FilGAP and its close relatives: a mediator of Rho–Rac antagonism that regulates cell morphology and migration

Abstract

Cell migration, phagocytosis and cytokinesis are mechanically intensive cellular processes that are mediated by the dynamic assembly and contractility of the actin cytoskeleton. GAPs (GTPase-activating proteins) control activities of the Rho family proteins including Cdc42, Rac1 and RhoA, which are prominent upstream regulators of the actin cytoskeleton. The present review concerns a class of Rho GAPs, FilGAP (ARHGAP24 gene product) and its close relatives (ARHGAP22 and AHRGAP25 gene products). FilGAP is a GAP for Rac1 and a binding partner of FLNa (filamin A), a widely expressed F-actin (filamentous actin)-cross-linking protein that binds many different proteins that are important in cell regulation. Phosphorylation of FilGAP serine/threonine residues and binding to FLNa modulate FilGAP's GAP activity and, as a result, its ability to regulate cell protrusion and spreading. FLNa binds to FilGAP at F-actin-enriched sites, such as at the leading edge of the cell where Rac1 activity is controlled to inhibit actin assembly. FilGAP then dissociates from FLNa in actin networks by myosin-dependent mechanical deformation of FLNa's FilGAP-binding site to relocate at the plasma membrane by binding to polyphosphoinositides. Since actomyosin contraction is activated downstream of RhoA-ROCK (Rho-kinase), RhoA activity regulates Rac1 through FilGAP by signalling to the force-generating system. FilGAP and the ARHGAP22 gene product also act as mediators between RhoA and Rac1 pathways, which lead to amoeboid and mesenchymal modes of cell movements respectively. Therefore FilGAP and its close relatives are key regulators that promote the reciprocal inhibitory relationship between RhoA and Rac1 in cell shape changes and the mesenchymal-amoeboid transition in tumour cells.

Rapid Remodeling of Invadosomes by Gi-coupled Receptors

“…RhoA and Rac are known to oppose each other at multiple levels, and their activity balance orchestrates cell shape, migration, and invasion (55)(56)(57). Active RhoA can inhibit Rac through activation of a GTPaseactivating protein (58). However, the decrease in Rac activity observed here cannot be attributed to RhoA activation, because endothelin lowered Rac activity without activating RhoA.…”

ADP-ribosylation Factor 6 (ARF6) Bidirectionally Regulates Dendritic Spine Formation Depending on Neuronal Maturation and Activity

“…On the contrary, the developmental expression pattern of RhoA appears to be the opposite in that its levels were low in the early stage of development and increase gradually during development (30). Because it is well known that RhoA and Rac1 have an antagonistic effect to each other (46), together with our current results, Rac1 activity seems to be a key determinant for spine formation and maturation in developing neurons, whereas in mature neurons, RhoA takes over the control, and the balance between RhoA and Rac1 activity regulates the formation and maintenance of mature spine structures.…”

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…ARHGAP24 is a binding partner of filamin A, an F-actin crosslinking protein 292 . ARHGAP24 is a canonical target of the nonsense-mediated mRNA decay (NMD) factor UPF3B that regulates the degradation of mutated transcripts, and mutations in the genes coding for UPF3B have been linked to intellectual disability 293 .…”