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    • R-848 As a result of the capability of modulating the dynami

    2021-10-20

    As a result of the capability of modulating the dynamic changes and rearrangement of cytoskeletons, the Rho GTPases, in which RhoA, Cdc42 and Rac1 are best-characterized, have been highlighted as significant contributors for orchestrating neuronal development (Duman et al., 2015, Heasman and Ridley, 2008, Miller et al., 2013, Quinn et al., 2008, Tolias et al., 2011, Van Aelst and Cline, 2004). In CNS development and diseases, the Rho GTPases switch between two states, a GTP-bound active state and a GDP-bound inactive state, which are mediated by three regulatory family (Cherfils and Zeghouf, 2013, Etienne-Manneville and Hall, 2002, Hall and Lalli, 2010, Heasman and Ridley, 2008). Rho R-848 nucleotide exchange factors (RhoGEFs), the positive regulators, promote and catalyze the release of bound GDP for GTP (Cook et al., 2014, Miller et al., 2013, Miyamoto and Yamauchi, 2010); Rho GTPase-activating proteins (RhoGAPs), the negative regulators, is able to increase or stimulate the hydrolysis of Rho GTPases (Fig. 1) (Moon and Zheng 2003). The other negative regulators, Rho guanine nucleotide-dissociation inhibitors (Rho GDIs) can bind to and prevent the dissociation of GDP (Fig. 1) (Olofsson 1999). In response to upstream signaling during different developmental stages, the Rho GTPases were precisely and coordinately mediated by their regulatory proteins. Moreover, the bidirectional regulation of Rho GTPases was necessary and required for spatial and temporal signals to guide downstream biological reactions, such as axon growth or retraction, synapse maturation or elimination, during the dynamics of neuronal morphology formation (Cherfils and Zeghouf, 2013, Tolias et al., 2011, Van Aelst and Cline, 2004). In addition to a deactivator role, increasing evidence has demonstrated that the RhoGAPs, as signaling intermediates, are deployed downstream of key molecules and transduce or link the extracellular and transmembrane signals to the dynamic reorganization of the cytoskeleton, as well as play an irreplaceable role in the regulation of neuronal morphology via GAP-dependent and -independent mechanisms (Fig. 1) (Bacon et al., 2013, Bernards and Settleman, 2005, Moon and Zheng, 2003, Yang and Kazanietz, 2007), including axon growth and guidance, synapse formation and plasticity (Moon and Zheng, 2003, Tolias et al., 2011). Defects or mutations in RhoGAPs also cause axonal and dendritic defects (Tolias et al. 2011), which are commonly recognized as the cause of several CNS diseases. Moreover, interference with RhoGAPs may mediate axon regeneration and synaptic plasticity (Mizuno et al., 2004, Tolias et al., 2011), which may contribute to better outcomes in CNS diseases, such as autism spectrum disorder.
    Basic characteristics of RhoGAPs The first RhoGAP, p50RhoGAP, was discovered 27years ago (Garrett et al. 1989) and was determined to promote the intrinsic GTPase activity of Rho GTPases. Subsequent studies have indicated that a protein sequence composed of approximately 170 amino acids was required and responsible for GAP activity and was named the RhoGAP domain. To date, several RhoGAPs have been reported. A human genome analysis indicated there are approximately 70 GAP domain containing proteins, which is far beyond the number of Rho GTPases. The over-abundance of RhoGAPs indicated that each RhoGAP may play a specialized role, and each GAP activity may be precisely regulated spatially and temporally. For example, several RhoGAPs are widely expressed; however, other RhoGAPs are specifically expressed in the brain, such as the brain-specific GAP Grit and α1-chimaerin. Moreover, an individual RhoGAP may target a specific Rho GTPase. p122RhoGAP and RARhoGAP specifically act for RhoA, whereas α1-chimaerin and ArhGAP15 are Rac1 specific (Tcherkezian and Lamarche-Vane 2007). Moreover, in addition to the GAP domain, nearly all RhoGAPs contain at least 2–3 additional domains, which may interact with different proteins and are implicated in different signaling pathways. For example, the C1 domain of α1-chimaerin may bind to phorbol esters, which, in turn, strengthen the interaction between α1-chimerin and the NMDA receptor (NMDAR) to mediate downstream signaling (Brose et al., 2004, Van de Ven et al., 2005). The Src homology 2 (SH2) or Src homology 3 (SH3) adapter domain of Rho GAPs may aid in the signal transduction of receptor tyrosine kinase pathways (Fig. 2). Thus, RhoGAPs may act as intermediator or scaffold proteins to transduce the signaling pathways between Rho GTPases and other non-Rho GTPase signaling pathways.