RhoGEF

RhoGEF, or Rho guanine nucleotide exchange factor, designates a class of proteins that activate Rho family GTPases by promoting the exchange of GDP for GTP. Through this activity they regulate cytoskeletal dynamics, cell polarity, adhesion, migration, and morphogenesis. RhoGEFs act downstream of receptor signaling to convert inactive GDP-bound GTPases into active GTP-bound forms.

The most studied class is the Dbl family, named after the founding oncoprotein Dbl. Dbl-family GEFs contain a DBL homology (DH) domain responsible for nucleotide exchange, typically followed by a PH domain that binds phosphoinositides and helps membrane targeting. Additional regulatory regions or modular domains control activity and localization.

There is also the DOCK family, which activates Rac and Cdc42 through a DOCK Homology 2 (DHR-2) domain and represents an evolutionarily distinct class of GEFs from the DH–PH family. Together, DH–PH and DOCK-family GEFs constitute the major groups that activate Rho GTPases.

RhoGEF activity is tightly regulated by autoinhibitory interaction, phosphorylation, and binding of adaptor proteins or lipids; upstream signals such as growth factors or mechanical cues can relieve inhibition. Specific RhoGEFs preferentially activate RhoA, Rac1, or Cdc42 to govern processes including actin polymerization, lamellipodia and filopodia formation, focal adhesion dynamics, and cell cycle progression. Dysregulation of RhoGEFs has been linked to cancer, neuropathologies, and developmental disorders.