A common cofilin activity cycle in invasive tumor cells and inflammatory cells

Abstract

In many cell types, the formation of membrane protrusions and directional migration depend on the spatial and temporal regulation of the actin-binding protein cofilin. Cofilin, which is important for the regulation of actin-polymerization initiation, increases the number of actin free barbed ends through three mechanisms: its intrinsic actin-nucleation activity; binding and severing of existing actin filaments; and recycling actin monomers from old filaments to new ones through its actin-depolymerization activity. The increase in free barbed ends that is caused by cofilin initiates new actin polymerization, which can be amplified by the actin-nucleating ARP2/3 complex. Interestingly, different cell systems seem to have different mechanisms of activating cofilin. The initial activation of cofilin in mammary breast tumors is dependent on PLCγ, whereas cofilin activation in neutrophils is additionally dependent on dephosphorylation, which is promoted through Rac2 signaling. Although the literature seems to be confusing and inconsistent, we propose that all of the data can be explained by a single activity-cycle model. In this Opinion, we give an overview of cofilin activation in both tumor cells and inflammatory cells, and demonstrate how the differences in cofilin activation that are observed in various cell types can be explained by different starting points in this single common activity cycle.

Evidence for a role of MRCK in mediating HeLa cell elongation induced by the C1 domain ligand HMI-1a3

“…To our surprise, HMI-1a3 had no effect on the levels of phosphorylated cofilin-1. Since cofilin-1 phosphorylation can be regulated in a highly localized manner (van Rheenen et al, 2009), the present results do not however rule out the possibility that HMI-1a3 induces cofilin-1 phosphorylation: Small but locally significant changes in cofilin-1 phosphorylation may not be detectable with the methods employed. Furthermore, it can be speculated that the increase in the proportion of phosphorylated cofilin-1 (relative to total cofilin-1) affects cofilin-1 function and thereby plays a role in mediating the cellular response.…”

The other side of the coin: Functional and structural versatility of ADF/cofilins

“…cofilin, twinfilin) can also be very active around the cellular protrusions (lamellipodia, invadopodia) in collaboration with some other type of actin binding proteins as well (e.g. Arp2/3, cortactin) (Oser and Condeelis, 2009;van Rheenen et al, 2009;Vartiainen et al, 2003).…”

Proteomic Analysis of Normal and Cancer Cervical Cell Lines Reveals Deregulation of Cytoskeleton-associated Proteins

“…Based on these indications, and the known biological contribution to cancer pathogenesis, proteins involved in cytoskeletal processes were further investigated. Thus, cofilin-1 (CFL1), an actin depolymerizing factor (ADF) that is implicated in aggressive cancer cell behavior (12)(13)(14)(15)(16)(17), was selected for further validation. The main function of cofilin-1 is the depolymerization of F-actin, a biological process crucial for normal mitosis, cytokinesis and cell migration (18).…”