**4. Filamin family of proteins**

The filamin (FLN) family of proteins consists of three proteins, namely Filamin-a (FLNa), Filamin-b (FLNb) and Filamin-c (FLNc). While FLNa and FLNb are enriched at the cell periphery and focal adhesions, FLNc is mainly localised in muscle Z-disc. These proteins function as actin filament cross-linking proteins and serve as scaffolds to over 90 different binding partners including channels, receptors, intracellular signalling molecules and transcription factors [49]. FLN proteins are required for the recycling, trafficking and stabilisation of membrane proteins and facilitate the signal transduction at specific locations within the cell. In addition, the FLN family of proteins act as cohesive proteins to stiffen the F-actin networks, cross-linking the filament structures and reconstituting many aspects of cell mechanics [49]. In humans, mutation in the FLNa gene results in disrupted neuronal cell migration, while FLNa overexpression also prevents migration [50]. However, genetic knockdown of FLNa in embryonic fibroblasts results in no defect in migration, suggesting a compensatory mechanism by FLNb. The main family member, FLNa, has been the predominant focus of research and has been shown to play a role in wound healing.

### **4.1. Filamin-a**

FLNa acts as a negative regulator of integrin activation by blocking talin binding to the β integrin tail, and subsequent proteolysis and depletion of FLN. Phosphorylation of the β integrin tail dissociates FLN from integrins, hence allowing activation of integrins via talin and other members. FLNa binding with different partners leads to different outcomes in cell adhesion, spreading and migration: association with F-actin leads to formation of orthogonal F-actin networks with unique mechanical and physiological properties; interaction with Migfilin and R-Ras induces and enhances integrin activation respectively; interaction with RalA induces filopodia formation, while interaction with ROCK and Rho GTPases leads to increased actin cytoskeleton remodelling required for cell migration [49].

Human wounds heal through a combination of granulation tissue formation (via production of extracellular matrix and neovascularisation) and wound contraction (via fibroblastmediated contraction). FLNa has been shown to protect fibroblasts against force-induced apoptosis by stabilising cell-matrix contacts [51]. Moreover, fibroblast spreading and adhesion are dependent on FLNa, consistent with its known role in cytoskeletal dynamics [52]. Studies in mice show that FLNa stabilises actin filaments in fibroblasts and mediates wound closure by promoting elastic deformation and maintenance of tension in the collagen matrix [53]. FLNa accumulates at membrane ruffles where it interacts with different binding proteins and regulates fibroblast interactions with their mechanical environment [54]. When FLNa was blocked using short hairpin RNA, fibroblasts were unable to maintain tension in collagen matrices, and they had reduced migration in vitro. In addition, FLNa-deficient fibroblasts were less able to realign collagen matrix fibres in response to tension, and they demonstrated impaired ability to form cell extensions, a deficit reversed with pharmacologic stabilisation of the actin cytoskeleton. When FLNa was deleted conditionally in dermal fibroblasts in a mouse model, full-thickness wounds healed significantly more slowly and was associated with decreased matrix deposition. No side effects or contradictions were observed in these mouse models suggesting that targeted therapies against FLNa may be worth pursuing. As researchers continue to unlock the molecular mechanisms of fibroblast mechanotransduction, novel therapies may be developed to target and manipulate fibroblast behaviour for a wide range of cutaneous diseases [55].
