Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
Inorganic ion
Predicted metabolite or user's structure
Generic receptor
Receptors with enzyme activity

Normal process
Pathological process
Covalent modifications
Transcription regulation
MicroRNA binding
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

G-protein signaling RhoA regulation pathway

Log In to Post A Comment

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].