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 , .
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 , .
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)
. G-proteins alpha-q/11 and
G-protein alpha-12 family can
also associate with LARG thus promoting
RhoA activation , , , . Activated RhoA may stimulate
PTK2 protein tyrosine kinase 2 (FAK1) that phosphorylates
LARG, thereby enhancing the activation of
RhoA , . In addition,
G-protein alpha-12 family can activate
RhoA by stimulating Rho guanine nucleotide exchange factor
(GEF) 1 (ARHGEF1(p115RhoGEF)) , . Ephrin-A receptors, activated by
Ephrin-A, associate with Neuronal guanine nucleotide
exchange factor (Ephexin), which stimulates activity of
Activated Ras-related C3 botulinum toxin substrate 1
(Rac1) by stimulation MCF.2 cell line derived transforming
sequence-like (DBS) activity promotes
RhoA activation , . RAP1,
GTP-GDP dissociation stimulator 1 (Rap1GDS1) bound with
Kinesin-associated protein 3 (KAP3) also activates
RhoA . 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 , , .
Geranylgeranylation by Geranylgeranyltransferase type I
(GGTase-I) is also essential for
RhoA biological activity . BMX non-receptor
tyrosine kinase (BMX) binding to
RhoA modulates its activity .
There are several known GAPs which negatively regulate
RhoA: Myosin IXb , Rho GTPase activating protein 26 (GRAF) , Rho GTPase activating protein 1 (RhoGAP1)  and Rho GTPase-activating protein (p200RhoGAP)
stimulated by FYN oncogene related to SRC, FGR, YES (Fyn)
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 , .
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. , . Also, RhoA can directly bind and
activate Phospholipase D1 phosphatidylcholine-specific
(PLD1) , , .
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