Annexin A2 at the interface of actin and membrane dynamics: a focus on its roles in endocytosis and cell polarization

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.

Figure 1

Structure of AnxA2. (a) Space filling view of AnxA2 (colours indicate hydrophobicity) looking “down” onto the membrane-binding surface of the molecule. One endonexin fold, repeated four times in AnxA2, is highlighted in yellow. (b) “Cartoon” of AnxA2 showing the molecule from the side. The protein is almost entirely made up of alpha-helices. The position of coordinated calcium atoms is shown in green.

Figure 2

Recruitment of AnxA2 to several sites in the endocytic pathway. AnxA2 is shown as little green structures, filamentous actin as wavy lines, and Src is represented as orange diamonds. EPEC: Association with the actin-rich pedestals of noninvasive enteropathogenic E.coli. Phagosome: AnxA2 is recruited to actin-rich phagosomes during pigmented retinal epithelial cell phagocytosis of rod outer segments. Macropinosome: AnxA2 is recruited to PI(4,5)P2-rich (purple shading) macropinosomes and is absolutely required for their actin-based rocketing (Comet). Macropinosomes or other early endosomes may mature into APPL2/OCRL1-positive early endosomes. These in turn mature into EEA1-positive endosomes. Endocytic trafficking appears to be involved in formation and reformation of the adherens junction (AJ) and extracellular AnxA2/S110A10 complex, which may be released in exosomes when multivesicular late endosomes (MVBs) fuse with the plasma membrane that may contribute to tight junction stability by cross-linking adjacent membranes. The role of AnxA2 in formation of the apical domain is more speculative but may involve formation of a preformed vacuolar apical compartment (VAC), which then may fuse with the apical surface.