TLN2

Talin 2 is a protein in humans that is encoded by the TLN2 gene. It belongs to the talin protein family. This gene encodes a protein related to talin 1, a cytoskeletal protein that plays a significant role in the assembly of actin filaments. Talin-2 is expressed at high levels in cardiac muscle and functions to provide linkages between the extracellular matrix and actin cytoskeleton at costamere structures to transduce force laterally.^[3]

Structure

Human talin-2 is 271.4 kDa and 2542 amino acids in length.^[4] The size of talin-2 protein is similar to talin-1, and is relatively similar (74% identity, 86% similarity); the size of the talin-2 gene (200 kb) is however much larger than that of talin-1 (30 kb), due to differences in intron sizes.^[5] Talin-2 mRNA is expressed in multiple tissues, including cardiac muscle, mouse embryonic stem cells, brain, lung, skeletal muscle, kidney and testis; however expression is highest in cardiac muscle.^[5][6][7][8] A detailed analysis of the TLN2 gene revealed that the alternative splicing of TLN2 is complex and encodes multiple mRNA transcripts and protein isoforms. Studies revealed a promoter associated with a CpG island that accounts for most of the TLN2 expression in adult tissues. This promoter is separated from the first coding exon by approximately > 200 kb of alternatively spliced noncoding exons. Interestingly, the testis and kidney talin-2 isoforms lack the N-terminal 50% of the protein, and evidence suggests that this is the isoform expressed in elongating spermatids.^[9] Talin is also post-translationally modified via calpain 2-mediated cleavage, which may target it for ubiquitin-proteasome-mediated degradation and turnover of associated cell adhesion structures.^[10]

Function

The expression of talin-2 in striated muscle is developmentally regulated. Undifferentiated myoblasts primarily express talin-1, and both mRNA and protein expression of talin-2 is upregulated during differentiation; ectopic expression of talin-2 in undifferentiated myoblasts dysregulates the actin cytoskeleton, demonstrating that the timing of talin-2 expression during development is critical. In mature cardiomyocytes and skeletal muscle, talin-2 is expressed at costameres and intercalated discs, thus demonstrating that talin2 links integrins and the actin cytoskeleton in stable adhesion complexes involving mature sarcomeres.^[8][11] Talin-2 appears to play a role in skeletal muscle development; specifically, in myoblast fusion, sarcomere assembly, and the integrity of myotendinous junctions. Ablation of both talin isoforms, talin-2 and talin-1 prevented normal myoblast fusion and sarcomere assembly, as well as assembly of integrin adhesion complexes, which was attributed to disrupted interactions between integrins and the actin cytoskeleton.^[12] Interestingly, the mRNA expression of talin-2 has been shown to be regulated by the muscle-specific fragile X mental retardation, autosomal homolog 1 (FXR1) protein, which binds talin2 mRNAs directly and represses translation. Knockout of FXR1 upregulates talin-2 protein, which disrupts the architecture of desmosomes and costameres in cardiac muscle.^[13]

Talin-2, like talin-1 appears to join ligand-bound integrins and the actin cytoskeleton, which enhances the affinity of integrins for the extracellular matrix and catalyzes focal adhesion-dependent signaling pathways,^[14] as well as reinforces the cytoskeletal-integrin structure in response to an applied force.^[15] Interestingly, the strength of the interaction between talin and integrin appears to be fine-tuned through differential expression of isoforms in different tissues. The talin-2/β1D-integrin isoforms that are expressed and colocalize in striated muscle form a markedly strong interaction, and a few amino acid deletions in the β1-integrin tail can alter this interaction by 1000-fold.^[16]

Talin-2 is found within the neuronal synaptic region in brain tissue, and plays a role in clathrin-mediated endocytosis, coordinating phosphatidylinositol synthesis, and modulating actin dynamics through interactions with PIP kinase type 1γ, the major phosphatidylinositol 4,5-bisphosphate-synthesizing enzyme of the brain.^[17]

Clinical significance

In patients with temporal lobe epilepsy, talin-2 protein was detected in cerebrospinal fluid, whereas expression was absent in non-epileptic patients.^[18] Furthermore, postencephalitic epilepsy patients that were refractory to drug treatment exhibited markedly elevated levels of talin-2 protein in cerebrospinal fluid and reciprocally decreased levels in serum.^[19] These data suggest that talin-2 may prove useful as a biomarker for epilepsy, and may be pathologically linked to this disease.

Studies have also shown that TLN2 is a direct target of miR-132, which is epigenetically silenced in prostate cancer,^[20] suggesting that talin-2 may play a role in modulating cell adhesion in prostate cancer.

Interactions

TLN2 has been shown to interact with:

• ACTA1,^[21]
• CD61,^[22][23]
• ITGB1,^[24]
• LAYN,^[25][26]
• PTK2,^[27][28]

References

Further reading