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Séminaire impromptu - Ben GoultEmerging role for talin as a mechanosensitive signalling platform

Abstract :

The Cytoskeleton Club will welcome next monday on Monday April 10th, 2017 at 14h30 in the conference hall at the CGFB (PGF) in Bordeaux-Carreire Campus 

 Adhesions between cells and the surrounding extracellular matrix (ECM) are fundamental to the development of multicellular life and is mediated by the integrin family of cell surface receptors.

The central role of talin as a cytoplasmic adapter protein in these cell-matrix adhesions is well established; activating integrins enabling cell-ECM attachment and coupling integrins to the actin cytoskeleton. In this scenario talin is perfectly positioned to act as a mechanosensor sensing external mechanical stimuli and converting them into intracellular biological signals.

Our recent work on the mechanical properties of talin shows that it acts as a mechanosensitive signalling platform (MSP). The mechanosensing functions of talin rely on conformational changes in the multiple talin rod domains in response to force, that regulate interactions between talin and other cellular factors. By stretching single talin molecules using magnetic tweezers we have characterised the mechanical response of talin and identified two stages of talin mechanosensing. An initial unfolding event in domain R3 is a key regulatory checkpoint involved in adhesion assembly.  Here, force dependent conformational changes in R3 result in the recruitment of vinculin, which triggers adhesion maturation. This initial unfolding event happens at a force of just 5 pN.

However, once the adhesion has formed our data reveal the emerging role of talin as an MSP. The other 12 talin rod domains unfold at forces between 7-20 pN and we have identified that each one of these domains binds different signalling molecules in their folded and unfolded states. These discrete conformational changes enable talin to serve as a platform able to recruit numerous signalling molecules in a context dependent fashion. This enables many differential signalling complexes to form under different scenarios (different integrins, cell types, matrix stiffness etc.).

This talk will outline the emerging concept of talin as a mechanosensitive signalling platform and suggest that signalling through talin might be one of the key signalling mechanisms in integrin-mediated adhesion. 

Selected publications

Bouchet BP, Gough RE, van de Willige D, Ammon Y-C, Post H, Jacquemet G, Altelaar AFM, Heck AJR, Goult BT*and Akhmanova A*. (2016) Talin-KANK1 interaction controls the cortical microtubule stabilizing complexs to focal adhesions. eLife 5:18124

Yao M*, Goult BT*, Klapholz B, Hu E, Guo Y, Sheetz MP and Yan J. (2016) The mechanical response of talin Nature Comms. 7:11966

Kumar A, Ouyang M, Van den Dries K, McGhee EJ, Tanaka K, Anderson MD, Groisman A, Goult BT, Anderson KI and Schwartz MA. (2016) Talin sensor reveals novel features of focal adhesion force transmission and mechanosensitivity. J. Cell Biol. 213(3):371-383

Atherton P, Stutchbury B, Wang D-Y, Jethwa D, Tsang R, Meiler-Rodriguez E, Wang P, Bate N, Zent R, Barsukov IL, Goult BT, Critchley DR and Ballestrem C. (2015) Vinculin controls talin engagement with the actomyosin machinery. Nature Comms. 6:10038

Yao M*, Goult BT*, Chen H, Cong P, Sheetz MP and Yan J. (2014) Mechanical activation of vinculin binding to talin locks talin in an unfolded conformation. Scientific Reports 4:4610