The Role of WAVE2 Signaling in Cancer

Abstract

The Wiskott-Aldrich syndrome protein (WASP) and WASP family verprolin-homologous protein (WAVE)-WAVE1, WAVE2 and WAVE3 regulate rapid reorganization of cortical actin filaments and have been shown to form a key link between small GTPases and the actin cytoskeleton. Upon receiving upstream signals from Rho-family GTPases, the WASP and WAVE family proteins play a significant role in polymerization of actin cytoskeleton through activation of actin-related protein 2/3 complex (Arp2/3). The Arp2/3 complex, once activated, forms actin-based membrane protrusions essential for cell migration and cancer cell invasion. Thus, by activation of Arp2/3 complex, the WAVE and WASP family proteins, as part of the WAVE regulatory complex (WRC), have been shown to play a critical role in cancer cell invasion and metastasis, drawing significant research interest over recent years. Several studies have highlighted the potential for targeting the genes encoding either part of or a complete protein from the WASP/WAVE family as therapeutic strategies for preventing the invasion and metastasis of cancer cells. WAVE2 is well documented to be associated with the pathogenesis of several human cancers, including lung, liver, pancreatic, prostate, colorectal and breast cancer, as well as other hematologic malignancies. This review focuses mainly on the role of WAVE2 in the development, invasion and metastasis of different types of cancer. This review also summarizes the molecular mechanisms that regulate the activity of WAVE2, as well as those oncogenic pathways that are regulated by WAVE2 to promote the cancer phenotype. Finally, we discuss potential therapeutic strategies that target WAVE2 or the WAVE regulatory complex, aimed at preventing or inhibiting cancer invasion and metastasis.

Keywords: Arp2/3; Rac1; WASP; WAVE2; cancer; phosphorylation; signaling.

Figure 1

Structural domains and components of active and inactive WAVE regulatory complex (WRC). The multi-protein complex WRC is a stable heterocomplex consisting of HSPC300, wave homology domain (WHD), Abl interactor 1/2/3 (Abi1/2/3), NCK associated protein 1 (NckAP1/Hem1), specifically Rac1-associated protein 1 (Sra1/PIR121). WAVE2 is autoinhibited in a basal state through the interaction between the complex proteins and the VCA region. Upon certain phosphorylation signals the closed complex is released into an open and active WRC which is then translocated to the cell membrane via interactions with the phosphatidylinositol-(3,4,5)-triphosphate (PIP3) and insulin receptor substrate of 53 kDa (IRSp53). The binding of Rho family of GTPases (GTP-Rac) increases the affinity of WAVE2 for IRSp53. This IRSp53 promotes the ability of WAVE2 to stimulate actin-related protein 2/3 complex (Arp2/3)-mediated actin polymerization.

Figure 2

Upstream signals via membrane proteins cause activation of WAVE2 and have broad physiological and pathological ramifications. The potential WRC ligands or membrane proteins such as ion channels, G-protein-coupled receptors, adhesion receptors and scaffolding proteins are involved in recruiting WRC towards the cell membrane which causes polymerization of actin cytoskeleton. This event is extremely crucial for cell structure, migration, spreading, adhesion, division and invasion. High expression of WAVE2 and its constitutively active state is responsible for pathological conditions such as cancer.

Figure 3

Regulation of WAVE2 by several phosphorylation events: WRC is known as a signal integrator for sensing signals from Rac GTPases, phospholipids and protein kinases that sense growth factors and substrate adhesions. Cyclin-dependent kinase 1—CDK1, CDK5 and casein kinase 2 (CK2) are known to inhibit WAVE2 by keeping it in an inactive state whereas, AKT, ABI, Erk, PKA and PI3K (through VEGF) are known to release inactive WRC into an active WAVE2 complex.