α-Actinins are a major class of actin filament cross-linking proteins expressed in virtually all cells. In muscle, actinins cross-link thin filaments from adjacent sarcomeres. In non-muscle cells, different actinin isoforms play analogous roles in cross-linking actin filaments and anchoring them to structures such as cell-cell and cell-matrix junctions. Although actinins have long been known to play roles in cytokinesis, cell adhesion and cell migration, recent studies have provided further mechanistic insights into these functions. Roles for actinins in synaptic plasticity and membrane trafficking events have emerged more recently, as has a 'non-canonical' function for actinins in transcriptional regulation in the nucleus. In the present paper we review recent advances in our understanding of these diverse cell biological functions of actinins in non-muscle cells, as well as their roles in cancer and in genetic disorders affecting platelet and kidney physiology. We also make two proposals with regard to the actinin nomenclature. First, we argue that naming actinin isoforms according to their expression patterns is problematic and we suggest a more precise nomenclature system. Secondly, we suggest that the α in α-actinin is superfluous and can be omitted.
The non-muscle α-actinin isoforms (actinin-1 and -4) are closely related dimeric actin filament cross-linking proteins. Despite high sequence similarity, unique properties have been ascribed to actinin-4 in particular. For example, actinin-4, but not actinin-1, is essential for normal glomerular function in the kidney, is overexpressed in several cancers and can translocate to the nucleus to regulate transcription. To understand the molecular basis for such isoform-specific functions we have, for the first time, comprehensively compared these proteins in terms of alternative splicing, actin-binding properties, heterodimer formation and molecular interactions. We find that the Ca2+-insensitive variant of actinin-4 is expressed only in the nervous system and thus cannot be regarded as a smooth muscle isoform, as is the case for the Ca2+-insensitive variant of actinin-1. The actin-binding properties of actinin-1 and -4 are similar and are unlikely to explain isoform-specific functions. Surprisingly, we reveal that actinin-1/-4 heterodimers, rather than homodimers, are the most abundant form of actinin in many cell lines. Finally, we use a proteomics approach to identify potential isoform-specific interactions. The results of the present study indicate that actinin-1 and -4 can readily form heterodimers composed of monomers that may have different properties and interacting proteins. This significantly alters our view of non-muscle actinin function.
Actinins are cytoskeleton proteins that crosslink actin filaments. Evolution of the actinin family resulted in the formation of calcium-insensitive muscle isoforms (actinin-2 and- 3) and calcium-sensitive non-muscle isoforms (actinin-1 and -4) with regard to their actin-binding function. Although the non-muscle actinin isoforms show 87% amino acid identity, they are currently viewed as distinct entities. Each isoform is reported to exert distinct effects on cell migration, adhesion and proliferation depending on the cell type studied. Actinin-4 is the predominant isoform reported to be associated with the cancer phenotype. Actinin-4 protein levels are elevated in a number of cancers including breast, ovarian, colorectal, bladder, pancreatic, ovarian and glioblastomas. Actinin-4 enhances the motility and metastatic potential of various carcinoma cell lines. This suggests that actinin-4 may have some unique characteristic that facilitates its role in cancer. We aimed to compare the actin-binding affinities, actin-bundling capacities and calcium sensitivities of the non-muscle actinins. We found that the non-muscle actinins have similar actin-binding affinities and calcium sensitivities with regard to their actin-binding and actin-bundling functions. Actinin structure consists of two anti-parallel monomers that form a homodimer. Heterodimer formation is reported to occur between the muscle actinin isoforms however this has not been systematically examined for the non-muscle isoforms. Through yeast two-hybrid analysis and in vitro binding assays we have shown that non-muscle actinin homodimers and heterodimers form with equal affinity. Using native gel electrophoresis we have shown that non-muscle actinin heterodimer formation occurs in a number of cancer cell lines studied. Comparison of non-muscle actinin protein levels indicates that the heterodimer represents the most abundant form of actinin present in the majority of cell lines studied. siRNA- mediated knockdown of actinin-4 resulted in a decrease in heterodimer levels and an increase in actinin-1 homodimer levels. Taken together this data suggests that actinin-1 and actinin-4 cannot be viewed as distinct entities from each other but rather as proteins that can exist in both homodimeric and heterodimeric forms. The ability to behave in this manner may have functional implications. This may be of importance considering that these proteins are central to such processes as cell migration and adhesion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 482. doi:1538-7445.AM2012-482
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