WAVE2 Protein Complex Coupled to Membrane and Microtubules

Kazuhide Takahashi

doi:10.1155/2012/590531

Abstract

E-cadherin is one of the key molecules in the formation of cell-cell adhesion and interacts intracellularly with a group of proteins collectively named catenins, through which the E-cadherin-catenin complex is anchored to actin-based cytoskeletal components. Although cell-cell adhesion is often disrupted in cancer cells by either genetic or epigenetic alterations in cell adhesion molecules, disruption of cell-cell adhesion alone seems to be insufficient for the induction of cancer cell migration and invasion. A small GTP-binding protein, Rac1, induces the specific cellular protrusions lamellipodia via WAVE2, a member of WASP/WAVE family of the actin cytoskeletal regulatory proteins. Biochemical and pharmacological investigations have revealed that WAVE2 interacts with many proteins that regulate microtubule growth, actin assembly, and membrane targeting of proteins, all of which are necessary for directional cell migration through lamellipodia formation. These findings might have important implications for the development of effective therapeutic agents against cancer cell migration and invasion.

Highlights

The cell adhesion molecule E-cadherin is among the key molecules in the formation of the epithelial junctional complex [1,2,3]
As lamellipodia formation and dissociation of IQ moti-containing guanine nucleotide-activating protein 1 (IQGAP1) and kinesin-1 are inhibited by a phosphoinositide 3-kinase (PI3K) inhibitor, the dissociation of IQGAP1 and kinesin-1 from the Rac1CLIP-170 complex is a prerequisite for lamellipodia formation in response to growth factor stimulation; this depends on PI3K that is activated by the activated growth factor receptor (Figure 1(a))
Lamellipodia formation is preceded by membrane targeting of WAVE2 along microtubules

Summary

Introduction

The cell adhesion molecule E-cadherin is among the key molecules in the formation of the epithelial junctional complex [1,2,3]. E-cadherin forms homodimers in the extracellular domain between adjacent cells [4] and interacts intracellularly with a group of proteins collectively named catenins [5, 6] Both the cadherin cytoplasmic domain and the associated catenins are required for full cell adhesion [7, 8], and α-catenin is suggested to play a role in anchoring the cadherin-catenin complex to actin-based cytoskeletal components that include α-actinin and vinculin [9]. Constitutive tyrosine phosphorylation of βcatenin and concomitant loss of PTP might cause loss of Ecadherin-mediated cell-cell adhesion in cancer cells. Another mode of dysfunction of cell-cell adhesion is induced by perturbation of F-actin assembly to which the E-cadherin-catenin complex anchors. We focus on recent advances in the understanding of the mechanisms underlying regulation of cell migration and invasion that have been possible through the use of biochemical and pharmacological approaches

Regulation of Cell Migration

Membrane Targeting of WAVE2 along Microtubules

Control of Directional Lamellipodia Formation toward Growth Factor

Conclusion