Control of adhesion and protrusion in cell migration by Rho GTPases

Abstract

Cell migration is a critical process that underpins a number of physiological and pathological contexts such as the correct functioning of the immune system and the spread of metastatic cancer cells. Central to this process are the Rho family of GTPases, which act as core regulators of cell migration. Rho GTPases are molecular switches that associate with lipid membranes and act to choreograph molecular events that underpin cell migration. Specifically, these GTPases play critical roles in coordinating force generation through driving the formation of cellular protrusions as well as cell-cell and cell-matrix adhesions. Here we provide an update on the many roles of Rho-family GTPases in coordinating protrusion and adhesion formation in the context of cell migration, as well as describing how their activity is controlled to by a variety of complex signalling networks.

Figure 1

Rho GTPases in protrusion formation summary. (i) RhoA can signal to the formin FHOD3, via the ROCK family kinases, to promote the invasion of cancer cells into 3D fibronectin rich ECM. This form on invasive migration occurs downstream of the upregulated endocytic recycling of the α5β1 integrin, and does not require the action of the Arp2/3 complex. (ii) Cdc42 can drive the formation of filopodia by activating the formin FMNL2 and/or Arp2/3. (iii) RhoA-FAM65 interaction can re-orientate the Golgi apparatus towards the leading edge of the cell in 2D environments, facilitating efficient migration. (iv) Fatty acid synthesis alters the biochemical and biophysical properties of the plasma membrane, stabilising the presence of Rho GTPases in the membrane. This may have important implications for understanding how the metabolic state of a cell may affect its ability to migrate. (v) Different GEFs can promote differential Rac1 signalling, either promoting a migratory output by ensuring Rac1 binds to FLI2 (P-Rex1) or preventing a migratory output (Tiam1).

Figure 2

Rho family GTPases in the context of adhesion. (a) Rac1 and CDC42 control the directionality of groups of migrating cells when activated via the mechanical stretch of E-cadherin and P-cadherin respectively. Non-canonical notch signalling leads to the formation of a VE-Cadherin-LAR-TRIO complex that leads to the activation of Rac1. (b) RhoA signalling can promote focal complex maturation, leading to the recruitment of integrin associated proteins. These proteins include the Git1/2-β-Pix complex that binds to paxillin and signals to promote Rac1 signalling and supress RhoA signalling. RhoJ can enhance focal complex turnover, by recruiting the β-Pix-GIT complex in order to block RhoA signalling, blocking RhoA mediated focal adhesion maturation. RhoU, when stabilised by PAK4 can also promote the turnover of focal adhesions.