Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Actinin Family

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101924


Historical Background

Alpha-actinin was first identified in 1964 by Setsuro and Fumiko Ebashi in a biochemical fraction from muscle that promoted actomyosin contraction (Ebashi et al. 1964). However, it was experiments that they performed with Koscak Maruyama that defined what is now regarded as the primary function of alpha-actinin, namely, the cross-linking of actin filaments. This cross-linking ability was observed in vitro as the formation of gels when alpha-actinin was mixed with F-actin, while bundling of actin filaments was observed by electron microscopy. The name alpha-actinin was Maruyama’s suggestion, with another factor that he had identified and characterized being designated beta-actinin. Beta-actinin is unrelated to alpha-actinin and is now almost exclusively called Cap Z, or capping protein, reflecting its function in the Z-disk of the muscle sarcomere where it caps the barbed (+) end of actin filaments. Thus the alpha in alpha-actinin, while of historical interest, is now not strictly necessary, and we and some others have adopted the custom of omitting it.

For a decade from its discovery in 1964, actinin was studied almost exclusively in the context of muscle and became recognized as a component of the sarcomeric Z-disk, functioning primarily to cross-link thin filaments, rather than directly regulating actomyosin contraction. However, from 1975 onward the presence of actinin in other cell types became apparent, in large part through the use of anti-actinin antibodies to detect actinin in non-muscle cells (Lazarides and Burridge 1975). While they share an ability to bundle actin filaments, as well as a characteristic molecular weight of 100 kDa, it was found that different actinin proteins are present in different tissues, for example, in fast-twitch versus slow-twitch muscle fibers, skeletal versus smooth muscle, and muscle versus non-muscle cells. Notably, the bundling of actin filaments by actinins isolated from platelets and Hela cells was found to be inhibited by Ca++, whereas muscle and smooth muscle actinins are Ca++ insensitive in this regard. The cloning of cDNA sequences from vertebrate and Dictyostelium actinin genes in 1987 and 1988 revealed the domain organization of actinins and explained the differing properties of actinins isolated from various tissues (Blanchard et al. 1989). The diverse roles of actinins in multiple cellular processes including cell adhesion, cell motility, cytokinesis, and endocytosis were recognized from early localization studies, and the molecular interactions underlying these roles have been revealed, particularly through the application of the yeast two hybrid system from the mid-1990s onward (Otey and Carpen 2004). The human genetics of actinins as well as their role in cancer and kidney function have come to the fore since 1998 (Feng et al. 2015; Honda 2015; Murphy and Young 2015). Insights into the detailed structure of the actinin dimer and its binding to actin filaments have been revealed incrementally over the same period (Sjoblom et al. 2008), with the landmark description of a high-resolution X-ray crystallographic structure of the full-length actinin dimer published in 2014 – fittingly marking the 50th anniversary of the discovery of actinins (Ribeiro Ede et al. 2014).

Actinin Protein Structure

The domain structure of actinins consists of an N-terminal actin-binding domain (ABD), a central rod domain containing four spectrin-like repeats (SLRs), and a C-terminal calmodulin-like (CAM) domain (Blanchard et al. 1989; Fig. 1a). The actinin-binding domain is made up of two calponin homology (CH) domains, while the CAM domain is comprised of two pairs of EF-hand motifs (EF1/2 and EF3/4). The exception to this domain organization are fungal actinins which generally have two SLRs instead of four in their rod domains. Antiparallel dimerization of actinin via the SLRs places an ABD at either end of the rod domain, providing actinins with their ability to form relatively rigid cross-links between actin filaments. The recently determined X-ray crystallographic structure of human actinin-2 (Ribeiro Ede et al. 2014) provides a detailed picture of the interactions between the subunits in the actinin dimer (Fig. 1b, c). The SLRs of the rod are aligned with repeats 1 and 2 paired with repeats 4 and 3 from the opposite subunit, respectively. This structure represents a “closed” conformation for actinin in which EF3/4 from one subunit binds to the “neck” region between the ABD and the first SLR of the opposing monomer (Young and Gautel 2000). This interaction is thought to stabilize the neck region and restrict the movement the ABDs (Ribeiro Ede et al. 2014). Binding of phospholipids, most notably PIP2, to a site within the ABD is able to disrupt this intramolecular interaction and switch actinin to an open conformation, providing the ABD with greater flexibility and promoting the interaction of EF3/4 with other proteins such as titin (see below).
Actinin Family, Fig. 1

Structure of actinin-2 in a closed conformation as determined by X-ray crystallography. (a) Schematic representation of the antiparallel actinin-2 dimer. Each subunit consists of an N-terminal actin-binding domain (ABD), a rod domain composed of four spectrin-like repeats (SLR1–4), and a C-terminal calmodulin-like (CAM) domain comprised of two pairs of EF-hand motifs (EF1/2 and EF3/4). In the closed conformation, EF3/4 from one subunit binds to a neck region between the ABD and rod of the other subunit in the dimer. (b) The dimeric structure of actinin-2 assembled from two halves of the actinin-2 protomer (ABD-SR1-SR2/SR3-SR4-CaM) through a crystallographic twofold axis (dashed line; ellipse in c). Overall dimensions are indicated. Color code: ABD, red; neck, yellow; SR1–SR4, green; EF1–2, violet; EF3–4, blue. (c) Same as in (b) rotated 90° around the horizontal axis (Figure reproduced with permission from Ribeiro Ede et al. (2014))

Actinin: Genes, Isoforms, and Evolution

Actinins most likely evolved in a common ancestor of amoebas, fungi and yeast and are the ancestors of the broader spectrin and dystrophin families of actin-binding proteins. Invertebrates generally have a single actinin-encoding gene, while gene duplication events have given rise to the presence of several actinin genes in vertebrate genomes. Mammals have four actinin genes, with alternative splicing giving rise to further protein isoforms (Table 1). The various actinin isoforms differ primarily in their expression patterns, and in whether or not their binding to actin filaments is sensitive to Ca++. Filament binding of Ca++-sensitive variants is inhibited by Ca++ concentrations above 10-7 M. Actinin-2 and actinin-3 are Ca++-insensitive proteins that are expressed in muscle. They are thus regarded as muscle actinins, though it should be noted that actinin-2 is also expressed in neurons. Actinin-3 expression is restricted to fast muscle fibers of skeletal muscle.
Actinin Family, Table 1

Overview of the mammalian actinin genes and splice variants


Splice variant


Most prominent expression

Associated genetic diseases/traits


Exon 19a


Most tissues and cell types

Congenital macrothrombocytopenia


Exon 19b


Muscle, smooth muscle, postnatal CNS





Cardiac and skeletal muscle, brain





Skeletal muscle

Sports performance


Exon 19a


Most tissues and cell types

Focal segmental glomerulosclerosis


Exon 19b


Embryonic and postnatal CNS


Ca++ sensitivity in actinin-1 and actinin-4 arises through alternative splicing of two versions of a duplicated exon (exon 19a and 19b) encoding part of the EF1/2 motif in the CAM domain. CNS central nervous system. This table has been adapted from Foley and Young (2014)

Actinin-1 and actinin-4 have both Ca++-sensitive variants, which are widely expressed, and Ca++-insensitive variants, which are found predominantly in smooth muscle and the central nervous system (Blanchard et al. 1989; Foley and Young 2013). These variants arise through alternative splicing of two versions of a duplicated exon encoding part of the EF1/2 motif in the CAM domain. The expression of Ca++-insensitive actinin isoforms in muscle tissues and neurons may allow stable cross-linking of actin filaments despite continuous Ca++ flux in these electrically excitable cell types. Ca++-sensitivity of actinin-1 and actinin-4 is thought to be facilitated by the juxtaposing of CAM and ABD domains from opposing monomers in the actinin dimer; however, the precise mechanism by which Ca++ binding to EF1/2 inhibits actin binding is not clear.

Cellular Functions of Actinins

Virtually, all mammalian cell types express at least one actinin isoform. As one of the major cross-linkers of actin filaments, actinins are involved in a very wide variety of cellular processes that are dependent on the actin cytoskeleton. However, actinins interact with many other proteins besides actin including components of cell/cell and cell/matrix adhesion complexes, signaling proteins, ion channels, transporters, and other cytoskeletal elements. While the cross-linking of actin filaments is a constant in virtually all cellular functions of actinins, the set of other proteins associated with actinin varies depending on the cellular context. Most of these interactions are probably common to most or all actinin isoforms, reflecting the high degree of sequence similarity between actinins; however, some isoform-specific interactions have been reported (Seto et al. 2013; Fukumoto et al. 2015). In the following section, we briefly outline the function of actinins in several cellular contexts, highlighting some of the relevant molecular interactions. This discussion is illustrative of the diversity of actinin function and is not intended to be exhaustive either in terms of either the number of processes or molecular interactions described.

The Sarcomeric Z-Disk of Muscle Cells

In muscle, thin actin filaments from adjacent sarcomeres are cross-linked in the Z-disk by actinin-2 and actinin-3. Actinin is thus a major structural component of the Z-disk, visible as struts between antiparallel actin filaments arranged in a tetragonal lattice when examined by electron microscopy in transverse sections (Gautel and Djinovic-Carugo 2016). Of perhaps equal importance to cross-linking thin filaments is the role that actinin plays in anchoring to the Z-disk the amino terminus of the giant titin protein, which stretches from the Z-disk to the M-line, acting as a molecular blueprint for the organization of the entire sarcomere. The Z-repeat region of titin binds to EF3/4 of actinin, and regulation of the number of titin Z-repeats through alternative splicing is proposed to dictate the number of rows of actinin cross-links between overlapping antiparallel thin filaments (Sorimachi et al. 1997; Young et al. 1998). This could effectively control Z-disk thickness – a parameter that varies between muscle types, probably to match the strain forces experienced in different muscles. This titin interaction is blocked when actinin is in a closed conformation (Young and Gautel 2000). The switching of actinin to its open conformation by PIP2, or some other mechanism, could thus serve to promote both thin filament cross-linking and the integration of titin into the Z-disk. A model has been produced of how actinin-2 in an open conformation, in which the ABDs have the conformational flexibility, might cross-link antiparallel actin filaments in the sarcomeric Z-disk (Ribeiro Ede et al. 2014; Fig. 2a). Apart from the Z-repeats, an adjacent region of titin can interact with the central SLR of the actinin rod domain (Young et al. 1998). The rod domain and other actinin domains also act as attachment sites for several other Z-disk proteins that are not as important structurally but that may play essential roles in sarcomere assembly, the regulation of muscle function, or mechanical strain sensing and signaling (Gautel 2011; Gautel and Djinovic-Carugo 2016; Fig. 2b). Among these interacting proteins, calsarcin (myozenin/FATZ) is interesting because calsarcin-2 binds with higher affinity to actinin-2 compared to actinin-3 (Seto et al. 2013). This differential interaction can influence calsarcin inhibition of calcineurin and has been proposed to play a role in the reprogramming of the metabolic phenotype of fast muscle fibers that is observed in actinin-3-deficient muscle (Seto et al. 2013). This example illustrates a broader phenomenon, whereby the binding of proteins to actinin can serve to localize signaling or enzymatic activity to the Z-disk or sequester these activities away from other regions of the sarcomere.
Actinin Family, Fig. 2

Molecular interactions of actinin in the sarcomeric Z-disk. (a) A model of actinin-2 cross-linking antiparallel actin filaments. Actinin-2 in open conformation was modeled assuming structural plasticity in the flexible neck, which allows for suitable orientation of ABDs. Titin Zr-7 bound to EF3/4 is shown in cyan (Reproduced with permission from Ribeiro Ede et al. (2014)) (b) Molecular interactions of actinin in the sarcomeric Z-disk. Actinin (purple) cross-links antiparallel actin filaments (brown) from adjacent sarcomeres. Two regions of titin (green), the Z-repeats (zr) and the zq regions, interact with the actinin rod and CAM domains, respectively. Other interactions are indicated by black arrows. The rod domain interacts with myotilin and myozenin (calsarcin/FATZ), while LIM domain-binding protein-3 (LDB3/ZASP/Cypher) binds to the CAM domain. An interaction with CapZ has also been reported (see the following reviews for specific references: Djinovic-Carugo et al. 2002; Gautel 2011; Gautel and Djinovic-Carugo 2016)


Cytokinesis involving an actomyosin-based contractile ring is a feature of cell division in most eukaryotes with the exception of plants and algae. The major structural components of the contractile ring are actin filaments, myosin II, and actin cross-linking proteins including actinin. Since cytokinesis predates muscle contraction in evolutionary terms, the sarcomeric cytoskeleton may represent an adaptation and specialization of an actin/myosin/actinin-based contractile machinery that originally evolved to perform cell division in early eukaryotes. An involvement of actinin in cytokinesis has been conserved from fungal species (Schizosaccharomyces pombe) through to mammals (Mukhina et al. 2007; Laporte et al. 2012), though redundancy of function between actinin and other actin cross-linking proteins is apparent.

In fission yeast, the contractile ring assembles from protein complexes termed nodes. While actinin is not essential for cytokinesis in fission yeast under normal growth conditions, the formation of the contractile ring is delayed (Laporte et al. 2012). However, actinin null yeast show severe cytokinesis defects under stressful conditions of low temperature and high salt (Wu et al. 2001). Fimbrin, another actin cross-linking protein, seems to be able to compensate to a large extent for loss of actinin, since cells null for both these proteins have a lethal defect in contractile ring formation that is far more severe than observed with the loss of either protein alone (Wu et al. 2001; Laporte et al. 2012). The mechanisms of cytokinesis in mammals are broadly similar to fission yeast. Important roles for actinin-1 and actinin-4 in the remodeling of the cortical actin network prior to cytokinesis as well as during the ingression of the cleavage furrow in mammalian cells have been described. For example, actinin knockdown caused reduced F-actin levels, increased furrow ingression rates, and the formation of ectopic furrows (Mukhina et al. 2007). Notably, Ca++-sensitive actinin isoforms were found to be required for some aspects of actin reorganization during mammalian cytokinesis – one of the few demonstrations of a requirement for the Ca++-sensitivity of actinins (Jayadev et al. 2012). Overall, the emerging picture from both mammalian and yeast studies suggests that organization of the contractile ring is a cooperative process that is regulated by an antagonistic interplay between myosin II and cross-linking proteins including actinin and that a balance of cross-linking and motor activity must be achieved for cytokinesis to occur in a controlled fashion.

Cell Adhesion Sites

Actinin is found at both cell/extracellular matrix and cell/cell adhesion sites. Interactions of actinins with transmembrane cell adhesion molecules such as intracellular adhesion molecules (ICAMs), integrins, L-selectin, densin, Gp1b-IX, and BP180 (Otey and Carpen 2004) suggest that actinins can provide a direct link between the plasma membrane and the cytoskeleton. However, actinins also interact with multiple cytosolic components of adhesion complexes such as vinculin, zyxin, α-catenin, palladins, and PDLIM proteins, many of which can themselves bind to transmembrane adhesion molecules and/or actin filaments (reviewed in Djinovic-Carugo et al. 2002; Otey and Carpen 2004; Sjoblom et al. 2008; Fig. 3). These interactions provide more indirect routes by which actinin might link F-actin to transmembrane proteins, and there are some evidence to support this type of linkage. For example, recent studies of focal adhesions using super-resolution microscopy reported a layered arrangement of proteins with actinin co-localized with actin, separated from integrins by a 40 nm core focal adhesion region containing talin, vinculin, and paxillin (Kanchanawong et al. 2010). This suggests that actinin does not directly interact with integrins at focal adhesions and is more likely anchored to the core region via interactions with vinculin, for example.
Actinin Family, Fig. 3

Molecular interactions of actinins at cell/cell and cell/matrix adhesions. Actinin can interact directly with several transmembrane cell adhesion molecules as well as a number of cytosolic components of both cell/cell and cell/matrix adhesions (see Otey and Carpen 2004 and references therein). Through these interactions actinin (purple) can either directly or indirectly link actin filaments (brown) to the plasma membrane (orange) at adhesion sites. Interactions are indicated by black arrows with the origin of the arrow indicating the region(s) of actinin involved in the interaction (when known)

The exact composition and structural organization of various adhesion complexes in different cell types will vary substantially, and so the role of actinin in these structures is likely to be context dependent. However, a number of common regulatory mechanisms that modulate interactions of actinins with F-actin and other binding partners can be identified. These include phosphoinositide and Ca++ binding, which have been discussed above, and phosphorylation (Otey and Carpen 2004). Tyrosine phosphorylation of both actinin-1 and actinin-4 has been shown to alter their F-actin binding. Actinin-1 phosphorylation on tyrosine 12 by focal adhesion kinase inhibits its binding to actin filaments, and it has been shown that decreased actinin-1 tyrosine-12 phosphorylation as a consequence of inhibition of FAK by the Shp2 phosphatase could promote incorporation of actinin into maturing focal complexes(von Wichert et al. 2003). In the case of actinin-4, growth factor signaling through Src and p38 MAP kinases was shown to lead to phosphorylation of tyrosine 4 and 31, inhibiting actin binding (Shao et al. 2010). However, phosphorylation of a tyrosine at position 265 was found to enhance actin binding (Shao et al. 2010). Phosphorylation and dephosphorylation of actinins may thus serve to regulate their incorporation into cell adhesion and other structures.

Neuronal Synapses

Actinin have also been found to have important roles at synapses – the highly specialized cell/cell junctions of neuronal cells (see Foley and Young 2014 for a more detailed, fully referenced, description of the summary below). Surprisingly, it is actinin-2 that has been best studied in this regard, but actinin-1 and actinin-4 are likely to perform similar functions. Immunofluorescence and electron microscopy have localized actinin-2 to the postsynaptic compartment of excitatory synapses on dendritic spines. Interactions of actinins with numerous synaptic proteins have been described. These include the GluA4, GluN1, and GluN2B ionotrophic glutamate receptor subunits, the α and β subunits of Ca++/calmodulin-dependent protein kinase II (CaMKII), densin-180 (a synaptically localized putative adhesion molecule), synaptopodin, RIL (a protein implicated in GluA glutamate receptor transport), the metabotrophic mGlu5b glutamate, and A2A adenosine receptors (Fig. 4). The involvement of actinins in Ca++/calmodulin-dependent inactivation of GluN (NMDA-type) glutamate receptors has been described, with Ca++/calmodulin proposed to displace actinin from the cytoplasmic tail of the receptors leading to channel inactivation. Competitive interactions of actinin and Ca++/calmodulin have also been reported to regulate cell surface localization of the L-type Ca++ channel CaV1.2. These examples are indicative of potentially wider role for actinins in the regulated linkage of ion channels to the actin cytoskeleton in neurons.
Actinin Family, Fig. 4

Molecular interactions of actinins at synapses. Schematic drawing showing the molecular interactions of actinins (purple) with actin filaments (brown) and various categories of synaptic proteins. Interactions are indicated by black arrows with the origin of the arrow indicating the region of actinin involved in the interaction (when known) (This figure has been adapted from Foley and Young (2014))

Actin is the main cytoskeletal element at synapses the actin cytoskeleton and mediates changes in synapse morphology associated with synaptic plasticity. Given their interaction with key regulators of synaptic plasticity such as CaMKII, actinins may play a role in this structural plasticity of synapses, but this is an area that requires further investigation.

Endocytosis and Exocytosis

Actinins have been shown to interact with components of the vesicular trafficking machinery such as the Rab effectors Rabphilin-3A and RN-tre, as well as the vesicle coat protein clathrin and have been implicated in regulating the plasma membrane localization of several transmembrane receptors, transporters, and ion channels (see Foley and Young 2014 and references therein). For example, an interaction of actinins with the adenosine A2A G protein-coupled receptor is involved in agonist-induced internalization. Similarly actinin-4 plays a role in Ca++-dependent endocytosis and inhibition of the Na+/H+ exchanger 3 plasma membrane transporter. Actinin-4 was also implicated in insulin-induced trafficking of the GLUT4 glucose transporter to the plasma membrane in muscle cells, via interactions between actinin-4 and the cytosolic region of GLUT4. Finally, actinin-1 and actinin-4 have also been linked to the transferrin receptor recycling pathway in two separate reports. These and other studies provide increasing evidence of a significant role for actinins in vesicular trafficking events to and from the plasma membrane.

Diseases Associated with Human Actinin Mutation or Overexpression

Diseases and phenotypic traits associated with mutation or overexpression of each of the human actinin genes have now been identified (Table 1) and are discussed below.


A number of recent studies have linked actinin-1 mutations with the platelet disorder congenital macrothrombocytopenia (CMTP; Gueguen et al. 2013; Kunishima et al. 2013; Bottega et al. 2015; Yasutomi et al. 2015) – a rare condition characterized by a reduced number of platelets in the peripheral vascular system along with increased platelet size. Actinin-1 joins a long list of genes for which CMTP-causing mutations have been described. To date 13 CMTP-linked actinin mutations have been described, all are missense mutations and exhibit dominant inheritance.

Most of the mutations are within the ABD and CAM domains, but one falls within the central rod domain (Yasutomi et al. 2015). Expression of CMTP-linked actinin-1 mutant proteins in Chinese hamster ovary cells, human fibroblast cells, and primary mouse fetal liver-derived megakaryocytes lead to abnormal alterations in actin cytoskeleton organization (Gueguen et al. 2013; Kunishima et al. 2013; Bottega et al. 2015). The first insights into the molecular mechanisms by which these mutations affect actinin function come from the observation that some of the mutations that map to the ABD increase the affinity of actinin-1 association with F-actin, both in in vitro assays and in cultured cells (Murphy et al. 2016). This is similar to actinin-4 mutations discussed below. Individuals carrying these actinin-1 mutations display a mild macrothrombocytopenia, in the absence of other pathologies. This points to a specific role for actinin-1 in platelet formation, possibly through its actin-binding and bundling ability, which cannot be compensated for by other actinin isoforms.


Actinin-2 is expressed in cardiac as well as skeletal muscle fibers, and a number of studies have identified dominantly inherited actinin-2 missense mutations that cause a range of myopathies (see Murphy and Young 2015 and references therein). These reports include cases of dilated cardiomyopathy (DCM) caused by a mutation in the ABD that abrogates an interaction with the Z-disk component MLP and hypertrophic cardiomyopathy (HCM) linked to three mutations in actinin-2.

One of these same mutations, as well as three novel mutations, were found in families affected by HCM and other heterogeneous cardiac conditions, while another actinin-2 mutation was associated with individuals in a large family that had a history of HCM and juvenile atrial arrhythmias. The eight cardiomyopathy-linked mutations identified to date do not map to a particular region of actinin-2, with some located in the ABD, some in the central rod, and one in the CAM domain. The molecular mechanisms by which they lead to disease are thus not immediately obvious.


An actinin-3 polymorphism, causing the nonsense mutation p.Arg577X, was identified in 1999, and it is now apparent that approximately one billion people worldwide are homozygous for this sequence variant and completely lack expression of actinin-3 protein (MacArthur and North 2004). Actinin-3 expression is restricted expression in type 2 fast glycolytic skeletal muscle fibers that are responsible for the generation of rapid and forceful contractions. This specialized function may explain why a loss of actinin-3 is apparently not detrimental. However, while the homozygous mutant genotype (577XX) does not cause any disease, numerous studies have now shown that it is associated with poorer performance in sprint and power sports, with the 577RR genotype overrepresented in elite sprint and power athletes (Berman and North 2010). There are some reports that the 577XX genotype might confer an advantage in endurance sports, but the evidence for this is not as consistent. These intriguing findings beg the question of when the 577X mutation arose and how/why it spread in human populations. It seems that this mutation expanded under positive selection to achieve a very high frequency in specific populations (e.g., European and Asian), but not others (e.g., African) (Berman and North 2010). Actinin-3 knockout mice display muscle metabolism conversion from the anaerobic pathway, typically utilized in fast muscle fibers, to the oxidative aerobic pathway, which is generally seen in slow muscle fibers (MacArthur et al. 2007). One can speculate therefore that more efficient aerobic muscle metabolism may be the trait associated with the p.Arg577X genotype that has been positively selected for in specific human populations.


Five dominant actinin-4 mutations that cause the kidney disease focal segmental glomerulosclerosis (FSGS) have been identified (reviewed recently by Feng et al. 2015). These mutations lie within or adjacent to the ABD, and three of them have been reported to result in an actinin-4 protein with an increased affinity for actin. An important role for actinin-4 in kidney function is underlined by the observation that actinin-4 knockout mice exhibit altered podocyte morphology, develop glomerular disease, and, finally, experience kidney failure (Kos et al. 2003). In mice, though perhaps not in humans, both actinin-1 and actinin-4 are expressed in podocytes, yet actinin-1 cannot compensate for a loss of actinin-4 (Kos et al. 2003). This suggests actinin-4 has unique functions in the kidney and that actinin-1 and actinin-4 are not functionally redundant.

Another unique aspect to actinin-4 is its role in cancer. Actinin-4 overexpression has been described in many tumor types and has been linked to infiltrative phenotypes and poor outcomes in several cancers (reviewed recently by Honda 2015). Overexpression of actinin-1 in tumors has not been prominently reported, again suggestive of isoform-specific functions of actinin-4 related to the promotion of a metastatic phenotype. The preferential binding of the focal adhesion protein zyxin to actinin-1 over actinin-4 has recently been reported (Fukumoto et al. 2015). This observation suggests a mechanism, whereby overexpression of actinin-4 promotes cell motility and invasion by displacing actinin-1 and zyxin from focal adhesions, which leads to an increase in immature focal adhesions and promotes motility (Fukumoto et al. 2015).

Overall, understanding isoform-specific interactions and functions is an area of great interest in order to reveal the molecular basis for the diseases and phenotypes associated with each actinin.


The actinins are an important family of proteins with multiple functions in many fundamental cellular processes. The vertebrate actinins provide a textbook example of sub-functionalization and neo-functionalization following gene duplication, with each isoform maintaining the core ancestral function of cross-linking actin filaments but acquiring its own specialized roles. Despite over 50 years of research, there are many interesting questions about actinins that remain unanswered, and novel functions for these fascinating proteins continue to reveal themselves. For example, evidence for a non-canonical role for actinin-4 as a transcriptional regulator has emerged recently (Honda 2015). This and several other aspects of actinin function have not been discussed here for the sake of brevity. It is clear that there is plenty more to be discovered about the multifunctional actinin protein family.


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.School of Biochemistry and Cell BiologyUniversity College CorkCorkIreland