Actin binding proteins

Abstract

In order to metastasize away from the primary tumor site and migrate into adjacent tissues, cancer cells will stimulate cellular motility through the regulation of their cytoskeletal structures. Through the coordinated polymerization of actin filaments, these cells will control the geometry of distinct structures, namely lamella, lamellipodia and filopodia, as well as the more recently characterized invadopodia. Because actin binding proteins play fundamental functions in regulating the dynamics of actin polymerization, they have been at the forefront of cancer research. This review focuses on a subset of actin binding proteins involved in the regulation of these cellular structures and protrusions, and presents some general principles summarizing how these proteins may remodel the structure of actin. The main body of this review aims to provide new insights into how the expression of these actin binding proteins is regulated during carcinogenesis and highlights new mechanisms that may be initiated by the metastatic cells to induce aberrant expression of such proteins.

The Hidden Conundrum of Phosphoinositide Signaling in Cancer

“…Importantly, cancer cells display upregulated expression of many cytoskeleton associated and regulatory proteins and they are essential for their migratory and invasive property as one third of proteins that are induced in metastatic cancers are related to adhesion and cytoskeletal reorganizations [80]. Spatial and temporal reorganization of actin cytoskeleton controls different cellular events involved in metastatic cascades, such as conversion of indolent epithelial cells into mesenchymal state, detachment from the primary tumor, migration/invasion and extravasation for secondary/tertiary growth [81]. The first evidence of intimate association between cytoskeletal protein and phosphoinositide was demonstrated by Anderson and Marchesi [82].…”

“…The fine-tuned activity of these actin binding and regulating proteins controls the nucleation/formation of actin filaments and their polymerization. Furthermore, the coordinated interplay between these processes controls the formation as well as the geometry of actin filaments in cellular machineries like cell adhesion complex, lamellipodia, filopodia and invadopodia which are essential for migrating and invading tumor cells [81]. …”

“…PI(4,5)P 2 regulation of actin nucleating activity of Arp2/3 protein complex via wiskott-aldrich syndrome protein (WASP) and Rho family small GTPases is the most extensively studied in the context of tumor cells migration/invasion and metastasis [81, 83-85]. This depends upon PI(4,5)P 2 along with active Cdc42 and Rac1 binding to the N-terminus of N-WASP and PI(4,5)P 2 binding to basic motifs [84, 85].…”

The interplay between the proteolytic, invasive, and adhesive domains of invadopodia and their roles in cancer invasion

“…[77][78][79] Additional reports indicate that actin polymerization in invadopodia of certain cancer cells (e.g., MDA-231 breast cancer cell line) can also be induced by specific Diaphanous-related formins, whose cell type specificity, and mode of action and regulation, are still unclear. 80 The actin bundle, thus formed, is further stabilized and mechanically reinforced by cortactin 5 and fascin, 73,81,82 producing a stable "invasive protrusion" that pushes against the ventral cell membrane, promoting its penetration into the ECM. 5,27,28,36,39,68,83 To get a closer look at the constituents of the invasive domain ( Fig.…”

“…72 Actin polymerization in the core of invadopodia is regulated by small Rho-family GTPases, mostly, CDC42, 1,28 which can directly activate the N-WASP-WIP complex, which, in turn, drives actin polymerization by the Arp2/3 complex. [73][74][75][76] Arp 2/3 actin nucleation is promoted by the severing activity of cofillin. [77][78][79] Additional reports indicate that actin polymerization in invadopodia of certain cancer cells (e.g., MDA-231 breast cancer cell line) can also be induced by specific Diaphanous-related formins, whose cell type specificity, and mode of action and regulation, are still unclear.…”