Biology Reference
In-Depth Information
function in their natural environment. For example, the development of the
nervous system in vertebrates requires many complex patterns of cellular
migration. Epithelial cells need to migrate in order to close wounds in the
epithelial layer, whereas fibroblast motility is crucial for tissue remodelling.
Conversely, improper regulation of cell migration is the basis of many
abnormal processes, resulting, for example, in the invasiveness of tumour
cells.
Control of actin by Rho GTPases in migrating cells
Migrating vertebrate cells in tissue culture show a unique polarized
morphology, a broad, flat lamellum extending in the direction of migration
that terminates in a ru
ing lamellipodium (the leading edge) (Abercrombie et
al., 1970; Small et al., 2002) and a narrow, retracting tail at the rear of the cell.
This morphological polarization depends on the underlying organization of
the actin cytoskeleton. Actin filament polymerization is nucleated at the
leading edge, which generates a highly crosslinked meshwork of actin
filaments in the lamellipodium whose growing ends face the front of the cell
(Henson et al., 1999; Small et al., 1978; Svitkina et al., 1997; see chapter by
Pollard). The constant growth of these filaments, most likely coupled with the
action of a myosin motor, both pushes the leading edge forward and generates
a retrograde flow of actin towards the cell centre (Cramer, 1997; Henson et al.,
1999; Lin et al., 1997; Wang, 1985; Waterman-Storer and Salmon, 1999).
Contraction of actin bundles in the cell body may be required for retraction of
the cell's rear (Cramer et al., 1997; Small et al., 1998). The coupling of these
actin motions inside the cell to adhesions to the extracellular matrix drives cell
motion.
More than 10 years ago, it was discovered that activation of members of the
Rho family of GTPases can induce changes in the actin cytoskeleton and
adhesions that are typically associated with migrating cells. In fibroblasts,
RhoA activity results in the generation of contractile actin bundles and large
adhesions to the substrate. Rac1 activity induces actin polymerization to drive
lamellipodial protrusion and the formation of small adhesions, and Cdc42
generates cell polarity and induces the formation of filopodia (Hall, 1998;
Nobes and Hall, 1999; van Aelst and D'Souza-Schorey, 1997).
Rho GTPases act as molecular switches that can be activated by a variety of
extracellular stimuli. They cycle between a GTP-bound active form, which can
activate downstream effectors, and an inactive GDP-bound form. Rho
proteins are tightly regulated by different classes of upstream factors that
control the exchange of GDP for GTP and the rate of GTP hydrolysis (Kjoller
and Hall, 1999; Symons and Settleman, 2000; van Aelst and D'Souza-Schorey,
1997). Signalling through Rho GTPases is further complicated by their large
