TLN1 contains a cancer-associated cassette exon that alters talin-1 mechanosensitivity.
TLN1 contains a cancer-associated cassette exon that alters talin-1 mechanosensitivity.
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DOI：
10.1083/jcb.202209010
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发表时间：
2023-05-01
影响因子：
7.8
通讯作者：
Goult, Benjamin Thomas
中科院分区：
文献类型：
--
作者：
Gallego-Paez, Lina M.;Edwards, William J. S.;Chanduri, Manasa;Guo, Yanyu;Koorman, Thijs;Lee, Chieh-Yu;Grexa, Nina;Derksen, Patrick;Yan, Jie;Schwartz, Martin A.;Mauer, Jan;Goult, Benjamin Thomas
Gallego-Paez等人在TLN 1基因中鉴定了一个以前未注释的盒式外显子，该外显子改变了talin-1蛋白的机械性质。这种新的外显子可以在许多健康组织（包括皮肤和胰腺）中容易地检测到，并且在某些癌症亚型中显著富集。Talin-1是连接整合素与细胞骨架的核心机械敏感性衔接蛋白。TLN 1基因由57个外显子组成，编码2，541个氨基酸的TLN 1蛋白。TLN 1以前被认为是作为一个单一的同种型表达。然而，通过差异前体mRNA剪接分析，我们发现了一个癌症富集的，未注释的51个核苷酸的外显子在TLN 1外显子17和18之间，我们称之为外显子17 b。TLN 1由N-末端FERM结构域组成，连接到13个力依赖性开关结构域R1-R13。外显子17 b的包含在R1和R2之间的区域中紧接Gln 665之后引入17个氨基酸的框内插入，这降低了打开R1-R2开关所需的力，从而潜在地改变下游机械转导。这种异构体的生化分析显示增强黏着斑蛋白结合，表达这种变体的细胞显示改变的粘附动力学和运动性。最后，我们发现TGF-β/SMAD 3信号通路调节这种亚型转换。未来的研究将需要考虑这两种TLN 1亚型的平衡。
Gallego-Paez et al. identify a previously unannotated cassette exon in the TLN1 gene that alters the mechanical properties of the talin-1 protein. This novel exon can be readily detected in many healthy tissues including skin and pancreas, and is significantly enriched in certain cancer subtypes. 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.
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影响因子：
28.2
作者：
Driehuis, Else;Kolders, Sigrid;Clevers, Hans
通讯作者：
Clevers, Hans
影响因子：
39.3
作者：
Liu S;Ren J;Ten Dijke P
通讯作者：
Ten Dijke P
DOI：
10.1111/j.1742-4658.2009.06893.x
发表时间：
2009-03
期刊：
The FEBS journal
影响因子：
--
作者：
Debrand E;El Jai Y;Spence L;Bate N;Praekelt U;Pritchard CA;Monkley SJ;Critchley DR
通讯作者：
Critchley DR
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
影响因子：
12.4
作者：
Hornsveld, M.;Tenhagen, M.;Derksen, P. W. B.
通讯作者：
Derksen, P. W. B.