Annexin A2 complexes with S100 proteins: structure, function and pharmacological manipulation.
Bottom Line: The interaction between AnxA2 and S100A10 has been very well characterized historically; more recently, other S100 proteins have been shown to interact with AnxA2 as well.The biochemical evidence for the occurrence of these protein interactions will be discussed, as well as their function.Recent studies aiming to generate inhibitors of S100 protein interactions will be described and the potential of these inhibitors to further our understanding of AnxA2 S100 protein interactions will be discussed.
Affiliation: School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK.Show MeSH
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Mentions: The ratio of monomeric AnxA2 to (S100A10-AnxA2)2 can vary widely, and the differences in ratio are due to coordinated expression of AnxA2 and S100A10 (Munz et al., 1997) as well as post-translational control (Puisieux et al., 1996). Interfering with the expression of one of the partners in the (S100A10-AnxA2)2 complex affects the expression of the other partner, indicating their intimate relationship in vivo. In most reports, knockdown of AnxA2 affects the levels of S100A10; however, the reverse has also been observed in some cases and thus the ‘direction’ of the regulatory effect seems to differ between cell types. For example, in endothelial cells, knockdown of AnxA2 not only results in the disappearance of AnxA2 but also in that of S100A10, while knockdown of S100A10 does not affect expression of AnxA2 (Brandherm et al., 2013). In complex with S100A10, AnxA2 may protect S100A10 from being rapidly polyubiquitinated and degraded (He et al., 2008). Interestingly, the residues 86–95 subject to ubiquitination of S100A10 are the residues responsible for binding with the AnxA2 N-terminal, suggesting that once ubiquitinated, S100A10 may not bind AnxA2 anymore. The amount of S100A10 in the cell would thus dictate the amount of the (S100A10-AnxA2)2 complex in the cell (Figure 2). This may be important to determine the intracellular fate of AnxA2. Although AnxA2 itself can associate with cellular membranes (Zobiack et al., 2001), S100A10 binding increases the Ca2+ sensitivity of AnxA2 and its capacity to bind membranes and (submembranous) F-actin (Ikebuchi and Waisman, 1990; Harder and Gerke, 1994; Filipenko and Waisman, 2001; Monastyrskaya et al., 2007). Depletion of S100A10 by RNA silencing or phosphorylation on Ser11 on AnxA2 (which inhibits interaction with S100A10) disrupts the membrane association of AnxA2 (Regnouf et al., 1995; Deora et al., 2004). Similar observations have been made for S100A6 which has also been proposed to interact with AnxA2. Depletion of S100A6 from pancreatic cancer cells was accompanied by diminished levels of membrane AnxA2 associated with a pronounced reduction in the motility of pancreatic cancer cells (Nedjadi et al., 2009). Under certain conditions of stress, AnxA2 can become expressed on the cell surface, in a mechanism that requires the interaction with S100A10 as well as phosphorylation of AnxA2 on tyrosine at position 23 (Deora et al., 2004).
Affiliation: School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK.