G-protein signaling RhoA regulation pathway
RhoA regulation pathway
Ras homolog gene family, member A ( RhoA ) is a member of a family of smallGTPases. Rho GTPases control multiple cellular processes, including actin and microtubuledynamics, gene expression, the cell cycle, cell polarity and membrane transport, throughtheir ability to bind to numerous downstream effectors, which lead to diverse paralleldownstream signaling pathways [1], [2].
There are three classes of regulatory proteins that affect the activation state ofRhoA molecules: guanine nucleotide exchange factors (GEFs) thatpromote exchange ofGTP for GDP; GTPase-activating proteins (GAPs) that enhance the intrinsic GTP-hydrolysisactivity, leading to GTPase inactivation; and guaninenucleotide-dissociation inhibitors(GDIs) that bind to prenylated GDP-bound Rho proteins and allow translocation betweenmembranes and the cytosol [3], [2].
RhoA pathway can be activated by different signaling events that lead tovarious Rho GEFs activation. Insulin-like growth factor 1 ( IGF-1 ) signalingpromotes 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-12family can also associate with LARG thus promoting RhoA activation[5], [6], [7], [8]. ActivatedRhoA may stimulate PTK2 protein tyrosine kinase 2 ( FAK1 ) thatphosphorylates LARG, thereby enhancing the activation of RhoA [9], [10]. In addition, G-protein alpha-12 family can activateRhoA 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 exchangefactor ( Ephexin ), which stimulates activity of RhoA [13].
Activated Ras-related C3 botulinum toxin substrate 1 ( Rac1 ) by stimulationMCF.2 cell line derived transforming sequence-like ( DBS ) activity promotesRhoA activation [14], [15]. RAP1, GTP-GDP dissociationstimulator 1 ( Rap1GDS1 ) bound with Kinesin-associated protein 3 ( KAP3 )also activates RhoA [16]. Epithelial cell transforming sequence 2oncogene ( 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 alsoessential for RhoA biological activity [20]. BMX non-receptor tyrosinekinase ( 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], RhoGTPase activating protein 1 ( RhoGAP1 ) [24] and Rho GTPase-activatingprotein ( 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 itsactivation. GDIs may also be critical for RhoA cellular compartmentalization[26], [27].
Once activated, the GTPases bind to a spectrum of effectors to stimulate downstreamsignaling pathways. Binding of RhoA to key effectors Rho-associated coiled-coilcontaining protein kinase 1 ( ROCK ), Diaphanous homolog 1 ( DIA1 ) andRhophilin Rho GTPase binding protein 1 ( Rhophilin 1 ) leads to actinpolymerization and cytoskeleton rearrangements, Protein kinase N1 ( PRK1 ) is aRhoA effector involved in endosomal trafficking. [28], [1]. Also, RhoA can directly bind and activate Phospholipase D1phosphatidylcholine-specific ( PLD1 ) [29], [30], [31].
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