G-protein signaling Regulation of CDC42 activity
Regulation of CDC42 activity Cell division cycle 42 ( CDC42 ) is a member of the RAS superfamily of smallGTPases. It plays an essential role in control of cell growth and polarity in manyeukaryotic cells , , . CDC42 acts as binary switch by cycling between an inactive (GDP-bound) and anactive (GTP-bound) conformational state. Guanine nucleotide exchange factors (GEFs) areessential for CDC42 activation. They promote the exchange of GDP for GTP togenerate 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 celltransforming sequence 2 oncogene ( ECT2 ) , SPATA13spermatogenesis associated 13 ( ASEF2 ) , Dedicators ofcytokinesis 6, 9 and 11 ( DOCK6, Zizimin 1, DOCK11 ) , , , MCF.2 cell line derived transformingsequence-like ( DBS ) , Differentially expressed in FDCP 6 homolog( DEF6 )  and MCF.2 cell line derived transforming sequence (DBL ) . GEF activity of Dbl towards CDC42 isenhanced upon Tyrosine kinase, non-receptor, 2 ( ACK1) -dependent phosphorylation, . A group of proteins called GTPase-activating proteins (GAPs) inactivates CDC42by catalyzing the hydrolysis of GTP to GDP. Main GAPs for CDC42 are Deleted inliver cancer 1 ( RHG7 ) , Rho GTPase activating protein 17 (Rich1 ) , CDC42 GTPase-activating protein ( CDGAP ) , Breakpoint cluster region ( BCR ) , Active BCR-relatedgene ( ABR ) , RalA binding protein 1 ( RalBP1 )  and Chimerin (chimaerin) 2 ( B-chimaerin ), activated by1,2-diacyl-glycerol ( DAG ) . Rho GTPase-activating proteins arealso GAPs for CDC42. Rho GTPase-activating protein ( p200RhoGAP ) activityis stimulated by FYN oncogene related to SRC, FGR, YES ( Fyn ) phosphorylation. Rho GTPase activating protein 5 ( RhoGAP5 ) GAP activity isabrogated 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 E1B19kDa 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 andCaspase-3, promote proteosomal degradation of LyGDI ,, while binding of ERM protein Ezrin ( VIL2 (ezrin) ) removesRhoGDI alpha from binding with CDC42 leading to its activation .