TLN1 contains a cancer-associated cassette exon that alters talin-1 mechanosensitivity.


Gallego-Paez, Lina M ORCID: 0000-0003-0255-8131, Edwards, William JS ORCID: 0000-0002-4530-9218, Chanduri, Manasa ORCID: 0000-0002-9353-1438, Guo, Yanyu ORCID: 0000-0001-6368-9237, Koorman, Thijs ORCID: 0000-0002-6064-3353, Lee, Chieh-Yu ORCID: 0000-0002-1942-4335, Grexa, Nina ORCID: 0000-0002-4949-0333, Derksen, Patrick ORCID: 0000-0003-0732-7762, Yan, Jie ORCID: 0000-0002-8555-7291, Schwartz, Martin A ORCID: 0000-0002-2071-1243 et al (show 2 more authors) (2023) TLN1 contains a cancer-associated cassette exon that alters talin-1 mechanosensitivity. The Journal of cell biology, 222 (5). e202209010-.

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Abstract

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.

Item Type: Article
Uncontrolled Keywords: Humans, Neoplasms, Adaptor Proteins, Signal Transducing, Talin, Mechanotransduction, Cellular, Exons
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 04 Mar 2024 09:22
Last Modified: 04 Mar 2024 09:22
DOI: 10.1083/jcb.202209010
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3179052
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