Crosstalk between WIP and Rho family GTPases

Abstract

Through actin-binding proteins such as the neural Wiskott-Aldrich syndrome protein (N-WASP) and WASP-interacting protein (WIP), the Rho family GTPases RhoA, Rac1 and Cdc42 are major modulators of the cytoskeleton. (N-)WASP and WIP control Rho GTPase activity in various cell types, either by direct WIP/(N-)WASP/Cdc42 or potential WIP/RhoA binding, or through secondary links that regulate GTPase distribution and/or transcription levels. WIP helps to regulate filopodium generation and participates in the Rac1-mediated ruffle formation that determines cell motility. In neurons, lack of WIP increases dendritic spine size and filamentous actin content in a RhoA-dependent manner. In contrast, WIP deficiency in an adenocarcinoma cell line significantly reduces RhoA levels. These data support a role for WIP in the GTPase-mediated regulation of numerous actin-related cell functions; we discuss the possibility that this WIP effect is linked to cell proliferative status.

Keywords: RhoA; differentiation; filamentous actin/invasiveness; proliferation.

Figure 1.

Scheme summarizing several pathways that control cell proliferation during glioma progression, including the recently identified position of WIP. Representative groups are shown of membrane receptors such as tyrosine kinase receptors (IGFR, GFR) or seven-transmembrane receptors (such as Wnt receptor). Through various mechanisms, these receptors can trigger generic PI3K-Akt signaling, which controls WIP activity. In many tumor cell types, certain proto-oncogenic proteins, such as the mutant versions of p53, enhance these membrane receptor activities. The oncogenic function of WIP operates by controlling YAP/TAZ stability/degradation. In some tumor cell types, YAP/TAZ can work together with beta-catenin; this collaboration enhances the relevance of this regulatory pathway, as an abundance of genes could be upregulated to ensure proliferation and survival. Levels of active GTPases such as RhoA are modified in some WIP-deficient cells, whereas in other cases Rac activity can compensate WIP-deficient function and/or WIP levels.