Complex roles of filamin-A mediated cytoskeleton network in cancer progression

The cytoskeleton, a complex network of protein fibers in eukaryotic cells, provides a dynamic structural framework that is crucial for maintaining normal cell activity, including cell shape, cellular motion, division, and intracellular transport among other processes [1-3]. Eukaryotic cells contain three main types of cytoskeletal filaments: microfilaments, intermediate filaments, and microtubules [1,3]. Microfilaments (also called actin filaments or F-actin) are composed of linear polymers of actin subunits that form the thinnest filaments of the cytoskeleton. The actin filament is a polar macromolecule characterized by the elongation of one filament end coupled with shrinkage at the other. This dynamic interplay generates force and causes net movement of the intervening strand [4]. Actin filaments also act as tracks for the movement of myosin molecules that attach to the microfilament and "walk" along them [5]. In addition, actin filaments cross-link into bundles to form the dynamic actin cytoskeletal network, which is in turn finely tuned by multiple families of cytoskeletal proteins [6], called actin binding proteins. These proteins typically share a conserved, α-actinin-like F-actin binding domain (ABD) [7-9].One actin binding protein that contains the actinin-like F-actin binding domain is the filamin family. This family is composed of three homologous proteins (FLNA, FLNB, and FLNC) that are products of different genes and their mRNA splice variants [10]. The three filamin genes are highly conserved and filamin proteins exhibit 60-80% overall amino acid identity, with the greatest divergence observed at the two hinge regions, sharing 45% identity [11]. Filamin-A (FLNA), also known as human actin-binding protein 280 (ABP-280) or filamin-1, is encoded by the X-linked gene FLNA[12,13]. As shown in Figure 1, the human filamin-A is a homodimer with large subunits of 280KD, forming a V-shaped structure [11,14-16]. At the NH2 terminus of the monomer, there is an act