**3.2. Ehm2**

**3.1. Talin**

140 Wound Healing - New insights into Ancient Challenges

Talin, a member of the FERM family of proteins, is concentrated in regions of cell-substrate and cell-cell contacts. Using its FERM domain, talin acts as a "hyper-activator" of integrin receptors linking the cytoplasmic tail of integrin receptors to the actin cytoskeleton and increasing the affinity of the integrin extracellular domain to the extracellular matrix, hence regulating cell adhesion-dependent processes including tissue remodelling [43]. Talin knockout results in abnormal cellular migration and early embryonic lethality [8]. Integrin adhesion receptors connect the extracellular matrix to the actin cytoskeleton and serve as bidirectional mechanotransducers during wound healing mediating actin cytoskeletal remodelling in response to stiffening of the extracellular matrix [44]. The inside out-signalling of integrin receptors regulates the ligand binding affinity of the cell surface receptors in response to changes in environmental factors important for cell survival, including tissue injury [45]. Cytoplasmic talin is activated in response to phosphatidylinositol 4,5-biphosphate (PIP2) binding which also terminates the auto-inhibition of talin through the talin head-rod binding. Once activated, the talin subdomain interacts with the β integrin tails, forms the talin specific

**Figure 4.** Talin activation of integrin receptor subunits. (A) PIP2 binding to the cytoplasmic talin activates the talin protein by ending the auto-inhibitory interaction with the rod domain. (B) Talin subdomain engages with the membrane proximal NPxY motif in the β integrin cytoplasmic tail. (C) Talin-specific loop structure forms with binding to the MP helical region of the integrin cytoplasmic chain, hence disrupting the connection between α/β subunit integrin cytoplasmic tails. Pulling forces at the β integrin tail reorient the transmembrane domains, hence disrupting the packing of

the α/β transmembrane domains. Figure adapted from [46].

Ehm2 is a member of the FERM family that has been identified as a positive regulator of keratinocyte adhesion and motility. Ehm2 is upregulated in response to tissue injury and its levels are up to three times higher in acute wounds compared with chronic wound samples [34]. Ehm2 expression is highest in wounds undergoing active healing, where high expression was observed at the wound edge suggesting a functional role for Ehm2 during wound repair. In vitro knock-down of Ehm2 reduces NWasp protein expression and cellular adhesion, migration and motility without affecting cell growth, cell cycle or apoptosis, suggesting that Ehm2 is an important actin modulator of cell migration during healing of acute wounds [34]. Therefore, in common with other FERM family members, these findings suggest that Ehm2 promotes wound healing via the process of reepithelialisation.
