Rhofamily

Rhofamily, commonly referred to as the Rho family, is a group of small GTPases within the Ras superfamily. These proteins act as molecular switches that regulate a wide range of cellular processes by cycling between active GTP-bound and inactive GDP-bound states. The activity of Rho proteins is controlled by regulators that accelerate nucleotide exchange or hydrolysis, as well as by inhibitors that sequester the proteins in the cytosol.

Members and subfamilies: The best characterized members are RhoA, RhoB, and RhoC, along with related proteins such as Rac1-3 and Cdc42, which together coordinate the organization of the actin cytoskeleton. Other less-studied Rho family members include RhoD, RhoV, and several atypical Rho proteins. The family governs diverse signaling pathways through distinct effector interactions.

Regulation and effectors: Rho proteins are activated by guanine nucleotide exchange factors (GEFs) and inactivated by GTPase-activating proteins (GAPs); GDP-dissociation inhibitors (GDIs) regulate subcellular localization and trafficking. Upon activation, Rho proteins interact with effector molecules such as ROCK1/2 (Rho-associated kinases), mDia/formins, PAK kinases, and WAVE complexes, translating GTP binding into cytoskeletal rearrangements.

Functions: They regulate actin polymerization, stress fiber formation, focal adhesions, and cell polarity. Through these activities, Rho proteins influence cell adhesion, migration, division, vesicle trafficking, and certain gene expression programs.

Clinical and research relevance: Dysregulation of Rho signaling is linked to cancer progression and metastasis, fibrosis, and neurological disorders. Components of the Rho pathway, especially ROCK kinases, are targets of pharmacological inhibitors used in research and some clinical settings.

History: The Rho family was identified in the 1980s as Ras-related GTPases. The name reflects its status as a Ras homolog with a conserved role in cytoskeletal regulation.