Regulation of RhoA activity by adhesion molecules and mechanotransduction

Abstract

The low molecular weight GTP-binding protein RhoA regulates many cellular events, including cell migration, organization of the cytoskeleton, cell adhesion, progress through the cell cycle and gene expression. Physical forces influence these cellular processes in part by regulating RhoA activity through mechanotransduction of cell adhesion molecules (e.g. integrins, cadherins, Ig superfamily molecules). RhoA activity is regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) that are themselves regulated by many different signaling pathways. Significantly, the engagement of many cell adhesion molecules can affect RhoA activity in both positive and negative ways. In this brief review, we consider how RhoA activity is regulated downstream from cell adhesion molecules and mechanical force. Finally, we highlight the importance of mechanotransduction signaling to RhoA in normal cell biology as well as in certain pathological states.

Fig. (1)

Mechanical forces in cell physiology. A, Diagrams of external and cell-generated mechanical forces that are applied to cells. Blue arrows depict the types of applied mechanical force vectors on cell bodies. Orange arrows represent the balancing opposing force vectors that coincide with the morphological response of the cell body. B, Transendothelial migration of leukocytes through endothelial cell (EC) junctions at sites of inflammation (red tinted cells) provides a model that likely incorporates all of the types of external and cell-generated forces and various adhesion receptors. Shear stresses are applied to both ECs and the adherent leukocyte due to the flow of blood. The adhesive interactions illustrated during leukocyte transendothelial migration (i.e. EC-EC, EC-leukocyte, and EC-ECM interactions) likely involve combinations of external and cell-generated forces applied through the various cell adhesion molecules: β2- and β1-integrins, ICAM-1, and VE-cadherin. The mechanotransduction by these adhesion receptors contributes to the passage of leukocytes through the endothelium without disrupting this layer.

Fig. (2)

Regulation of RhoA activity by mechanical force on adhesion receptors. Tensional force applied to cell adhesion receptors (e.g. integrins or cadherins) is transduced through the plasma membrane to activate certain Rho GEFs (e.g. LARG and GEF-H1) that promote exchange of GDP with GTP on RhoA. GTP-bound RhoA stimulates downstream effectors (e.g. ROCK and mDia) that regulate actin cytoskeletal dynamics. Rho GAPs shut off RhoA signaling through hydrolysis of GTP to restore inactive GDP-bound RhoA. RhoA signaling is further attenuated by binding of GDIs to RhoA, extraction from the membrane and sequestering in the cytosol.