Annexin 2 has an essential role in actin-based macropinocytic rocketing

Merrifield, Christien J.; Rescher, Ursula; Almers, Wolfhard; Proust, J.; Gerke, Volker; Sechi, Antonio; Moss, Stephen E.

doi:10.1016/s0960-9822(01)00321-9

Cited by 98 publications

(101 citation statements)

References 21 publications

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“…Consistent with these reports, we observed upregulation of annexins A2 and A4 concomitant with acquisition of phagocytic competence in functionally differentiated ARPE19 cells (Turowski et al, 2004). Although the function of annexin (anx) A4 is not known, anx A2 has roles in endocytosis (Emans et al, 1993;Harder and Gerke, 1993;Jost et al, 1997; and pinocytosis (Merrifield et al, 2001), and in macrophages anx A2 associates with phagosomes (Diakonova et al, 1997). These observations suggested to us that up-regulation of annexin A2 in differentiated RPE cells may be required for the development of phagocytic capability.…”

Section: Introductionsupporting

confidence: 83%

“…It has been proposed that phosphatidylinositol 4,5-bisphosphate (PtdIns4,5P 2 ) at the site of formation of the phagocytic cup and its subsequent hydrolysis as the cup closes are the key signaling events regulating the cycle of actin polymerization and depolymerization (Botelho et al, 2000;Scott et al, 2005). Because anx A2 is a potent regulator of actin dynamics (Merrifield et al, 2001;Hayes et al, 2006) and binds both cholesterol-rich membranes, Ca 2ϩ , and PtdIns4,5P 2 Rescher et al, 2004;Gerke et al, 2005), it is well placed to function as a sensor of these second messengers and signaling intermediates, linking . Tyrosine kinase signaling is defective in anx A2-deficient retinas.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Introductionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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

Law

Hajjar

et al. 2009

MBoC

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“…By contrast, the pinocytic pathway is frequently assumed to use a shuttling system, although the recently proposed RAB-conversion mechanism is reminiscent of a maturation process 48 . Newly formed phagosomes 49 and macropinosomes 50,51 , the largest forms of endosomes, are propelled by an actin comet tail towards the cell centre, but myosin has not been directly implicated in this movement. Actin and myosins are associated with endosomes and lysosomes, but their role in transport between these organelles is probably not direct 52 .…”

Section: Subsequent Transport Stepsmentioning

confidence: 99%

Powering membrane traffic in endocytosis and recycling

Soldati

Schliwa

2006

Nat Rev Mol Cell Biol

314

279

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| Early in evolution, the diversification of membrane-bound compartments that characterize eukaryotic cells was accompanied by the elaboration of molecular machineries that mediate intercompartmental communication and deliver materials to specific destinations. Molecular motors that move on tracks of actin filaments or microtubules mediate the movement of organelles and transport between compartments. The subjects of this review are the motors that power the transport steps along the endocytic and recycling pathways, their modes of attachment to cargo and their regulation.The emergence of eukaryotic cells was accompanied by the development of endomembrane systems that compartmentalize biochemical pathways and biosynthetic processes. An evolutionary trend towards increasing complexity and subcellular specialization necessitated the development of machineries for intercompartmental communication. Molecular assemblies evolved to confer specificity to the interactions of donor and acceptor compartments (budding, sorting, tethering and fusion). Cytoskeletal polymers such as actin filaments and microtubules, which help segregate genetic material and determine cell shape and subcellular architecture, were co-opted as tracks for transport. In animal cells, microtubules support long-range transport, whereas the more flexible actin filaments serve short-range movements both near the cell periphery and in the cell interior. Also, actin filaments can be woven into dense networks of short fibres through the action of crosslinkers and branchpromoting complexes. On the other hand, in many plant cells, bundled actin filaments can form extended tracks for long-distance transport. Owing to the gel-like nature of the cytoplasm, the Brownian movement of organelles is severely restricted and cargoes have to be transported to their destinations at the expense of energy. Furthermore, seemingly random, but motor-dependent, movement is proposed to increase the probability of vesicle collisions and therefore promote fusion events. Movement is powered by three ATP-dependent motors: myosin, kinesin and dynein. Over the course of eukaryotic evolution, these motors have diversified into a large number of families with specific tasks (FIG. 1).Here, we review the involvement of molecular motors in the movement of endosomes and in vesicular trafficking along the endocytic and recycling pathways. These pathways are summarized in FIG. 2. We do not, however,

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“…Several functional roles have been proposed for annexin A2, such as signal transduction, membrane fusion, cell adhesion, DNA synthesis, and cell proliferation [5,6] . Annexin A2 is a 36 kDa protein that has been found on the surface of endothelial cells, monocytic cell lines and macrophages [7,8] .…”

Section: Introductionmentioning

confidence: 99%

Yeast two-hybrid screening of proteins interacting with plasmin receptor subunit: C-terminal fragment of annexin A2

Laumonnier

Syrovets

et al. 2011

Acta Pharmacol Sin

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Aim: To identify proteins that interact with the C-terminal fragment of annexin A2 (A2IC), generated by plasmin cleavage of the plasmin receptor, a heterotetramer (AA2t) containing annexin A2. Methods: The gene that encodes the A2IC fragment was obtained from PCR-amplified cDNA isolated from human monocytes, and was ligated into the pBTM116 vector using a DNA ligation kit. The resultant plasmid (pBTM116-A2IC) was sequenced with an ABI PRISM 310 Genetic Analyzer. The expression of an A2IC bait protein fused with a LexA-DNA binding domain (BD) was determined using Western blot analysis. The identification of proteins that interact with A2IC and are encoded in a human monocyte cDNA library was performed using yeast two-hybrid screening. The DNA sequences of the relevant cDNAs were determined using an ABI PRISM BigDye terminator cycle sequencing ready reaction kit. Nucleotide sequence databases were searched for homologous sequences using BLAST search analysis (http://www.ncbi.nlm.nih.gov). Confirmation of the interaction between the protein LexA-A2IC and each of cathepsin S and SNX17 was conducted using a small-scale yeast transformation and X-gal assay. Results: The yeast transformed with plasmids encoding the bait proteins were screened with a human monocyte cDNA library by reconstituting full-length transcription factors containing the GAL4-active domain (GAL4-AD) as the prey in a yeast two-hybrid approach. After screening 1×10 7 clones, 23 independent β-Gal-positive clones were identified. Sequence analysis and a database search revealed that 15 of these positive clones matched eight different proteins (SNX17, ProCathepsin S, RPS2, ZBTB4, OGDH, CCDC32, PAPD4, and actin which was already known to interact with annexin A2). Conclusion: A2IC A2IC interacts with various proteins to form protein complexes, which may contribute to the molecular mechanism of monocyte activation induced by plasmin. The yeast two-hybrid system is an efficient approach for investigating protein interactions.Keywords: yeast yeast two-hybrid system; human monocyte; plasmin receptor; C-terminal fragment of annexin A2 (A2IC); protein-protein interaction Acta

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Annexin 2 has an essential role in actin-based macropinocytic rocketing

Cited by 98 publications

References 21 publications

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

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

Powering membrane traffic in endocytosis and recycling

Yeast two-hybrid screening of proteins interacting with plasmin receptor subunit: C-terminal fragment of annexin A2

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