Disease relevance of Actn1

• Calcineurin, which binds to the Z-disc in cardiomyocytes via alpha-actinin, promotes cardiac hypertrophy in response to numerous pathologic stimuli [1].
• We previously had shown that anti-DNA Abs that cross-react with alpha-actinin may be important in the pathogenesis of murine and human lupus nephritis; in murine models, we had found that a significant proportion of pathogenic serum and kidney-deposited Igs are alpha-actinin reactive [2].
• We conclude that enhanced alpha-actinin expression may determine the extent of Ig deposition in the Ab-mediated kidney disease in lupus [2].
• Thymic B lymphocyte clones from patients with myasthenia gravis secrete monoclonal striational autoantibodies reacting with myosin, alpha actinin, or actin [3].
• When a stab wound was made in brain, F-actin and alpha-actinin were upregulated in reactive astrocytes [4].

High impact information on Actn1

• These contractions leave periodic rows of matrix bound beta3-integrin and paxillin while generating waves of rearward moving actin bound alpha-actinin and MLCK [5].
• This analysis also showed for the first time the coexistence and alpha and beta tubulin, vimentin, alpha actinin and three other polypeptides present in intermediate-filament-enriched cytoplast cytoskeletons (spots 12, 24 and 31) [6].
• The participation of alpha-actinin in the capping of cell membrane components [7].
• The enrichment of alpha-actinin under the clustered surface molecules was already apparent in early stages (patching) of the capping process, with or without 10 mM sodium azide present [7].
• Prolonged incubation of the cells with the different ligands resulted in endocytosis of the ligand-receptor complex. alpha-Actinin was not associated with the inernalized complex, however, suggesting that it may dissociate from the patched or capped surface structures at some stage during endocytosis [7].

Biological context of Actn1

• In contrast, the transfection of vinculin constructs deficient in amino acids 1-288 (containing the talin- and alpha-actinin-binding site) or substituting tyrosine for phenylalanine (phosphorylation site, amino acid 822) in F9Vin(-/-) cells resulted in partial restoration of stiffness [8].
• In this paper we suggest that tyrosine kinase-activated phospholipase C hydrolyzes PIP2 bound to alpha-actinin and vinculin, leading to the simultaneous generation of second messengers and reorganization of the cytoskeleton [9].
• Down-regulation of several key actin-binding proteins, such as alpha-actinin, vinculin, gelsolin, and tropomyosins (TMs), is considered to contribute to the disorganized cytoskeleton present in many neoplastic cells [10].
• Fine mapping of the alpha-actinin binding site within cysteine-rich protein [11].
• Our data indicate that we can achieve transient N-RAP protein knockdown using the RNA interference technique and that alpha-actinin organization into myofibrils in cardiomyocytes is closely linked to N-RAP protein levels [12].

Anatomical context of Actn1

• In vitro assays showed that Alp directly enhances the capacity of alpha-actinin to cross-link actin filaments, indicating that the loss of Alp function contributes to destabilization of actin anchorage sites in cardiac muscle [13].
• Evidence that talin, vinculin and alpha-actinin are important in the assembly of focal adhesions, obtained using antisense technology and protein microinjection, is reviewed [14].
• This plasma membrane is underlaid by a filamentous, cytoplasmic web containing actin, proteins of the spectrin and band 4.1 families, alpha-actinin and vinculin [15].
• By contrast, the distribution of structural and intracellular membrane proteins, including alpha-actinin, the Ca-ATPase and dihydropyridine receptors, is not affected, even at sites close to the sarcolemma [16].
• In Balb/c 3T3 cells, alpha-actinin in the cytoskeleton contains PIP2, while alpha-actinin in cytosol does not [9].

Associations of Actn1 with chemical compounds

• The levels of PIP2 bound to alpha-actinin decrease in response to platelet-derived growth factor (PDGF) [9].
• Association of alpha-actinin with clustered integrin is therefore not sufficient to induce the co-localization of F-actin [17].
• During the same time interval, alpha-actinin is mobilized to the cell periphery at cell "ruffles." However, 12(S)-HETE showed little or no effects on actin-binding proteins filamin and tropomyosin or on microtubules [18].
• During recovery, which was initiated by removing NaN3 and 2-deoxyglucose from the medium, lamellipodia appeared rapidly and alpha-actinin dispersed from contracted aggregates [19].
• The critical lysine residue localizes within a short alpha-helix, raising the possibility that mutagenesis-induced alterations in alpha-actinin-binding capacity might be attributed to the disruption of a key structural element [11].

Physical interactions of Actn1

• Nonphosphorylated and Thr(286)-autophosphorylated CaMKII bind to alpha-actinin with similar efficacy, but autophosphorylation at Thr(305/306) or Ca(2+)/calmodulin binding significantly reduce this binding [20].

Enzymatic interactions of Actn1

• The protein appears to be located in focal contacts where it codistributes with beta 1 integrins. pp120 is distinct from the beta 1 subunit of integrins and from vinculin and alpha-actinin. pp120 is rapidly dephosphorylated in cells suspended by trypsinization but becomes rapidly phosphorylated in cells attaching and spreading on fibronectin [21].

Co-localisations of Actn1

• Analysis of both wild-type and desmin-null fibers revealed that the costamere protein talin colocalized with the Z-disk protein alpha-actinin, even at very high strains and stresses [22].
• During myofibril assembly in cultured chick cardiomyocytes, N-RAP and filamin appear to co-localize with alpha-actinin in the earliest myofibril precursors found near the cell periphery, as well as in the nascent myofibrils that form as these structures fuse laterally [23].
• PKC-epsilon-GFP bound with a striated pattern that co-localized with alpha-actinin, a marker of the Z-line of the sarcomere [24].

Regulatory relationships of Actn1

• Synaptopodin regulates the actin-bundling activity of alpha-actinin in an isoform-specific manner [25].

Other interactions of Actn1

• Alp also colocalizes at the intercalated disc with alpha-actinin and gamma-catenin, the latter being a known disease gene for human RV dysplasia [13].
• At the subcellular level in later embryonic and postnatal mouse cardiomyocytes, Scn1b was present in T-tubules as identified by immunostaining of alpha-actinin, and in the intercalated disks as identified by immunostaining of connexin 43 [26].
• Western blot analysis demonstrated decreased concentrations of z-disk proteins alpha-actinin and plectin and membrane scaffolding proteins dystrophin and beta-spectrin in muscle exposed to lengthening contractions compared with contralateral control muscle [27].
• The beating cells of both groups, stained positive with anti alpha-actinin, desmin, cardiac troponin I and connexin antibodies, and revealed similar ultrastructural features [28].
• In vitro studies demonstrated that individual domains within Cypher localize independently to the Z-line via interactions with alpha-actinin or other Z-line components [29].

Analytical, diagnostic and therapeutic context of Actn1

• Immunofluorescence microscopy showed that vinculin and alpha-actinin were released from the cytoskeletons together with actin [30].
• Immunoblotting studies on the avascular chick retina revealed polypeptide bands at Mr approximately 130 000, approximately 100 000, and 42 000 which were specific for vinculin, alpha-actinin and actin, respectively [31].
• Confocal microscopy of isolated cardiomyocytes revealed intense tropomodulin immunoreactivity in transgenic mice together with abnormal coincidence of tropomodulin and alpha-actinin reactivity at Z discs [32].
• Mouse spleen lymphocytes synthesize a protein which comigrates with skeletal muscle alpha-actinin on two-dimensional gel electrophoresis and is immunoprecipitated by an antibody directed against skeletal muscle alpha-actinin [33].
• Although some molecular properties and the effects described above on actin solution of HSP90 and HSP100 resemble those of alpha-actinin, the HSPs were distinguished from alpha-actinin by various means, including visualization of molecular shapes by electron microscopy with the aid of the low-angle rotary shadowing technique [34].

References