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Seminars in Cell & Developmental Biology Nov 2018Eukaryotic cells have a highly evolved system of protein secretion, and dysfunction in this pathway is associated with many diseases including cancer, infection,... (Review)
Review
Eukaryotic cells have a highly evolved system of protein secretion, and dysfunction in this pathway is associated with many diseases including cancer, infection, metabolic disease and neurological disorders. Most proteins are secreted using the conventional endoplasmic reticulum (ER)/Golgi network and as such, this pathway is well-characterised. However, several cytosolic proteins have now been documented as secreted by unconventional transport pathways. This review focuses on two of these proteins families: annexins and galectins. The extracellular functions of these proteins are well documented, as are associations of their perturbed secretion with several diseases. However, the mechanisms and regulation of their secretion remain poorly characterised, and are discussed in this review. This review is part of a Special Issues of SCDB on 'unconventional protein secretion' edited by Walter Nickel and Catherine Rabouille.
Topics: Annexins; Galectins; Humans; Protein Transport
PubMed: 29501720
DOI: 10.1016/j.semcdb.2018.02.022 -
JCI Insight Jul 2022Membrane instability and disruption underlie myriad acute and chronic disorders. Anxa6 encodes the membrane-associated protein annexin A6 and was identified as a genetic...
Membrane instability and disruption underlie myriad acute and chronic disorders. Anxa6 encodes the membrane-associated protein annexin A6 and was identified as a genetic modifier of muscle repair and muscular dystrophy. To evaluate annexin A6's role in membrane repair in vivo, we inserted sequences encoding green fluorescent protein (GFP) into the last coding exon of Anxa6. Heterozygous Anxa6gfp mice expressed a normal pattern of annexin A6 with reduced annexin A6GFP mRNA and protein. High-resolution imaging of wounded muscle fibers showed annexin A6GFP rapidly formed a repair cap at the site of injury. Injured cardiomyocytes and neurons also displayed repair caps after wounding, highlighting annexin A6-mediated repair caps as a feature in multiple cell types. Using surface plasmon resonance, we showed recombinant annexin A6 bound phosphatidylserine-containing lipids in a Ca2+- and dose-dependent fashion with appreciable binding at approximately 50 μM Ca2+. Exogenously added recombinant annexin A6 localized to repair caps and improved muscle membrane repair capacity in a dose-dependent fashion without disrupting endogenous annexin A6 localization, indicating annexin A6 promotes repair from both intracellular and extracellular compartments. Thus, annexin A6 orchestrates repair in multiple cell types, and recombinant annexin A6 may be useful in additional chronic disorders beyond skeletal muscle myopathies.
Topics: Animals; Annexin A6; Annexins; Calcium; Mice; Muscle, Skeletal; Myocytes, Cardiac
PubMed: 35866481
DOI: 10.1172/jci.insight.158107 -
International Journal of Molecular... Jun 2018The vertebrate annexin superfamily (AnxA) consists of 12 members of a calcium (Ca) and phospholipid binding protein family which share a high structural homology. In... (Review)
Review
The vertebrate annexin superfamily (AnxA) consists of 12 members of a calcium (Ca) and phospholipid binding protein family which share a high structural homology. In keeping with this hallmark feature, annexins have been implicated in the Ca-controlled regulation of a broad range of membrane events. In this review, we identify and discuss several themes of annexin actions that hold a potential therapeutic value, namely, the regulation of the immune response and the control of tissue homeostasis, and that repeatedly surface in the annexin activity profile. Our aim is to identify and discuss those annexin properties which might be exploited from a translational science and specifically, a clinical point of view.
Topics: Animals; Annexins; Biomarkers; Carcinogenesis; Communicable Diseases; Host-Pathogen Interactions; Humans; Translational Research, Biomedical
PubMed: 29914106
DOI: 10.3390/ijms19061781 -
Scientific Reports Apr 2023Hepatocellular carcinoma (HCC) is a highly lethal liver cancer with late diagnosis; therefore, the identification of new early biomarkers could help reduce mortality. We...
Hepatocellular carcinoma (HCC) is a highly lethal liver cancer with late diagnosis; therefore, the identification of new early biomarkers could help reduce mortality. We determine the tissue and plasma status of five annexins during hepatocarcinogenesis by diethylnitrosamine-induced cirrhosis-HCC. We found that Anxa5 was the earliest upregulated gene at week 12 after HCC initiation, while Anxa1 and Anxa2 were upregulated in advanced HCC stages (weeks 18 and 22). Furthermore, the protein level of Annexin A1, A2, A5 and A10 was increased from the early stages. Immunofluorescence and subcellular fractionation revealed Annexin A1, A2, and A5 in the cytoplasm and nuclei of tumor cells. Notably, increased plasma levels of Annexin A5 significantly (r = 0.8203) correlated with Annexin A5 levels in liver tissue from week 12 and gradually increased until week 22. Using the TCGA database, we found that the expression of ANXA2 (HR = 1.7, p = 0.0046) and ANXA5 (HR = 1.8, p = 0.00077) was associated with poor survival in HCC patients. In conclusion, we have identified Annexin A1 and A5 as potentially useful early biomarkers for poor prognosis in HCC patients.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Annexin A1; Annexin A5; Annexin A2; Annexins; Biomarkers, Tumor
PubMed: 37117324
DOI: 10.1038/s41598-023-34117-8 -
Methods (San Diego, Calif.) Oct 2015Characterization of exosomal cargo is of significant interest because this cargo can provide clues to exosome biogenesis, targeting, and cellular effects and may be a... (Review)
Review
Characterization of exosomal cargo is of significant interest because this cargo can provide clues to exosome biogenesis, targeting, and cellular effects and may be a source of biomarkers for disease diagnosis, prognosis and response to treatment. With recent improvements in proteomics technologies, both qualitative and quantitative characterization of exosomal proteins is possible. Here we provide a brief review of exosome proteomics studies and provide detailed protocols for global qualitative, global quantitative, and targeted quantitative analysis of exosomal proteins. In addition, we provide an example application of a standard global quantitative analysis followed by validation via a targeted quantitative analysis of urine exosome samples from human patients. Advantages and limitations of each method are discussed as well as future directions for exosome proteomics analysis.
Topics: Amino Acid Sequence; Annexins; Antigens, CD; Bibliometrics; Biological Transport; Biomarkers; DNA-Binding Proteins; Endosomal Sorting Complexes Required for Transport; Exosomes; Humans; Mass Spectrometry; Molecular Sequence Data; Protein Processing, Post-Translational; Proteome; Proteomics; Transcription Factors
PubMed: 25837312
DOI: 10.1016/j.ymeth.2015.03.018 -
Journal of Nuclear Medicine : Official... Oct 2008Cells can die by several pathways, such as accidental death, apoptosis, autophagy, pyroptosis, and oncosis. These are important in normal physiology and many disease... (Review)
Review
Cells can die by several pathways, such as accidental death, apoptosis, autophagy, pyroptosis, and oncosis. These are important in normal physiology and many disease states, such as cancer and cardiovascular disease. Specific biochemical changes occur in cells undergoing apoptosis that provide potential targets for molecular imaging agents. Several of these molecular steps have been evaluated to date, including phosphatidylserine exposure at the extracellular face of the plasma membrane, detected by proteins such as annexin V; caspase activation in the intracellular compartment, detected by labeled enzyme substrates or inhibitors; and mitochondrial membrane potential collapse, detected by reduced levels of phosphonium cations that normally accumulate in healthy mitochondria. Phase I clinical trials have been performed with 1 of these agents, annexin V. Future work will likely include development of new agents that detect targets not exploited by current agents, translational research on the significance of imaging the different forms of cell death, and further improvements in the techniques for labeling existing agents to improve sensitivity and reduce nonspecific background.
Topics: Animals; Annexins; Apoptosis; Caspases; Cell Membrane; Diagnostic Imaging; Enzyme Activation; Humans; Membrane Potentials; Models, Biological; Nuclear Medicine; Radioisotopes
PubMed: 18794267
DOI: 10.2967/jnumed.108.052803 -
Biological Chemistry Oct 2016Annexins are a highly conserved protein family that bind to phospholipids in a calcium (Ca2+) - dependent manner. Studies with purified annexins, as well as... (Review)
Review
Annexins are a highly conserved protein family that bind to phospholipids in a calcium (Ca2+) - dependent manner. Studies with purified annexins, as well as overexpression and knockdown approaches identified multiple functions predominantly linked to their dynamic and reversible membrane binding behavior. However, most annexins are found at multiple locations and interact with numerous proteins. Furthermore, similar membrane binding characteristics, overlapping localizations and shared interaction partners have complicated identification of their precise functions. To gain insight into annexin function in vivo, mouse models deficient of annexin A1 (AnxA1), A2, A4, A5, A6 and A7 have been generated. Interestingly, with the exception of one study, all mice strains lacking one or even two annexins are viable and develop normally. This suggested redundancy within annexins, but examining these knockout (KO) strains under stress conditions revealed striking phenotypes, identifying underlying mechanisms specific for individual annexins, often supporting Ca2+ homeostasis and membrane transport as central for annexin biology. Conversely, mice lacking AnxA1 or A2 show extracellular functions relevant in health and disease that appear independent of membrane trafficking or Ca2+ signaling. This review will summarize the mechanistic insights gained from studies utilizing mouse models lacking members of the annexin family.
Topics: Animals; Annexins; Humans; Mice; Mice, Knockout
PubMed: 27318360
DOI: 10.1515/hsz-2016-0168 -
BMC Cancer Sep 2022Uptake of apoptotic cells induces a tolerogenic phenotype in phagocytes and promotes peripheral tolerance. The highly conserved Annexin core domain, present in all...
BACKGROUND
Uptake of apoptotic cells induces a tolerogenic phenotype in phagocytes and promotes peripheral tolerance. The highly conserved Annexin core domain, present in all members of the Annexin family, becomes exposed on the apoptotic cell-surface and triggers tolerogenic signalling in phagocytes via the Dectin-1 receptor. Consequently, Annexins exposed on tumour cells upon cell death are expected to induce tolerance towards tumour antigens, inhibiting tumour rejection.
METHODS
Expression analysis for all Annexin family members was conducted in cancer cell lines of diverse origins. Presentation of Annexins on the cell surface during apoptosis of cancer cell lines was investigated using surface washes and immunoblotting. Expression data from the GEO database was analysed to compare Annexin levels between malignant and healthy tissue.
RESULTS
Six Annexins at least were consistently detected on mRNA and protein level for each investigated cell line. AnxA1, AnxA2 and AnxA5 constituted the major part of total Annexin expression. All expressed Annexins translocated to the cell surface upon apoptosis induction in all cell lines. Human expression data indicate a correlation between immune infiltration and overall Annexin expression in malignant compared to healthy tissue.
CONCLUSIONS
This study is the first comprehensive analysis of expression, distribution and presentation of Annexins in cancer.
Topics: Annexin A5; Annexins; Antigens, Neoplasm; Humans; Neoplasms; RNA, Messenger
PubMed: 36123610
DOI: 10.1186/s12885-022-10075-8 -
British Journal of Pharmacology Apr 2015
Topics: Animals; Annexins; Helminth Proteins; Humans; Neglected Diseases; Schistosoma; Schistosomiasis
PubMed: 25776940
DOI: 10.1111/bph.13089 -
Frontiers in Endocrinology 2024Successful pregnancy requires the tolerance of the maternal immune system for the semi-allogeneic embryo, as well as a synchrony between the receptive endometrium and... (Review)
Review
Successful pregnancy requires the tolerance of the maternal immune system for the semi-allogeneic embryo, as well as a synchrony between the receptive endometrium and the competent embryo. The annexin family belongs to calcium-regulated phospholipid-binding protein, which functions as a membrane skeleton to stabilize the lipid bilayer and participate in various biological processes in humans. There is an abundance of the annexin family at the maternal-fetal interface, and it exerts a crucial role in embryo implantation and the subsequent development of the placenta. Altered expression of the annexin family and dysfunction of annexin proteins or polymorphisms of the gene are involved in a range of pregnancy complications. In this review, we summarize the current knowledge of the annexin A protein family at the maternal-fetal interface and its association with female reproductive disorders, suggesting the use of ANXA as the potential therapeutic target in the clinical diagnosis and treatment of pregnancy complications.
Topics: Pregnancy; Female; Humans; Embryo Implantation; Placenta; Endometrium; Pregnancy Complications; Annexins
PubMed: 38495790
DOI: 10.3389/fendo.2024.1314214