Rho Pathway
Rho is a family of small GTPase proteins within the Ras superfamily composed of seven subgroups: Rho; Rac, Cdc42, RhoD, RhoH/TTF, RhoBTB and Miro plus Rnd (Rnd1, Rnd2, Rnd3(RhoE)), a Rho-related subgroup that binds but does not hydrolyze GTP. The Rnd Rho-like proteins typically inhibit signaling by Rho-GTPases. Members of the Rho (RhoA, RhoC, RhoG, RhoH); Rac (Rac1, Rac2, Rac3, RhoG); Cdc42 (Cdc42, TC10, TLC (TC10-like), Chp, (Wrch-1); RhoD (RhoD and Rif); RhoH/TTF; RhoBTB (RhoBTB1 and RhoBTB2) and Miro (Miro-1, Miro-2) subgroups control a wide variety of cellular processes in including: actin cytoskeletal organization (impacting cell morphology, polarity, motility, vesicular transport, podia formation etc); cell growth, proliferation, differentiation, production of reactive oxygen species (ROS) and survival. The activation/inactivation of Rho-GTPase is modulated by integrated internal signaling and/or extracellular signaling from G-protein coupled receptors (GPCR), integrins and growth factor receptors.
Regulation of Rho proteins occurs at the levels of translocation from cytoplasm to the plasma membrane and GDP/GTP cycling. Rho proteins are inactive in the cytoplasm and activated when associated with the plasma membrane (PM). Regulation of Rho protein translocation involves release from binding proteins, guanine nucleotide dissociation inhibitors (GDI) (RhoGDI), which mask isoprenyl targeting moieties and isoprenyl targeting. Rho is retained in the cytoplasm in soluble RhoGDI/RhoGTPase complexes. Phosphorylation of RhoGDI by RhoGDI kinases; such as P21-activated kinase-1 (PAK1), a downstream effector of Rho proteins, or Src (Src may also phosphorylate and activate some GEFs) releases Rho-GTPases from the complex and allows their movement to the PM.
GDP/GTP cycling is regulated by the countering activities of nucleotide exchange factors (GEFs), which charge the GTPases with GTP and GTPase-activating proteins (RhoGAPs), which stimulate the hydrolysis of GTP and deactivate the GTPases. RhoGEFs typically contain Dbl-homology domains. Some members of the Rho-GEF family include the Vav family (vav1, vav2 and vav3); Tiam1, Grinch; p164; WGEF; Gef10; Smg GDS, Dbl, and the GPCR-trimeric G-protein subunit, Galpha12/13 activated GEFs: p115, PDZ-RhoGEF and LARG. There is an extensive number of RhoGAP proteins that regulate Rho-GTPase signaling. These include the PIP3-dependent ARAP family; the p190 family; the ARHGAP family; cdc4Gap (aka p50RhoGAP); RhoGAP; and p85 of PI3-K. GEF and GAPs are brought proximal to Rho-GTPase by activation of signaling molecules.
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