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Annexin A2 is required for the early steps of cytokinesis.

ABSTRACT: Cytokinesis requires the formation of an actomyosin contractile ring between the two sets of sister chromatids. Annexin A2 is a calcium- and phospholipid-binding protein implicated in cortical actin remodeling. We report that annexin A2 accumulates at the equatorial cortex at the onset of cytokinesis and depletion of annexin A2 results in cytokinetic failure, due to a defective cleavage furrow assembly. In the absence of annexin A2, the small GTPase RhoA-which regulates cortical cytoskeletal rearrangement-fails to form a compact ring at the equatorial plane. Furthermore, annexin A2 is required for cortical localization of the RhoGEF Ect2 and to maintain the association between the equatorial cortex and the central spindle. Our results demonstrate that annexin A2 is necessary in the early phase of cytokinesis. We propose that annexin A2 participates in central spindle-equatorial plasma membrane communication.

SUBMITTER: Benaud C

PROVIDER: S-EPMC4388614 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Annexin A2 is required for the early steps of cytokinesis.

Benaud Christelle C Le Dez Gaëlle G Mironov Svetlana S Galli Federico F Reboutier David D Prigent Claude C

EMBO reports 20150223 4

Cytokinesis requires the formation of an actomyosin contractile ring between the two sets of sister chromatids. Annexin A2 is a calcium- and phospholipid-binding protein implicated in cortical actin remodeling. We report that annexin A2 accumulates at the equatorial cortex at the onset of cytokinesis and depletion of annexin A2 results in cytokinetic failure, due to a defective cleavage furrow assembly. In the absence of annexin A2, the small GTPase RhoA-which regulates cortical cytoskeletal rea ...[more]

PMID: 25712672

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Drosophila citron kinase is required for the final steps of cytokinesis.

Project description:The mechanisms underlying completion of cytokinesis are still poorly understood. Here, we show that the Drosophila orthologue of mammalian Citron kinases is essential for the final events of the cytokinetic process. Flies bearing mutations in the Drosophila citron kinase (dck) gene were defective in both neuroblast and spermatocyte cytokinesis. In both cell types, early cytokinetic events such as central spindle assembly and contractile ring formation were completely normal. Moreover, cytokinetic rings constricted normally, leading to complete furrow ingression. However late telophases of both cell types displayed persistent midbodies associated with disorganized F actin and anillin structures. Similar defects were observed in dck RNA interference (RNAi) telophases, which, in addition to abnormal F actin and anillin rings, also displayed aberrant membrane protrusions at the cleavage site. Together, these results indicate that mutations in the dck gene result in morphologically abnormal intercellular bridges and in delayed resolution of these structures, suggesting that the wild-type function of dck is required for abscission at the end of cytokinesis. The phenotype of Dck-depleted cells is different from those observed in most Drosophila cytokinesis mutants but extraordinarily similar to that caused by anillin RNAi, suggesting that Dck and anillin are in the same pathway for completion of cytokinesis.

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Annexin A2 is a discriminative serological candidate in early hepatocellular carcinoma.

Project description:To date, the useful markers of hepatocellular carcinoma (HCC) remains incompletely developed. Here, we show that annexin A2 complement alpha-fetoprotein (AFP), a widely used liver cancer marker, in the serologically surveillance and early detection of HCC. First, differentially expressed proteins in HCC were identified using a subcellular proteomic approach. Annexin A2 was then selected for further verification. It was found to be overexpressed in HCC tissues (60.7%, 136/224). Using a self-established sandwich enzyme-linked immunosorbent assay, we found that annexin A2 significantly increased in the sera of HCC (n = 175, median, 24.75 ng/µl) compared with the healthy (n = 49, median, 16.69 ng/µl), benign tumors (n = 19, median, 19.92 ng/µl), hepatitis (n = 23, median, 6.48 ng/µl) and cirrhosis (n = 51, median, 7.39 ng/µl) controls and other malignant tumors (n = 87). Importantly, raised concentrations of annexin A2 were observed in 83.2% (79/95) of early stage (median, 24.32 ng/µl) and 78.4% (58/74) of AFP-negative (median, 24.09 ng/µl) patients. Annexin A2 alone had a better area under the receiver-operating characteristic curve (AUC = 0.79, 95% confidence interval: 0.73-0.85) in comparison with AFP (AUC = 0.73, 95% confidence interval: 0.66-0.80) in detecting of early stage HCC. Combining both markers notably improved the diagnostic efficiency of early HCC with an achieved sensitivity of 87.4%. Additionally, the expression characteristics of annexin A2 during hepatocarcinogenesis were detected in p21-HBx gene knockin transgenic mice model. The results showed that annexin A2 expression was substantially elevated in HCC-bearing mice, in accordance with the finding in human samples. In conclusion, annexin A2 may be an independent serological candidate for hepatitis B virus-related HCC, especially in the early stage cases with normal serum AFP.

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Role of annexin A2 in muscle repair

Project description:Repair of injured muscle involves repair of injured myofibers through the involvement of dysferlin and its interacting partners, including annexin. Studies with mice and patients have established that dysferlin deficit leads to chronic inflammation and adipogenic replacement of the diseased muscle. However, longitudinal analysis of annexin deficit on muscle pathology and function is lacking. Here we show that unlike annexin A1, but similar to dysferlin, lack of annexin A2 (AnxA2) causes poor myofiber repair and progressive weakening with age. However, unlike dysferlin-deficient muscle, AnxA2-deficient muscles do not exhibit chronic inflammation or adipogenic replacement. Deletion of AnxA2 in dysferlin deficient mice reduces inflammation, adipogenic replacement, and loss in muscle function caused by dysferlin deficit. These results show that: a) AnxA2 facilitates myofiber repair, b) chronic inflammation and adipogenic replacement of dysferlinopathic muscle requires AnxA2, and c) inhibiting AnxA2-mediated inflammation is a novel therapeutic avenue for dysferlinopathy.

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Blockade of Annexin A2 Prevents Early Microvasculopathy in Murine Models of Diabetic Retinopathy.

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Genotoxic agents promote the nuclear accumulation of annexin A2: role of annexin A2 in mitigating DNA damage.

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Diagnostic Value of Plasma Annexin A2 in Early-Stage High-Grade Serous Ovarian Cancer.

Project description:Ovarian cancer (OC) is commonly diagnosed at advanced stage when prognosis is poor. Consequently, there is an urgent clinical need to identify novel biomarkers for early detection to improve survival. We examined the diagnostic value of the calcium phospholipid binding protein annexin A2 (ANXA2), which plays an important role in OC metastasis. Annexin A2 plasma levels in patients with high grade serous OC (n = 105), benign ovarian lesions (n = 55) and healthy controls (n = 143) were measured by ELISA. Annexin A2 levels were found to be significantly increased in patients with stage I (p < 0.0001) and stage IA (p = 0.0027) OC when compared to healthy controls. In the logistic regression models followed by receiver operating characteristics (ROC) curve analyses, plasma annexin A2 showed 46.7% sensitivity at 99.6% specificity in distinguishing stage IA OC patients from healthy controls and 75% sensitivity at 65.5% specificity in the diagnosis of stage IA versus benign ovarian tumors. In the diagnosis of stage IA OC versus normal controls, the combination of plasma annexin A2 and CA125 showed 80% sensitivity at 99.6% specificity (AUC = 0.970) which was significantly higher than for CA125 (53.3% sensitivity at 99.6% specificity; AUC = 0.891) alone. The diagnostic accuracy in distinguishing stage IA OC from benign ovarian disease when combining annexin A2 and CA125 (71.4% accuracy at 100% sensitivity) was almost twice as high compared to CA125 (37.1% accuracy at 100% sensitivity) alone. In conclusion, annexin A2 in combination with CA125 has potential as a biomarker for the early detection of OC and to predict malignancy in patients with ovarian lesions, warranting further investigations.

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Project description:The facultative intracellular pathogen, Salmonella enterica, triggers its own uptake into non-phagocytic epithelial cells. Invasion is dependent on a type 3 secretion system (T3SS), which delivers a cohort of effector proteins across the plasma membrane where they induce dynamic actin-driven ruffling of the membrane and ultimately, internalization of the bacteria into a modified phagosome. In eukaryotic cells, the calcium- and phospholipid-binding protein Annexin A2 (AnxA2) functions as a platform for actin remodelling in the vicinity of dynamic cellular membranes. AnxA2 is mostly found in a stable heterotetramer, with p11, which can interact with other proteins such as the giant phosphoprotein AHNAK. We show here that AnxA2, p11 and AHNAK are required for T3SS-mediated Salmonella invasion of cultured epithelial cells and that the T3SS effector SopB is required for recruitment of AnxA2 and AHNAK to Salmonella invasion sites. Altogether this work shows that, in addition to targeting Rho-family GTPases, Salmonella can intersect the host cell actin pathway via AnxA2.

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Bridging of membrane surfaces by annexin A2.

Project description:The protein-mediated formation of membrane contacts is a crucial event in many cellular processes ranging from the establishment of organelle contacts to the docking of vesicles to a target membrane. Annexins are Ca2+ regulated membrane-binding proteins implicated in providing such membrane contacts; however, the molecular basis of membrane bridging by annexins is not fully understood. We addressed this central question using annexin A2 (AnxA2) that functions in secretory vesicle exocytosis possibly by providing membrane bridges. By quantitatively analyzing membrane contact formation using a novel assay based on quartz crystal microbalance recordings, we show that monomeric AnxA2 can bridge membrane surfaces Ca2+ dependently. However, this activity depends on an oxidative crosslink involving a cysteine residue in the N-terminal domain and thus formation of disulfide-linked dimers. Alkylated AnxA2 in which this cysteine residue has been modified and AnxA2 mutants lacking the N-terminal domain are not capable of bridging membrane surfaces. In contrast, a heterotetrameric complex comprising two membrane binding AnxA2 subunits linked by a S100A10 dimer can provide membrane contacts irrespective of oxidation status. Thus, monomeric AnxA2 only contains one lipid binding site and AnxA2-mediated linking of membrane surfaces under non-oxidative intracellular conditions most likely requires AnxA2-S100 complex formation.

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Role of the long non‑coding RNA‑Annexin A2 pseudogene 3/Annexin A2 signaling pathway in biliary atresia‑associated hepatic injury.

Project description:Biliary atresia (BA) is the most common cause of chronic cholestasis in children. The long non‑coding RNA (lncRNA) Annexin A2 pseudogene 3 (ANXA2P3) and Annexin A2 (ANXA2) have been suggested to serve pivotal roles in BA; however, the clinical significance and biological roles of ANXA2P3 and ANXA2 in BA remain to be elucidated. The present study aimed to elucidate the function of ANAX2P3 and ANXA2 in BA‑induced liver injury using a human liver cell line and liver tissues from patients with BA. Reverse transcription‑quantitative polymerase chain reaction, western blotting and immunohistochemistry were conducted to determine the expression levels of ANXA2 and ANXA2P3 in liver tissues from patients with BA. Classification of fibrosis was analyzed by Masson staining. The functional roles of ANXA2 and ANXA2P3 in liver cells were determined by Cell Counting kit‑8 assay, and flow cytometric and cell cycle analyses. Activation of the ANXA2/ANXA2P3 signaling pathway in liver cells was evaluated by western blot analysis. According to the present results, the expression levels of ANXA2 and ANXA2P3 were significantly increased in liver tissues from patients with BA. In addition, knocking down the expression of ANXA2P3 and ANXA2 may result in reduced liver cell proliferation, cell cycle arrest in G1 phase and increased apoptosis of liver cells in vitro. Furthermore, in cells in which ANXA2 and ANXA2P3 were overexpressed, cell apoptosis was reduced and cell cycle arrest in G2 phase. Taken together, these results indicated that ANXA2P3 and ANXA2 may have protective effects against liver injury progression and may be considered biomarkers in patients with BA.

| S-EPMC6317672 | biostudies-literature

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