G-protein signaling - RhoA regulation pathway

RhoA regulation pathway

Ras homolog gene family, member A (RhoA) is a member of a family of small GTPases. Rho GTPases control multiple cellular processes, including actin and microtubule dynamics, gene expression, the cell cycle, cell polarity and membrane transport, through their ability to bind to numerous downstream effectors, which lead to diverse parallel downstream signaling pathways [1], [2].

There are three classes of regulatory proteins that affect the activation state of RhoA molecules: guanine nucleotide exchange factors (GEFs) thatpromote exchange of GTP for GDP; GTPase-activating proteins (GAPs) that enhance the intrinsic GTP-hydrolysis activity, leading to GTPase inactivation; and guaninenucleotide-dissociation inhibitors (GDIs) that bind to prenylated GDP-bound Rho proteins and allow translocation between membranes and the cytosol [2], [3].

RhoA pathway can be activated by different signaling events that lead to various Rho GEFs activation. Insulin-like growth factor 1 (IGF-1) signaling promotes activation of Insulin-like growth factor 1 receptor (IGF-1 receptor) that forms a complex with Rho guanine nucleotide exchange factor (GEF) 12 (LARG) [4]. G-proteins alpha-q/11 and G-protein alpha-12 family can also associate with LARG thus promoting RhoA activation [5], [6], [7], [8]. Activated RhoA may stimulate PTK2 protein tyrosine kinase 2 (FAK1) that phosphorylates LARG, thereby enhancing the activation of RhoA [9], [10]. In addition, G-protein alpha-12 family can activate RhoA by stimulating Rho guanine nucleotide exchange factor (GEF) 1 (ARHGEF1(p115RhoGEF)) [11], [12]. Ephrin-A receptors, activated by Ephrin-A, associate with Neuronal guanine nucleotide exchange factor (Ephexin), which stimulates activity of RhoA [13].

Activated Ras-related C3 botulinum toxin substrate 1 (Rac1) by stimulation MCF.2 cell line derived transforming sequence-like (DBS) activity promotes RhoA activation [14], [15]. RAP1, GTP-GDP dissociation stimulator 1 (Rap1GDS1) bound with Kinesin-associated protein 3 (KAP3) also activates RhoA [16]. Epithelial cell transforming sequence 2 oncogene (ECT2), Rho/rac guanine nucleotide exchange factor (GEF) 2 (ARHGEF2) and Rho guanine nucleotide exchange factor (GEF) 3 (ARHGEF3) are known GEFs for RhoA [17], [18], [19].

Geranylgeranylation by Geranylgeranyltransferase type I (GGTase-I) is also essential for RhoA biological activity [20]. BMX non-receptor tyrosine kinase (BMX) binding to RhoA modulates its activity [21].

There are several known GAPs which negatively regulate RhoA: Myosin IXb [22], Rho GTPase activating protein 26 (GRAF) [23], Rho GTPase activating protein 1 (RhoGAP1) [24] and Rho GTPase-activating protein (p200RhoGAP) stimulated by FYN oncogene related to SRC, FGR, YES (Fyn) [25].

Rho GDP dissociation inhibitors (GDIs) alpha, beta and gamma (RhoGDI alpha, LyGDI, and RhoGDI gamma) bind to RhoA and negatively modulate its activation. GDIs may also be critical for RhoA cellular compartmentalization [26], [27].

Once activated, the GTPases bind to a spectrum of effectors to stimulate downstream signaling pathways. Binding of RhoA to key effectors Rho-associated coiled-coil containing protein kinase 1 (ROCK), Diaphanous homolog 1 (DIA1) and Rhophilin Rho GTPase binding protein 1 (Rhophilin 1) leads to actin polymerization and cytoskeleton rearrangements, Protein kinase N1 (PRK1) is a RhoA effector involved in endosomal trafficking. [1], [28]. Also, RhoA can directly bind and activate Phospholipase D1 phosphatidylcholine-specific (PLD1) [29], [30], [31].

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