Polarized cellular responses, for example,
cell migration, require the co-ordinated assembly of signalling complexes at a particular
subcellular location, such as the
leading edge of cells.
Small GTPases of the
Ras superfamily play central roles in many (
polarized) responses to
growth factors,
chemokines or
integrin ligands. These
small GTPases are functionally distinct, yet remarkably homologous in their
primary sequence and especially in their effector domains. Therefore it has long been unclear how
GTPase signalling specificity is regulated.
Small GTPases carry a
lipid anchor, in the context of a
hypervariable region, which mediates membrane association. However, whereas the
lipid has long been proposed to be the critical regulator of
subcellular GTPase targeting, there is now increasing evidence that specific
protein-protein interactions are important as well. This review discusses recent findings on
GTPase targeting and proposes a revised model for
GTPase signalling. In this model, the
hypervariable domain acts in conjunction with the
lipid tail to target the
GTPase to specific membrane-associated
protein complexes. Here, local
GTPase activation occurs, leading to subsequent exposure of the effector domain, binding to
effector proteins and the initiation of downstream signalling.
