Regulation of CDC42 activity
Cell division cycle 42 (CDC42) is a member of the RAS
superfamily of small GTPases. It plays an essential role in control of cell growth and
polarity in many eukaryotic cells , , .
CDC42 acts as binary switch by cycling between an
inactive (GDP-bound) and an active (GTP-bound) conformational state. Guanine nucleotide
exchange factors (GEFs) are essential for CDC42 activation.
They promote the exchange of GDP for GTP to generate the activated form of
CDC42 capable of recognizing downstream targets .
Among known GEFs for CDC42 are FYVE, RhoGEF and PH domain
containing 1 and 4 (FGD1,
Frabin) , , Epithelial cell
transforming sequence 2 oncogene (ECT2) ,
SPATA13 spermatogenesis associated 13 (ASEF2) , Dedicators of cytokinesis 6, 9 and 11 (DOCK6,
Zizimin 1, DOCK11) , , , MCF.2 cell line derived transforming
sequence-like (DBS) , Differentially
expressed in FDCP 6 homolog (DEF6)  and
MCF.2 cell line derived transforming sequence (DBL) . GEF activity of Dbl towards CDC42
is enhanced upon Tyrosine kinase, non-receptor, 2
(ACK1)-dependent phosphorylation , .
A group of proteins called GTPase-activating proteins (GAPs) inactivates
CDC42 by catalyzing the hydrolysis of GTP to GDP. Main GAPs
for CDC42 are Deleted in liver cancer 1
(RHG7) , Rho GTPase activating protein 17
(Rich1) , CDC42 GTPase-activating protein
(CDGAP) , Breakpoint cluster region
(BCR) , Active BCR-related gene
(ABR) , RalA binding protein 1
(RalBP1)  and Chimerin (chimaerin) 2
(B-chimaerin), activated by 1,2-diacyl-glycerol
(DAG) . Rho GTPase-activating proteins are
also GAPs for CDC42. Rho GTPase-activating protein
(p200RhoGAP) activity is stimulated by FYN oncogene related
to SRC, FGR, YES (Fyn) phosphorylation . Rho
GTPase activating protein 5 (RhoGAP5) GAP activity is
abrogated by RAS p21 protein activator (GTPase activating protein) 1
(p120GAP) binding , .
Fibroblast growth factor receptor 1 (FGFR1) can regulate
activity of CDC42 by binding to BCL2/adenovirus E1B 19kDa
interacting protein 2 (NIP2) coupled with Rho GTPase
activating protein 1 (RhoGAP1) and removing their inhibitory
GAP activity from CDC42 .
Rho GDP dissociation inhibitors (GDI) alpha, beta and gamma (RhoGDI
alpha, LyGDI, RhoGDI
gamma) are inhibitors of CDC42 activity
, . The apoptosis-related cysteine peptidases
Caspase-1 and Caspase-3, promote proteosomal
degradation of LyGDI , ,
while binding of ERM protein Ezrin (VIL2 (ezrin)) removes
RhoGDI alpha from binding with
CDC42 leading to its activation .
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