RhoGDI

Rho GDP-dissociation inhibitors (RhoGDIs) are a family of cytosolic regulatory proteins that modulate the activity and localization of the Rho family of small GTPases, including RhoA, Rac1, and Cdc42. In humans, three genes encode RhoGDI proteins: ARHGDIA (RhoGDI1), ARHGDIB (RhoGDI2), and ARHGDIG (RhoGDI3). These proteins help control the cycling of Rho GTPases between active GTP-bound and inactive GDP-bound states and influence their cellular distribution.

The primary mechanism of RhoGDI action is to bind prenylated, GDP-bound Rho GTPases in the cytosol, forming a soluble complex. This interaction masks the lipid modification that anchors GTPases to membranes and prevents premature activation by guanine nucleotide exchange factors (GEFs). By sequestering GTPases and regulating their membrane association, GDIs limit spontaneous nucleotide exchange and effector signaling, thereby modulating processes such as actin cytoskeleton organization, vesicular trafficking, and cell migration. The GDI–GTPase complex can also shuttle between membranes and the cytosol, contributing to the spatial control of signaling.

Specificity among GDIs varies: they can bind multiple Rho GTPases, but affinities, tissue distribution, and regulatory roles differ among the isoforms. RhoGDI1 is widely expressed and commonly associated with RhoA, Rac1, and Cdc42, while RhoGDI2 and RhoGDI3 show distinct expression patterns and may have preferred interactions in certain contexts.

Dysregulation of RhoGDI expression or function has been linked to altered Rho GTPase signaling in cancer, development, and neurological processes, underscoring their importance in regulating cytoskeletal dynamics and cellular behavior.