Role and mechanism of actin-related protein 2/3 complex signaling in cancer invasion and metastasis: A review

Abstract

The actin 2/3 complex (Arp2/3) regulates actin polymerization and nucleation of actin filaments, is associated with cell motility, and has been shown to play a key role in the invasion and migration of cancer cells. nucleation-promoting factor (NPF) such as N-WASP (neural-WASP famly verprolin-homologous protein family), WAVE (WASP famly verprolin-homologous protein family), and WASH (WASP and Scar homologue) undergo conformational changes upon receipt of multiple upstream signals including Rho family GTPases, cdc42 (Cell division control protein 42 homolog), and phosphatidylinositol 4,5-bisphosphate (PtdIns 4,5 P2) to bind and activate the Arp2/3 complex. Once activated, the Arp2/3 complex forms actin-based membrane protrusions necessary for cancer cells to acquire an invasive phenotype. Therefore, how to influence the invasion and migration of cancer cells by regulating the activity of the Arp2/3 complex has attracted great research interest in recent years. Several studies have explored the effects of phosphorylation modifications of cortactin and several NPFs (Nucleation Promoting Factor) including N-WASP and WAVE on the activity of the Arp2/3 complex and ultimately on cancer cell invasiveness, and have attempted to suggest new strategies for antiinvasive therapy as a result. Other studies have highlighted the potential of targeting genes encoding partial or complete proteins of the Arp2/3 complex as a therapeutic strategy to prevent cancer cell invasion and metastasis. This article reviews the role of the Arp2/3 complex in the development, invasion, and metastasis of different types of cancer and the mechanisms regulating the activity of the Arp2/3 complex.

Figure 1.

Two different conformations of the Arp2/3 complex: On the left, the Arp2/3 complex is in an inactive condition, with Arp2 and Arp3 separated by a large distance.^[5] When NPFs like N-WASP, WAVE, and WASH activate the Arp2/3 complex, it experiences conformational changes in which the Arp2 and Arp3 subunits approach each other and finally become the active Arp2/3 complex on the right. Arp2/3 = actin-related protein 2/3, JMY = junctionmediating and regulatory protein, NPF = Nucleation Promoting Factor, N-WASP = neural-WASP famly verprolin-homologous protein family, WASH = WASP and Scar homologue, WAVE = WASP famly verprolin-homologous protein family, WHAMM = WASP homolog associated with actin, membranes and microtubules.

Figure 2.

① Cortactin’s NTA binds to and activates the Arp2/3 complex, which regulates branching actin assembly as well as F-actin polymerization and contraction. ② The 6.5 F-actin repeat domain: The fourth in the repeat sequence is responsible for binding to F-actin (F-actin). Post-translational modifications of the 6.5 F-actin repeat domain can regulate the function of cortactin, and these modifications include phosphorylation and acetylation of PAK1, PAK3, ATAT1, and HDAC6. ③ An α-helix and a proline-rich region: Multiple tyrosine phosphorylation sites, such as Y421, Y446, Y470, Y486, etc., are found in these areas, which are phosphorylated by kinases such as Src, Fer, c-Met, and NCK1. ERK, PAK, MLCK, and other kinases phosphorylate two serine phosphorylation sites, S405 and S418, respectively. ④ SH3: Many cytoskeletal, membrane transport, and signaling proteins, such as N-WASP, ZO-1, CortB, and Dynamin2, bind to the C-terminal SH3 structural domain. Arp2/3 = actin-related protein 2/3, N-WASP = neural-WASP famly verprolin-homologous protein family.