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      Annexin A2 at the Interface of Actin and Membrane Dynamics: A Focus on Its Roles in Endocytosis and Cell Polarization

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          Abstract

          Annexins are a family of calcium- and phospholipid-binding proteins found in nearly all eukaryotes. They are structurally highly conserved and have been implicated in a wide range of cellular activities. In this paper, we focus on Annexin A2 (AnxA2). Altered expression of this protein has been identified in a wide variety of cancers, has also been found on the HIV particle, and has been implicated in the maturation of the virus. Recently, it has also been shown to have an important role in the establishment of normal apical polarity in epithelial cells. We synthesize here the known biochemical properties of this protein and the extensive literature concerning its involvement in the endocytic pathway. We stress the importance of AnxA2 as a platform for actin remodeling in the vicinity of dynamic cellular membranes, in the hope that this may shed light on the normal functions of the protein and its contribution to disease.

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          Most cited references103

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          A molecular network for de novo generation of the apical surface and lumen.

          To form epithelial organs cells must polarize and generate de novo an apical domain and lumen. Epithelial polarization is regulated by polarity complexes that are hypothesized to direct downstream events, such as polarized membrane traffic, although this interconnection is not well understood. We have found that Rab11a regulates apical traffic and lumen formation through the Rab guanine nucleotide exchange factor (GEF), Rabin8, and its target, Rab8a. Rab8a and Rab11a function through the exocyst to target Par3 to the apical surface, and control apical Cdc42 activation through the Cdc42 GEF, Tuba. These components assemble at a transient apical membrane initiation site to form the lumen. This Rab11a-directed network directs Cdc42-dependent apical exocytosis during lumen formation, revealing an interaction between the machineries of vesicular transport and polarization.
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            PTEN-mediated apical segregation of phosphoinositides controls epithelial morphogenesis through Cdc42.

            Formation of the apical surface and lumen is a fundamental, yet poorly understood, step in epithelial organ development. We show that PTEN localizes to the apical plasma membrane during epithelial morphogenesis to mediate the enrichment of PtdIns(4,5)P2 at this domain during cyst development in three-dimensional culture. Ectopic PtdIns(4,5)P2 at the basolateral surface causes apical proteins to relocalize to the basolateral surface. Annexin 2 (Anx2) binds PtdIns(4,5)P2 and is recruited to the apical surface. Anx2 binds Cdc42, recruiting it to the apical surface. Cdc42 recruits aPKC to the apical surface. Loss of function of PTEN, Anx2, Cdc42, or aPKC prevents normal development of the apical surface and lumen. We conclude that the mechanism of PTEN, PtdIns(4,5)P2, Anx2, Cdc42, and aPKC controls apical plasma membrane and lumen formation.
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              Annexins--unique membrane binding proteins with diverse functions.

              Annexins are a well-known multigene family of Ca(2+)-regulated phospholipid-binding and membrane-binding proteins. Recent work employing annexin-knockdown or - knockout models has provided new insights into the biological functions of different annexin proteins. Transient annexin depletion by RNA interference and the expression of dominant-negative mutant proteins has revealed roles for the proteins in membrane processes ranging from the control of membrane structure to certain membrane transport phenomena. Although such functions correlate well with the ability of annexins to interact with cellular membranes in a reversible and regulated manner, some activities are membrane independent, probably because annexins can also engage in specific protein-protein interactions. Among other things, this is evident in annexin A1- and A2-knockout mice, which show impaired regulation of neutrophil extravasation and defects in plasmin generation, respectively.
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                Author and article information

                Journal
                Int J Cell Biol
                IJCB
                International Journal of Cell Biology
                Hindawi Publishing Corporation
                1687-8876
                1687-8884
                2012
                22 February 2012
                : 2012
                : 852430
                Affiliations
                1Hubrecht Institute for Developmental Biology and Stem Cell Research, Uppsalalaan 8, 3584CT Utrecht, The Netherlands
                2Division of Cell Biology, UCL Institute of Ophthalmology, 11-43 Bath Street, EC1V 9EL London, UK
                Author notes
                *Matthew J. Hayes: annexin2@ 123456hotmail.com

                Academic Editor: Avri Ben-Ze'ev

                Article
                10.1155/2012/852430
                3296266
                22505935
                f75bdcbf-7793-466e-a14c-5a52063be069
                Copyright © 2012 Adam G. Grieve et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 August 2011
                : 16 November 2011
                : 13 December 2011
                Categories
                Review Article

                Cell biology
                Cell biology

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