker of pathological conditions, including perinatal brain distress, acute brain injury, brain tumors, neuroinflammatory/neurodegenerative disorders, psychiatric disorders. In the majority of these conditions, high S100B levels offer an indicator of cell damage when standard diagnostic procedures are still silent. The key question remains as to whether S100B is merely leaked from injured cells or is released in concomitance with both physiological and pathological conditions, participating at high concentrations in the events leading to cell injury. In this respect, S100B levels in biological fluids have been shown to increase in physiological conditions characterized by stressful physical and mental activity, suggesting that it may be physiologically regulated and raised during conditions of stress, with a putatively active role. This possibility makes this protein a candidate not only for a biomarker but also for a potential therapeutic target.
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Neurological biomarkers in the perioperative period.
Cata, JP, Abdelmalak, B, Farag, E
British journal of anaesthesia. 2011;(6):844-58
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The rapid detection and evaluation of patients presenting with perioperative neurological dysfunction is of great clinical relevance. Biomarkers have been defined as biological molecules that can be used as an indicator of new onset or progression of a biological process or effect of treatment. Biomarkers have become increasingly important in this setting to supplement other modalities of diagnosis such as EEG, sensory- or motor-evoked potential, transcranial Doppler, near-infrared spectroscopy, or imaging methods. A number of neuro-proteins have been identified and are currently under investigation for potential to provide insights into injury severity, outcome, and the ability to monitor cellular damage and molecular events that occur during neurological injury. S100B is a protein released by glial cells and is considered a marker of blood-brain barrier dysfunction. Clinical studies in patients undergoing cardiac and non-cardiac surgery indicate that serum levels of S100B are increased intraoperatively and after operation. The neurone-specific enolase has also been extensively investigated as a potential marker of neuronal injury in the context of cardiac and non-cardiac surgery. A third biomarker of interest is the Tau protein, which has been linked to neurodegenerative disorders. Tau appears to be more specific than the previous two biomarkers since it is only found in the central nervous system. The metalloproteinase and ubiquitin C terminal hydroxylase-L1 (UCH-L1) are the most recently researched markers; however, their usefulness is still unclear. This review presents a comprehensive overview of S100B, neuronal-specific enolase, metalloproteinases, and UCH-L1 in the perioperative period.