Mechanosignaling

What is talin?

Talin contains a 47-kDa N-terminal head, a neck and a 220kDa rod domain. The head domain comprises four subdomains termed F0, F1, F2 and F3, with the latter three forming a three-lobed FERM domain.

Integrin tail binding occurs via the F3 phosphotyrosine binding (PTB) domain via a unique interaction with the integrin membrane proximal region, which is sufficient for integrin activation [1]. The basic patches on all subdomains can dock onto the plasma membrane and further enhance integrin activation. Specific interactions through basic residues on F3 are also essential for integrin clustering [2].

Both F2 and F3 contribute to actin binding, with the F3 binding pocket being the same that binds integrin and PIPKIγ90 as well thus linking these adhesion components [3]. F3 also binds to layilin (a hyaluronan receptor) and signaling molecules FAK (reviewed in [4]). The neck region is susceptible to cleavage by calpain 2 [5].

The rod contains an additional integrin-binding site (IBS2), two actin-binding sites (ABD) and several vinculin-binding sites that are shown to be exposed by stretch in response to force, both in vitro [6][7][8] and in vivo [9]. Vinculin binding reinforces and increases the stability of adhesion sites [10]. Talin also contains numerous potential phosphorylation sites [11] which are suggested to directly or indirectly regulate the association of talin with other factors (reviewed in [4]).

Talin activation and membrane recruitment

Talin exists in an autoinhibited form in the cytosol due to the intermolecular association between the F3 subdomain and a helical bundle in the rod region [12][13]. This not only blocks integrin binding site on F3 but also F2 and F3 binding to membrane. Activation predominantly occurs inside FAs [14][15] and likely involves binding to membrane phospholipids such as phosphatidylinositol 4,5-bis-phosphate (PIP2) [16][17] (reviewed in [18]), vinculin and F-actin [14] or calpain cleavage [5]. This enhances talin’s affinity for the β-integrin subunit by revealing binding sites. Agonist stimulation has been shown to trigger a signaling pathway for membrane targeting of talin/activation of integrin αIIbβ3 [19], involving small GTPase Rap1, Rap-GEF or protein kinase C and adaptor protein RIAM [20][21].

Talin localization and function

Talin is abundant specifically at sites of cell-ECM linkage [22] where it appears to be a key endpoint for multiple signaling pathways that lead to integrin activation (reviewed in [23]). Talin behaves as a prominent structural platform that is required for the initial linkage between the contractile cytoskeleton and sites of integrin/fibronectin adhesion [24].

During cell spreading, talin undergoes cycles of stretching and vinculin binding due to contractile forces on the rearward moving actin filaments [25]. This phenomenon serves to convert matrix forces into biochemical signals at the adhesion site. Hence it not only organizes and stabilizes these initial linkages [10], but it also mediates signal transduction events through the integrins, vinculin and actin (reviewed in [4][18][26]).

The proteolytic cleavage of talin has been shown to be a critical event in the subsequent disassembly of other focal adhesion components [27] but not in integrin activation. Although talin is a key factor that translates mechanical forces into chemical responses primarily at sites of cell-matrix and cell-cell junctions, talin may also function in other cellular processes including membrane ruffling, cytokinesis, and phagocytosis (reviewed in [4]).

References

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2. Saltel F, Mortier E, Hytönen VP, Jacquier M, Zimmermann P, Vogel V, Liu W, and Wehrle-Haller B. New PI(4,5)P2- and membrane proximal integrin-binding motifs in the talin head control beta3-integrin clustering. J. Cell Biol. 2009; 187(5):715-31. [PMID: 19948488]
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