Annexin II regulates fibrin homeostasis and neoangiogenesis in vivo

Qi, Ling; Jacovina, Andrew T.; Deora, Arunkumar B.; Febbraio, Maria; Simantov, Ronit; Silverstein, Roy L.; Hempstead, Barbara; Mark, Willie; Hajjar, Katherine A.

doi:10.1172/jci19684

Cited by 338 publications

(305 citation statements)

References 56 publications

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“…CD105 (Endoglin) was a member of transforming growth factor β (TGFβ) superfamily, Related to angiogenesis and maintaining vascular. CD105was highly expressed on endothelial cells of nascent tumor blood vessels and vascular endothelial cells of the tumor margin and was considered to be an ideal target in tumor therapy to inhibit tumor angiogenesis (Li et al, 2014), CD105 strongly overexpressed in the endothelial cells of arteries and veins surrounding tumor tissues contrasted with tumor cell (Ling et al, 2004), Our experiment confirmed CD105 is mainly expressed in the vascular endothelial cells around tumor tissues. Microvessel density (MVD) in tumor tissues is directly correlated with the prognosis of patients with cancer, some research showed that in breast cancer, cervical cancer and other malignant tumor tissues, MVD labeled by CD105 is better than that labeled by CD34, Ⅷ factor related antigen, Etc.…”

Section: Discussionsupporting

confidence: 69%

“…In consequence of Annexin A2 could promote new blood vessels endothelial cells to form tube-like structure (Kumar et al, 1999;Ling et al, 2004), resulted in decrease of isolated vascular endothelial cells and lower MVD in specimens of strong positive (3+) Annexin A2 staining, Of course, the specific reason and mechanism needed further research.…”

Section: Discussionmentioning

confidence: 99%

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Annexin A2 and CD105 Expression in Pancreatic Ductal Adenocarcinoma is Associated with Tumor Recurrence and Prognosis

Huang

Hong²,

Wang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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To investigate the value of expression of annexin A2, microvessel density (MVD) and CD105 in pancreatic ductal adenocarcinoma (PDAC) tissues and adjacent normal tissues, immunohistochemical staining was used. The positive expression rate of Annexin A2 and the MVD in pancreatic ductal adenocarcinoma tissues was higher than that in in adjacent normal tissues (p<0.005). Expression of Annexin A2 and MVD correlated with histological grade (p<0.05). MVD of cancers in TNM stage Ⅱb was higher than that in TNM stageⅠ~Ⅱa (p<0.026). Cancerous tissues with Annexin A2 staining grade 3+ had lower MVD than the tissues with the other Annexin A2 staining grade (p<0.05). Patients with high MVD had worse prognosis. However , our study did not confirm Annexin A2 was an independent risk factor for patients with PDAC. We confirmed MVD labeled by CD105 was an independent risk factor for patients with PDAC and had moderate predictive value of prognosis.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Annexin A2 and CD105 Expression in Pancreatic Ductal Adenocarcinoma is Associated with Tumor Recurrence and Prognosis

Huang

Hong²,

Wang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…RPE-J cells were cultured as described previously (Finnemann, 2003). Wild-type and annexin A2 null mutant mice (Ling et al, 2004) were maintained on a regular diet of food and water ad libitum, in accordance with UK Home Office regulations. Mice were killed by cervical dislocation and immediately enucleated.…”

Section: Cell Culture and Micementioning

confidence: 99%

Annexin A2 Regulates Phagocytosis of Photoreceptor Outer Segments in the Mouse Retina

Law

Hajjar

et al. 2009

MBoC

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The daily phagocytosis of shed photoreceptor outer segments by pigment epithelial cells is critical for the maintenance of the retina. In a subtractive polymerase chain reaction analysis, we found that functional differentiation of human ARPE19 retinal pigment epithelial (RPE) cells is accompanied by up-regulation of annexin (anx) A2, a major Src substrate and regulator of membrane-cytoskeleton dynamics. Here, we show that anx A2 is recruited to the nascent phagocytic cup in vitro and in vivo and that it fully dissociates once the phagosome is internalized. In ARPE19 cells depleted of anx A2 by using small interfering RNA and in ANX A2 ؊/؊ mice the phagocytosis of outer segments was impaired, and in ANX A2 ؊/؊ mice there was an accumulation of phagocytosed outer segments in the RPE apical processes, indicative of retarded phagosome transport. We show that anx A2 is tyrosine phosphorylated at the onset of phagocytosis and that the synchronized activation of focal adhesion kinase and c-Src is abnormal in ANX A2 ؊/؊ mice. These findings reveal that anx A2 is involved in the circadian regulation of outer segment phagocytosis, and they provide new insight into the protein machinery that regulates phagocytic function in RPE cells. INTRODUCTIONThe retinal pigment epithelium (RPE) performs a range of functions that directly support the retina (Strauss, 2005), including the daily phagocytosis and digestion of shed photoreceptor outer segments (POS). The importance of this activity is exemplified in the dystrophic Royal College of Surgeons rat, which due to a failure in phagocytosis undergoes a progressive and rapid retinal degeneration characterized by accumulation of cellular debris and photoreceptor cell death. The gene responsible for this pathology was identified by positional cloning as the Mer tyrosine kinase (MerTK), a key signaling intermediate that is expressed in RPE cells and plays an essential role in the internalization of bound POS (Chaitin and Hall, 1983;D'Cruz et al., 2000). Recent studies have provided insight into other RPE cell proteins that have distinct roles either in the binding or the internalization of shed POS. For example, the apically expressed ␣v␤5 integrin is required for efficient binding of POS, and RPE cells from ␤5 Ϫ/Ϫ mice show markedly reduced binding of POS in vitro (Nandrot et al., 2004). Intriguingly, engagement of the ␣v␤5 integrin by its cognate ligand, milk fat globule-EGF8 (MFG-E8), is essential for the circadian synchronization of phagocytosis (Nandrot and Finnemann, 2006;Nandrot et al., 2007), and although phagocytosis of POS occurs in MFG-E8 Ϫ/Ϫ and ␤5 Ϫ/Ϫ mice, in both mutants the daily rhythm is absent. In contrast, focal adhesion kinase (FAK) and MerTK are not required for the initial binding of POS to the apical surface of the RPE, but they are sequentially activated by ␣v␤5 receptors and are essential for phagosome internalization (Feng et al., 2002;Finnemann, 2003).Between the pigment epithelium and neuroretina RPE cells extend apical processes into the interphotorecept...

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“…In addition, arterial injury in A2 Ϫ/Ϫ mice is followed by a 2-fold increase in thrombotic vascular occlusion with an equivalent reduction in blood flow recovery (9). Third, injury-induced carotid artery thrombosis in rats can be averted by pretreatment with recombinant A2 (10).…”

mentioning

confidence: 99%

“…Ϫ/Ϫ microvascular endothelial cells lack t-PA cofactor activity, and the fibrin content of highly perfused A2 Ϫ/Ϫ tissues is ϳ2-fold greater than that observed in wild type controls (9). In addition, arterial injury in A2 Ϫ/Ϫ mice is followed by a 2-fold increase in thrombotic vascular occlusion with an equivalent reduction in blood flow recovery (9).…”

mentioning

confidence: 99%

Feedback Regulation of Endothelial Cell Surface Plasmin Generation by PKC-dependent Phosphorylation of Annexin A2

He¹,

Sui

Xiong

et al. 2011

Journal of Biological Chemistry

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In response to blood vessel injury, hemostasis is initiated by platelet activation, advanced by thrombin generation, and tempered by fibrinolysis. The primary fibrinolytic protease, plasmin, can be activated either on a fibrin-containing thrombus or on cells. Annexin A2 (A2) heterotetramer (A2⅐p11) 2 is a key profibrinolytic complex that assembles plasminogen and tissue plasminogen activator and promotes plasmin generation. We now report that, in endothelial cells, plasmin specifically induces activation of conventional PKC, which phosphorylates serine 11 and serine 25 of A2, triggering dissociation of the (A2⅐p11) 2 tetramer. The resulting free p11 undergoes ubiquitinmediated proteasomal degradation, thus preventing further translocation of A2 to the cell surface. In vivo, pretreatment of A2 ؉/؉ but not A2 ؊/؊ mice with a conventional PKC inhibitor significantly reduced thrombosis in a carotid artery injury model. These results indicate that augmentation of fibrinolytic vascular surveillance by blockade of serine phosphorylation is A2-dependent. We also demonstrate that plasmin-induced phosphorylation of A2 requires both cleavage of A2 and activation of Toll-like receptor 4 on the cell surface. We propose that plasmin can limit its own generation by triggering a finely tuned "feedback" mechanism whereby A2 becomes serine-phosphorylated, dissociates from p11, and fails to translocate to the cell surface.The human hemostatic system represents a coordinated balance between procoagulant and anticoagulant/profibrinolytic activities. Together, these systems prevent blood loss while maintaining blood flow. Plasmin, the major protease of the fibrinolytic system, acts to digest insoluble fibrin into soluble fibrin degradation products. Plasmin generation is modulated by plasminogen activators and plasminogen activator inhibitors and is further regulated by binding of plasminogen and its activators to cell surface receptors (1). Membrane-associated annexin A2 (A2) 3 is part of a heterotetrameric complex in which the N termini of two copies of A2 bind to two copies of the S100 family protein, S100A10 (p11) (2). A2, a member of the annexin superfamily, consists of a highly conserved C-terminal phospholipid-binding core domain and an N-terminal ligandinteracting domain (3). Complex formation with p11 increases the affinity of A2 for calcium and phospholipids, thereby directing it to cellular membranes (4). Components of the (A2⅐p11) 2 tetramer, moreover, specifically bind tissue plasminogen activator (t-PA) and plasminogen and strongly enhance plasmin generation (5-8, 52).Several lines of evidence identify the (A2⅐p11) 2 complex as a significant regulator of fibrin balance in vivo. First, A2 Ϫ/Ϫ microvascular endothelial cells lack t-PA cofactor activity, and the fibrin content of highly perfused A2 Ϫ/Ϫ tissues is ϳ2-fold greater than that observed in wild type controls (9). In addition, arterial injury in A2 Ϫ/Ϫ mice is followed by a 2-fold increase in thrombotic vascular occlusion with an equivalent reduction in blood flo...

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Annexin II regulates fibrin homeostasis and neoangiogenesis in vivo

Cited by 338 publications

References 56 publications

Annexin A2 and CD105 Expression in Pancreatic Ductal Adenocarcinoma is Associated with Tumor Recurrence and Prognosis

Annexin A2 and CD105 Expression in Pancreatic Ductal Adenocarcinoma is Associated with Tumor Recurrence and Prognosis

Annexin A2 Regulates Phagocytosis of Photoreceptor Outer Segments in the Mouse Retina

Feedback Regulation of Endothelial Cell Surface Plasmin Generation by PKC-dependent Phosphorylation of Annexin A2

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