The neglected terminators: Rho family GAPs in neutrophils

Abstract

Background: GTPase-activating proteins (GAPs) accelerate the rate of hydrolysis of GTP bound to small GTPases, thereby limiting the prevalence and concentration of the active, GTP-bound form of these proteins. The large number of potential GAPs acting on members of the Rho family of small GTPases raises the question of specificity or redundancy. Results: In this review, we summarize experimental data obtained on the role of Rho family GAPs in neutrophils, highlight cases where more than one GAP is involved in a physiological function and show examples that GAPs can be involved not only in termination but also in initiation of cellular processes. We demonstrate that the expression-level regulation of GAPs may also occur in shortliving cells such as neutrophils. Finally, we provide insight into the existence and structure of molecular complexes in which Rho family GAPs are involved. Conclusion: GAPs play more complex and varied roles than being simple terminators of cellular processes. K E Y W O R D SGTPase activating proteins, Rho-family small GTPases, neutrophils

The role of ARHGAP9: clinical implication and potential function in acute myeloid leukemia

“…Upon immunization, Rho GAPs are critical for innate immunity and adaptive immunity [49][50][51]. Meanwhile, more than 11 members of Rho GAPs participate in various neutrophil functions that belong to adaptive immunity [52]. Given that the overlapping genes were mainly enriched in the immune system and immune tissues, we speculated that ARHGAP9 plays a significant role in the immune response in AML.…”

p190RhoGAPs, the ARHGAP35- and ARHGAP5-Encoded Proteins, in Health and Disease

“…Due to their enzymatic activity consisting of an increased GTP hydrolytic rate and thereby an attenuation of the biological function of small GTPases, GAPs are often labeled as signal terminators. However, thanks to interaction with key partners, GAPs may also function as signal initiators and/or transmitters [29,30]. Function of both p190RhoGAP isoforms is intrinsically linked to RhoA regulation, even if more recently, few roles independently of RhoA were suggested (Figure 3).…”

A novel BRET‐Based GAP assay reveals phosphorylation‐dependent regulation of the RAC‐specific GTPase activating protein ARHGAP25

“…As previously described, ARHGAP25 regulates not only the amount of filamentary actin but, more importantly, actin-depolymerization, and the latter is spatially critical at the cytoplasmic side of the forming phagosome during the engulfment of large particles. 28,32 Therefore, we speculate that the S363A + S379-380A mutant most likely inhibits actin-depolymerization specifically, thereby down-regulating phagocytosis. This could also explain the higher filamentary actin amount and superoxide production since the latter is known to be increased by actin-depolymerization inhibitors (e.g., cytochalasin B).…”

“…Geneticin (G18) was purchased from Gibco (Invitrogen, Waltham, MA, USA). [γ- 32 P]GTP was obtained from the Institute of Isotopes Co. Ltd. (Budapest, Hungary). CRIB-Rluc vector was a kind gift from András Balla, Cerulean-C1 and mVenus-N1 vectors were a gift from Péter Várnai.…”