TLN2

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

Structure
Human talin-2 is 271.4 kDa and 2542 amino acids in length. The size of talin-2 is_associated_with::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. Talin-2 is_associated_with::mRNA is expressed in multiple tissues, including is_associated_with::cardiac muscle, mouse is_associated_with::embryonic stem cells, is_associated_with::brain, is_associated_with::lung, is_associated_with::skeletal muscle, is_associated_with::kidney and is_associated_with::testis; however expression is highest in is_associated_with::cardiac muscle. A detailed analysis of the TLN2 is_associated_with::gene revealed that the alternative splicing of TLN2 is complex and encodes multiple is_associated_with::mRNA transcripts and is_associated_with::protein is_associated_with::isoforms. Studies revealed a promoter associated with a is_associated_with::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 is_associated_with::exons. Interestingly, the is_associated_with::testis and is_associated_with::kidney talin-2 is_associated_with::isoforms lack the N-terminal 50% of the is_associated_with::protein, and evidence sugests that this is the is_associated_with::isoform expressed in elongating is_associated_with::spermatids. Talin is also post-translationally modified via calpain 2-mediated cleavage, which may target it for is_associated_with::ubiquitin-is_associated_with::proteasome-mediated degradation and turnover of associated cell adhesion structures.

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

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

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

Clinical Significance
In patients with is_associated_with::temporal lobe epilepsy, talin-2 is_associated_with::protein was detected in is_associated_with::cerebrospinal fluid, whereas expression was absent in non-epileptic patients. Furthermore, postencephalitic is_associated_with::epilepsy patients that were refractory to drug treatment exhibited markedly elevated levels of talin-2 protein in is_associated_with::cerebrospinal fluid and reciprocally decreased levels in is_associated_with::serum. These data suggest that talin-2 may prove useful as a biomarker for is_associated_with::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 is_associated_with::prostate cancer, suggesting that talin-2 may play a role in modulating is_associated_with::cell adhesion in is_associated_with::prostate cancer.

Interactions
TLN2 has been shown to interact with:


 * is_associated_with::ACTA1,
 * is_associated_with::CD61,
 * is_associated_with::ITGB1,
 * is_associated_with::LAYN,
 * is_associated_with::PTK2,