The makings of the 'actin code': regulation of actin's biological function at the amino acid and nucleotide level.

The actin cytoskeleton plays key roles in every eukaryotic cell and is essential for cell adhesion, migration, mechanosensing, and contractility in muscle and non-muscle tissues. In higher vertebrates, from birds through to mammals, actin is represented by a family of six conserved genes. Although these genes have evolved independently for more than 100 million years, they encode proteins with ≥94% sequence identity, which are differentially expressed in different tissues, and tightly regulated throughout embryogenesis and adulthood. It has been previously suggested that the existence of such similar actin genes is a fail-safe mechanism to preserve the essential function of actin through redundancy. However, knockout studies in mice and other organisms demonstrate that the different actins have distinct biological roles. The mechanisms maintaining this distinction have been debated in the literature for decades. This Review summarizes data on the functional regulation of different actin isoforms, and the mechanisms that lead to their different biological roles in vivo We focus here on recent studies demonstrating that at least some actin functions are regulated beyond the amino acid level at the level of the actin nucleotide sequence.