RhoGAPs

RhoGAPs are a family of regulatory proteins that inactivate members of the Rho family of small GTPases by stimulating their intrinsic GTPase activity. By converting GTP-bound active forms to GDP-bound inactive forms, RhoGAPs help control actin cytoskeleton dynamics, cell shape, adhesion, and motility in many cell types.

Function and mechanism: RhoGAPs contain a RhoGAP domain that engages the active, GTP-bound form of a Rho GTPase and increases the rate of GTP hydrolysis. The catalytic process often involves an arginine finger that stabilizes the transition state, accelerating inactivation. Specificity varies; some GAPs preferentially accelerate GTP hydrolysis on RhoA, Rac1, or Cdc42, while others show broader activity. Regulation occurs through subcellular localization, interactions with lipids or scaffolding proteins, phosphorylation, and feedback from signaling networks.

Structure and regulation: Many RhoGAPs have additional domains (SH3, PH, PDZ, BAR, or ankyrin repeats) that regulate activity or target GAPs to membranes or complexes. Their activity is integrated with guanine nucleotide exchange factors (GEFs) and GDIs to shape Rho GTPase signaling in time and space.

Biological roles: RhoGAPs participate in processes such as lamellipodia and stress fiber formation, focal adhesion turnover, cell migration, and cytokinesis; in neurons they influence axon growth, dendritic spine morphology, and synaptic connectivity; in immune and endothelial cells they regulate barrier function and trafficking.

Clinical relevance: Dysregulation of RhoGAPs is linked to cancer progression and metastasis, and to neurodevelopmental and neurodegenerative disorders, as well as immune dysfunction. Research aims to map GAP specificity, regulation, and interactions to understand disease mechanisms and identify therapeutic targets.

Notable members: The ARHGAP (RhoGAP) family includes ARHGAP1 (p50RhoGAP) and ARHGAP35 (p190RhoGAP), among others, illustrating diversity in substrate preference and regulation.