Multiple Roles of Annexin A2 in Post-Transcriptional Regulation of Gene Expressio

Anni      Vedeler; Hanne      Hollas; Ann      Kari Grindheim; Aase      M. Raddum

Abstract

Increasing evidence points to the participation of the multifunctional protein Annexin A2 (AnxA2) in mRNA localisation as well as the translation of certain mRNAs on cytoskeleton-bound polysomes, and thereby in the regulation of the biosynthesis of specific proteins, such as c-Myc and AnxA2 itself, which are linked to cellular transformation. AnxA2 is most likely activated by signalling pathways, which result in its post-translational modifications and modulate its binding to various ligands, including specific mRNAs. Positive and polar residues in helices C-D in domain IV of AnxA2 bind to cis-acting elements in the 3’-UTRs of its cognate, c-myc, collagen prolyl 4-hydroxylase-α(I) and N-methyl-D-aspartate R1 mRNAs, thus contributing to post-transcriptional regulation of the expression of specific genes. The cis-acting elements appear to constitute a higher order structure, frequently containing the consensus sequence 5’-AA(C/G)(A/U)G; however, non-canonical AnxA2 binding sites may also be involved. In the case of c-myc mRNA, the association with AnxA2 appears to regulate its localisation and translation. In addition, the binding of AnxA2 to a pseudoknot structure present in infectious bronchitis viral RNA results in reduced efficiency of -1 ribosomal frameshifting, indicating its recruitment as a host protein during viral infection. Finally, the association of AnxA2 with endosomes and exosomes suggests a role in co-ordinated transport of mRNA and vesicles, i.e. processes that respond to extracellular signals and are expected to employ multifunctional proteins.

Keywords: Annexin A2, mRNA, post-transcriptional regulation, mRNP complexes, mRNA-binding proteins, AnxA2, DI-DIV, mRNA, C-terminal core, S100A10, AnxA6.