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G-protein signaling Regulation of CDC42 activity


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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 [1], [2], [3].

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[4].

Among known GEFs for CDC42 are FYVE, RhoGEF and PH domain containing 1 and 4 (FGD1, Frabin ) [5], [6], Epithelial celltransforming sequence 2 oncogene ( ECT2 ) [7], SPATA13spermatogenesis associated 13 ( ASEF2 ) [8], Dedicators ofcytokinesis 6, 9 and 11 ( DOCK6, Zizimin 1, DOCK11 ) [9], [10], [11], MCF.2 cell line derived transformingsequence-like ( DBS ) [12], Differentially expressed in FDCP 6 homolog( DEF6 ) [13] and MCF.2 cell line derived transforming sequence (DBL ) [14]. GEF activity of Dbl towards CDC42 isenhanced upon Tyrosine kinase, non-receptor, 2 ( ACK1) -dependent phosphorylation[15], [16].

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 ) [17], Rho GTPase activating protein 17 (Rich1 ) [18], CDC42 GTPase-activating protein ( CDGAP ) [19], Breakpoint cluster region ( BCR ) [20], Active BCR-relatedgene ( ABR ) [21], RalA binding protein 1 ( RalBP1 ) [22] and Chimerin (chimaerin) 2 ( B-chimaerin ), activated by1,2-diacyl-glycerol ( DAG ) [23]. 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[24]. Rho GTPase activating protein 5 ( RhoGAP5 ) GAP activity isabrogated by RAS p21 protein activator (GTPase activating protein) 1 ( p120GAP )binding [25], [26]. 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 [27].

Rho GDP dissociation inhibitors (GDI) alpha, beta and gamma ( RhoGDI alpha,LyGDI, RhoGDI gamma ) are inhibitors of CDC42 activity [28], [29]. The apoptosis-related cysteine peptidases Caspase-1 andCaspase-3, promote proteosomal degradation of LyGDI [30],[31], while binding of ERM protein Ezrin ( VIL2 (ezrin) ) removesRhoGDI alpha from binding with CDC42 leading to its activation [32].