Talin-1 is the core mechanosensitive adapter protein linking integrins to the cytoskeleton. The TLN1 gene is comprised of 57 exons that encode the 2,541 amino acid TLN1 protein. TLN1 was previously considered to be expressed as a single isoform. However, through differential pre-mRNA splicing analysis, we discovered a cancer-enriched, non-annotated 51-nucleotide exon in TLN1 between exons 17 and 18, which we refer to as exon 17b. TLN1 is comprised of an N-terminal FERM domain, linked to 13 force-dependent switch domains, R1-R13. Inclusion of exon 17b introduces an in-frame insertion of 17 amino acids immediately after Gln665 in the region between R1 and R2 which lowers the force required to open the R1-R2 switches potentially altering downstream mechanotransduction. Biochemical analysis of this isoform revealed enhanced vinculin binding, and cells expressing this variant show altered adhesion dynamics and motility. Finally, we showed that the TGF-β/SMAD3 signaling pathway regulates this isoform switch. Future studies will need to consider the balance of these two TLN1 isoforms.

中文翻译：

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TLN1 包含一个与癌症相关的盒式外显子，可改变 talin-1 机械敏感性

Talin-1 是将整合素连接到细胞骨架的核心机械敏感接头蛋白。 TLN1 基因由 57 个外显子组成，编码 2,541 个氨基酸的 TLN1 蛋白。 TLN1 以前被认为表达为单一亚型。然而，通过差异前mRNA剪接分析，我们在TLN1中外显子17和18之间发现了一个富含癌症的、未注释的51核苷酸外显子，我们将其称为外显子17b。 TLN1 由 N 端 FERM 结构域组成，与 13 个力依赖性开关结构域 R1-R13 连接。外显子 17b 的包含在 R1 和 R2 之间的区域的 Gln665 之后引入了 17 个氨基酸的框内插入，这降低了打开 R1-R2 开关所需的力，从而可能改变下游的机械转导。该亚型的生化分析显示纽蛋白结合增强，表达该变体的细胞显示出改变的粘附动力学和运动性。最后，我们证明 TGF-β/SMAD3 信号通路调节这种异构体开关。未来的研究需要考虑这两种 TLN1 亚型的平衡。