Rho/RacGAPs: embarras de richesse?

Abstract

Regulatory proteins such as guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) determine the activity of small GTPases. In the Rho/Rac family, the number of GEFs and GAPs largely exceeds the number of small GTPases, raising the question of specific or overlapping functions. In our recent study we investigated the first time ARHGAP25 at the protein level, determined its activity as RacGAP and showed its involvement in phagocytosis. With the discovery of ARHGAP25, the number of RacGAPs described in phagocytes is increased to six. We provide data that indicate the specific functions of selected Rho/RacGAPs and we show an example of differential regulation of a Rho/Rac family GAP by different kinases. We propose that the abundance of Rho/Rac family GAPs is an important element of the fine spatiotemporal regulation of diverse cellular functions.

Figure 1. Domain structure of selected GAPs with verified RacGAP activity. In case of p190-A the phosphorylation sites, discussed in this paper, are also indicated. Abbreviations: PH, pleckstrin homology domain; CC, coiled coil; SH3, Src Homology 3 domain; C2, calcium-dependent lipid binding domain; P, proline-rich domain; S/T kinase, serine/threonine kinase domain; Sec14, Sec14-like domain; SH2, Src Homology 2 domain; C1, cysteine-rich phorbol ester Binding domain; FF, domains with two conserved phenylalanine residues; PBR, polybasic region; (According to the review of Tcherkezian et al.³)

Figure 2. Differential effect of phosphorylation of p190-A by GSK3β (A and B) or PKCα (C and D) on the substrates Rho and Rac. (A and B). Both priming with cytosol and phosphorylation by GSK3β result in a decrease of the RhoGAP and RacGAP activity of p190-A. (C and D) Phosphorylation by PKCα reverses the modifying effect of acidic phospholipids and renders p190-A a better RhoGAP but a weaker RacGAP.