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Cancer associated talin point mutations disorganise cell adhesion and migration

Latifeh Azizi, Alana R. Cowell, Vasyl V. Mykuliak, Benjamin T. Goult, Paula Turkki, Vesa P. Hytönen

Preprint posted on 26 March 2020 https://www.biorxiv.org/content/10.1101/2020.03.25.008193v1

Article now published in Scientific Reports at http://dx.doi.org/10.1038/s41598-020-77911-4

The structure/function Talin field is cancer relevant

Selected by Amanda Haage

Why This Is Cool – Talin has a somewhat controversial role in caner to date. Most studies have looked at Talin expression as a prognostic marker, and results are mixed. Some cancers, such as colorectal and prostate cancers show significant correlation between high Talin expression and invasion, with in vitro knockout studies inhibiting migration, usually through a disruption in the epithelial-to-mesenchymal pathway (1, 2). Alternatively, low Talin expression has been show to correlate with malignancy in hepatocellular carcinoma, where rescue experiments halt motility (3). This preprint study is interesting in that the authors looked for Talin point mutants that were associated with cancer, instead of whole Talin expression. They then attempted to quantify how these mutants impacted adhesion, migration, and invasion (Table 1). Talin structure/function is an established sub-field that has largely investigated the role of Talin in development. Many mutants described here, or closely related ones, have been shown to have specific roles with disruption resulting in wide ranging effects (Table 1). This shift in looking at Talin mutants compared to the whole protein respects the role Talin has as a large adaptor and master regulator. It is also in line with the general shift of medical research to being more precise and targeted. We know Talin is essential (4), getting rid of Talin is not going to be an effective therapy, but perhaps a specific Talin target will be?

Mutation Talin Domain Results Summary Potential Function
    2D Speed Proliferation 3D invasion  
P229L F2 Same Increased Not Tested Integrin /Actin (5,6)
I392N F3 Increased Decreased Increased Integrin / Activation /Actin (5)
V577D R1 Same Same Not Tested Vinculin / Mechanosensing (7)
A893E R3 Same Same Not Tested Vinculin / Mechanosensing (7)
R1368W R7 Decreased Same Increased Actin (6)
Y1389C R7 Same Decreased Same Vinculin (7)
L1539P R8 Decreased Same Same Vinculin / DCL1 /RIAM (7)
S1750F R9 Same Same Not Tested Vinculin (7)
E1770Q R9 Same Same Not Tested Autoinhibition (8)
D2086V R11 Same Same Not Tested Integrin (5)
L2509P DD Decreased Increased Decreased Dimerization / Actin (6)

Table 1: Summary of results for each point mutant investigated

 

Why I selected It – This paper is particularly interesting in how it takes a large body of previous work, that is mostly from a developmental perspective, and moves it forward in the context of cancer. It’s a great base from which a hopeful researcher interested in studying the role of Talin in cancer, such as myself, can launch from for further in-depth studies. It’s an immediately and immensely useful study for our field.

Open Questions –

  1. Did any mutants display altered actin organization?
  2. Do you think the results would differ if you expressed the mutants in Talin1/2 negative cancer cells? Would cancer cell type have an impact?

Related References –

  1. Talin-1 in colorectal cancer
  1. Talin-1 in prostate Cancer
  1. Talin-1 in hepatocellular carcinoma
  1. Talin is required for Development
  1. Talin Integrin Binding Sites
  1. Talin Actin Binding Sites
  1. Talin Vinculin Binding & Mechanosensing
  1. Talin Autoinhibition

 

Posted on: 3 August 2020 , updated on: 15 August 2020

doi: https://doi.org/10.1242/prelights.23707

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Author's response

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-Did any mutants display altered actin organization?

In these experiments only expression of the mutant L2509P showed apparent changes in actin organization. However, we did not study actin organization in detail. With high resolution live imaging, we could find more differences, but those would most likely be due to changes in cytoskeletal dynamics rather than cytoskeletal organization.

-Do you think the results would differ if you expressed the mutants in Talin1/2 negative cancer cells? Would cancer cell type have an impact?

We did co-express some of the mutants with talin-2, but the expression level of talin-2 was high in our setup (equal to that of talin-1), making it difficult to estimate the impact of the mutations in various cancer cells. In a cancer cell line that shows downregulation of talin-1 and low endogenous levels of talin-2, it is likely that overexpression of talin mutant would cause more pronounced effect on cell behaviour. For example, uterine carcinomas could pose an interesting target to study.

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