Abstract
The Ras-related C3 botulinum toxin substrate 1 (Rac1) belongs to the family of Ras-homologous small GTPases. It is well characterized as a membrane-bound signal transducing molecule that is involved in the regulation of cell motility and adhesion as well as cell cycle progression, mitosis, cell death and gene expression. Rac1 also adjusts cellular responses to genotoxic stress by regulating the activity of stress kinases, including c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38 kinases as well as related transcription factors. Apart from being found on the inner side of the outer cell membrane and in the cytosol, Rac1 has also been detected inside the nucleus. Different lines of evidence indicate that genotoxin-induced DNA damage is able to activate nuclear Rac1. The exact mechanisms involved and the biological consequences, however, are unclear. The data available so far indicate that Rac1 might integrate DNA damage independent and DNA damage dependent cellular stress responses following genotoxin treatment, thereby coordinating mechanisms of the DNA damage response (DDR) that are related to DNA repair, survival and cell death.
Highlights
GTP-binding is facilitated by guanine nucleotide exchange factors (GEFs), while intrinsic GTP hydrolysis is stimulated by GTPase activating proteins (GAPs)
Actin cytoskeleton independent functions are regulated in a Rho-dependent manner, including the related C3 botulinum toxin substrate 1 (Rac1)-dependent activation of c-Jun-N-terminal kinases/stress activated protein kinases (JNK/SAPK) and p38 kinases [19,20], which are prototypical kinases activated by genotoxic stress [21] and regulate cell death [22,23]
Apart from regulating signaling pathways that get stimulated in response to endogenous and exogenous stress, Rho GTPases play a key role in the regulation of mechanisms of malignant transformation, tumor growth and metastasis [26,27,28], including the regulation of E-cadherin-dependent cell-cell contacts [29], focal adhesions [30], G1/S phase progression [31] and apoptosis [32]
Summary
Rac belongs to the family of Ras-homologous (Rho) GTPases, which are member of the Ras superfamily of low molecular weight monomeric GTP-binding proteins [1,2,3]. Rho GTPases cycle between an active GTP-bound and an inactive GDP-bound state, thereby acting as molecular switches [4]. In their active form, they are localized at the inner side of the outer cell membrane. Rho GTPases are activated upon binding of ligands to cellular growth factor and cytokine receptors as well as heterotrimeric G-protein coupled receptors [9,10]. GTP-binding is facilitated by guanine nucleotide exchange factors (GEFs), while intrinsic GTP hydrolysis is stimulated by GTPase activating proteins (GAPs). Rho GDI inhibits spontaneous GDP for GTP exchange and GTPase activity. Whether all of these functions of Rho GTPases predominantly depend on membrane-bound Rho proteins or whether nuclear Rho functions are involved as well is still enigmatic
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