Question

Describe the contrasting roles of Rac and RhoA in regulating cell migration.

Answer 1

For all type of cell migration Rac and RhoA play a central role although a relative contribution of each depends on the environment and cell type. Cell migration is essential for the development of multicellular animals. For example, neural crest cells migrate throughout the embryo to form different kinds of cells such as melanocytes, vascular smooth muscle and Schwann cells. They interchange between lamellipodium based and bleb based motility depending on the stiffness and composition of their environment including extracellular matrix components and surrounding cells. Most RhoA are active and stimulate their downstream targets when bound to GTP, and inactive when bound to GDP. RhoA and Rac are the most highly conserved Rho family members that contribute to the regulating cell migration in all animal model organisms.

Under normal conditions, lamellipodium driven migration requires active Rac proteins and indeed local Rac activation is sufficient to drive migration in vivo. Active Rac proteins interact with a WAVE associated complex of proteins. In addition to Rac , RhoA are active in lamellipodial regions and contribute to lamellipodium extension. RhoA is activated right at the front of lamellipodia. It is thought that RhoA activates formins such as mDia proteins at the leading edge of lamellipodia. The Rac activated PAK family of kinases play key roles in promoting integrin based adhesion turnover. RhoA also contribute to this balance. Different Rho family members may be used depending on the cell type and other signalling inputs. Although RhoA is active at the leading edge of lamellipodia high levels of RhoA activity induce actomysin mediated refraction of lamellipodia and play a role of migration. For example, cells switch from lamellipodium driven migration to bleb driven migration when RhoA activity goes up.