Cancer associated talin point mutations disorganise cell adhesion and migration
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
Categories: cancer biology, cell biology
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 –
- Did any mutants display altered actin 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?
Related References –
- Talin-1 in colorectal cancer
- Ji, L. et al. Talin1 knockdown prohibits the proliferation and migration of colorectal cancer cells via the EMT signaling pathway. Oncology Letters 18, 5408–5416. (2019).
- Talin-1 in prostate Cancer
- Sakamoto, S. et al. Talin1 promotes tumor invasion and metastasis via focal adhesion signaling and anoikis resistance. Cancer Res. 70, 1885–1895. (2010).
- Talin-1 in hepatocellular carcinoma
- Chen, P. et al. Downregulation of Talin1 promotes hepatocellular carcinoma progression through activation of the ERK1/2 pathway. Cancer Sci 108, 1157–1168. (2017).
- Talin is required for Development
- Monkley, S. et al. Disruption of the Talin Gene Arrests Mouse Development at the Gastrulation Stage. Dyn. 219:560–574 (2000).
- Talin Integrin Binding Sites
- Ellis, S. et al. In Vivo Functional Analysis Reveals Specific Roles for the Integrin-Binding Sites of Talin. Cell Sci. 1;24 (11). (2011).
- Ellis, S. et al. The Talin Head Domain Reinforces Integrin-Mediated Adhesion Promoting Adhesion Complex Stability and Clustering. PLoS Genetics 10(11). (2014).
- Talin Actin Binding Sites
- Franco-Cea, A. et al. Distinct Developmental Roles for Direct and Indirect Talin-Mediated Linkage to Actin. Biol. 1;345 (1):65-77. (2010).
- Talin Vinculin Binding & Mechanosensing
- Yao, M. et al. Mechanical Activation of Vinculin Binding to Talin Locks Talin in an Unfolded Conformation. Rep. 9;4:410. (2014).
- Talin Autoinhibition
- Ellis, S. et al. Talin Autoinhibition is Required for Morphogenesis. Curr Biol. 23;23(18). (2013).
- Haage, A. et al. Talin Autoinhibition Regulates Cell-ECM Adhesion Dynamics and Wound Healing In Vivo. Cell Rep. 27;25(9). (2018).
- Haage, A. et al. Precise Coordination of Cell-ECM Adhesion is Essential for Efficient Melanoblast Migration During Development. Development. (2020).
Posted on: 3 August 2020 , updated on: 15 August 2020
doi: https://doi.org/10.1242/prelights.23707
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