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Review
. 2021 Jan 15;22(2):836.
doi: 10.3390/ijms22020836.

Targeting WASF3 Signaling in Metastatic Cancer

Reid Loveless  1 , Yong Teng  1   2   3
Affiliations
Review

Targeting WASF3 Signaling in Metastatic Cancer

Reid Loveless et al. Int J Mol Sci. .

Abstract

Increasing evidence indicates that cancer metastasis is regulated by specific genetic pathways independent of those controlling tumorigenesis and cancer growth. WASF3, a Wiskott-Aldrich syndrome protein family member, appears to play a major role not only in the regulation of actin cytoskeleton dynamics but also in cancer cell invasion/metastasis. Recent studies have highlighted that WASF3 is a master regulator and acts as a pivotal scaffolding protein, bringing the various components of metastatic signaling complexes together both spatially and temporally. Herein, targeting WASF3 at the levels of transcription, protein stability, and phosphorylation holds great promise for metastasis suppression, regardless of the diverse genetic backgrounds associated with tumor development. This review focuses on the critical and distinct contributions of WASF3 in the regulation of signal pathways promoting cancer cell invasion and metastasis.

Keywords: WASF3; cancer; drug target; metastasis; signaling network.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Inactive and active WASF domain confirmations. At resting state, WASFs exist in an autoinhibited closed conformational state due to the interactions between members of the N-terminally located WASF homology domain (WHD) and the C-terminus. Members of the protein complex at WHD include HSPC300, ABI, NCKAP1 (NAP1), CYFIP1 (SRA1), and WASF1/2/3. Upon activation by Rac, WHD interactions are disrupted and WASFs adopts an open conformation where their verprolin-cofilin-acidic (VCA) region can interact with the actin-related protein (Arp) 2/3 complex and monomeric actin (G-actin). Phosphatidylinositol (3,4,5)-trisphosphate (PIP3) may also recruit the WASF complex to the membrane by binding to the basic domain (B) of WASFs.
Figure 2
Figure 2
The signaling network of WASF3 in cancer metastasis. The WASF3-dependent signaling pathways and related regulatory networks critical to controlling cancer metastasis are summarized here.
Figure 3
Figure 3
Different inhibitor strategies to abolish the activation of WASF3 signaling and suppress metastasis. Annotations in red identify nodes in this schema for which drugs are available to suppress WASF3 signaling. Only a few representative drugs are shown in each node.
See this image and copyright information in PMC

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