Vinculin, an adapter protein in control of cell adhesion signalling

Abstract

Vinculin, discovered in 1979 (Geiger, 1979), is an adapter protein with binding sites for more than 15 proteins. Biochemical and structural analyses have contributed to detailed knowledge about potential binding partners and the understanding of how their binding may be regulated. Despite all this information the molecular basis of how vinculin acts in cells and controls a wide variety of signals remains elusive. This review aims to highlight recent discoveries with an emphasis on how vinculin is involved in the coordination of a network of signals.

Introduction

Vinculin is a 117 kDa protein, which localises to integrin-mediated cell–matrix adhesions and cadherin-mediated cell–cell junctions. In C. elegans vinculin deficiency leads to the loss of muscular activity and lethality at an early larval stage (Barstead and Waterston, 1989). Mouse embryos deficient in vinculin are small and die at day E10.5 with major defects in brain and heart development (Xu et al., 1998a). Embryos at E9.5 are about a third smaller than normal embryos and their mutant tissue seems more fragile suggesting that vinculin plays a role in strengthening cell attachments to its environment. Mouse embryonic fibroblasts isolated from vinculin knock-out animals at E9.5 spread less, have smaller focal adhesions (FA) and show decreased adhesion strength to fibronectin, laminin, vitronectin and collagen, but they migrate faster than their wild-type counterparts (Xu et al., 1998a). Earlier studies using vinculin-null F9 embryonic carcinoma cells made similar observations (Coll et al., 1995). Re-expression of vinculin rescued these defects in vinculin-null cells (Coll et al., 1995, Xu et al., 1998b, Saunders et al., 2006). The phenotypic changes of reduced cell adhesion and an increase in cell motility associated with the loss of vinculin is thought to drive the formation of tumour metastases. Other studies showed that expression of vinculin in tumour cell lines with diminished levels of the endogenous protein suppressed their tumorigenic ability and increased adhesion strength (Rodríguez Fernández et al., 1992, Lifschitz-Mercer et al., 1997). However it remains to be established which signals lead to the enhanced tumourigenicity of vinculin-deficient cells.

During cell migration small dot-like adhesion sites (focal complexes; FX) form at the leading edge of a cell, which then mature into streak-shaped FA. In the lamellum, an area in front of the nucleus, adhesions start to disassemble (Fig. 1a). For controlled cell motility, the formation and disassembly of adhesion sites needs to be coordinated. However, it should be noted that FA do not only form during continuous cell migration, they can also be constantly formed in the cell periphery of stationary cells mostly at sites of local protrusions and retractions (Smilenov et al., 1999, Ballestrem et al., 2001; our observations). Although many of those FA, especially in less migratory cell types such as fibroblasts or epithelial cells, seem relatively stable over time, there is an astonishing level of mobility of proteins therein (Lele et al., 2008). Many FA proteins, including vinculin, can cycle in and out of these FA. The rate of vinculin cycling is dependent on its activity status (Fig. 1b), which in turn can affect the cycling rate of other FA proteins (Cohen et al., 2006, Humphries et al., 2007). Although, it is known that vinculin is recruited to FA very early during their development, little is known about the molecular basis of how these events are controlled. Similarly, even though it is known that the activation status of vinculin controls its mobility, we are far from understanding how this can control key signals in FA.