Multifunctional Roles of the Actin-Binding Protein Flightless I in Inflammation, Cancer and Wound Healing

Abstract

Flightless I is an actin-binding member of the gelsolin family of actin-remodeling proteins that inhibits actin polymerization but does not possess actin severing ability. Flightless I functions as a regulator of many cellular processes including proliferation, differentiation, apoptosis, and migration all of which are important for many physiological processes including wound repair, cancer progression and inflammation. More than simply facilitating cytoskeletal rearrangements, Flightless I has other important roles in the regulation of gene transcription within the nucleus where it interacts with nuclear hormone receptors to modulate cellular activities. In conjunction with key binding partners Leucine rich repeat in the Flightless I interaction proteins (LRRFIP)1/2, Flightless I acts both synergistically and competitively to regulate a wide range of cellular signaling including interacting with two of the most important inflammatory pathways, the NLRP3 inflammasome and the MyD88-TLR4 pathways. In this review we outline the current knowledge about this important cytoskeletal protein and describe its many functions across a range of health conditions and pathologies. We provide perspectives for future development of Flightless I as a potential target for clinical translation and insights into potential therapeutic approaches to manipulate Flightless I functions.

Stem cells expand potency and alter tissue fitness by accumulating diverse epigenetic memories

“…In contrast, the large number of wound-induced memory ATAC peaks in our study went beyond those described for inflammatory memory. Many of these memory-associated genes encoded cytoskeletal organization and Rho signaling/actomyosin-regulated proteins essential for the extensive polarized cell migration that occurs during re-epithelialization ( 26 – 28 ) (Fig. 3A and table S5).…”

Targeting AVIL, a New Cytoskeleton Regulator in Glioblastoma

“…Gelsolin has been found to inhibit apoptosis through multiple mechanisms, including direct interactions with the mitochondria. It interacts with mitochondrial gatekeeper VDAC1, stabilizing the mitochondria and preventing loss of mitochondrial membrane integrity [47]. In this way it can act as common proto-oncogenic BH3 family of anti-apoptotic proteins raising the threshold required for cell death to occur.…”

“…To grow and metastasize, tumor cells need a large number of sustained nutrients, oxygen, and the ability to dispose of waste [46]. They can obtain this by inducing the formation of new blood vessels that feed directly to the tumor (angiogenesis), and it has been shown that, in the absence of angiogenesis, the generation of lethal tumor mass is not possible [47]. Endothelial cells with gelsolin knocked out showed significantly higher levels of migration, and when gelsolin was overexpressed, the inhibition of angiogenesis was restored [48].…”

Increased Expression of Flightless I in Cutaneous Squamous Cell Carcinoma Affects Wnt/β-Catenin Signaling Pathway

“…Flii expression is increased during development and tissue repair and its levels can vary in different tumor types, such as breast, prostate and colorectal cancers, with high Flii levels being linked to negative patient prognosis [11][12][13]. Factors which affect the level of Flii have yet to be fully identified; however, Flii has been shown to have several binding partners which regulate actin dynamics (e.g., paxillin, talin), transcription and translation (e.g., LRRFIP1, Akt, Ulk1) and inflammation (e.g., LPS, caspase-1, LRRFIP2, Myd88) via signaling pathways important during cancer progression [14]. Flii intracellular roles have been linked to its function in cellular adhesion and migration [10,15], collagen remodeling [16][17][18], nuclear receptor co-activation promotion of transcriptional activity associated with different cancer cell lines [11,12], hormone receptor regulation of lipid metabolism [19], chromatic remodeling [20] and osteogenic differentiation [21].…”

“…Flii intracellular roles have been linked to its function in cellular adhesion and migration [10,15], collagen remodeling [16][17][18], nuclear receptor co-activation promotion of transcriptional activity associated with different cancer cell lines [11,12], hormone receptor regulation of lipid metabolism [19], chromatic remodeling [20] and osteogenic differentiation [21]. A number of studies have shown both beneficial and detrimental effects of Flii in cancer progression (for a detailed review see [14]); however, in the context of human cSCC, increased Flii within invading cells at the tumor edge and overexpression in a mouse model of cSCC lead to significantly larger, more necrotic tumors due to decreased apoptosis and increased invasion of tumor cells [22]. In contrast, reducing Flii results in lower levels of invasion of human cSCC cell lines in vitro and decreased development and progression of cSCC tumors in mice in vivo [22].…”