G-protein signaling - Regulation of CDC42 activity

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

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 [4].

Among known GEFs for CDC42 are FYVE, RhoGEF and PH domain containing 1 and 4 (FGD1, Frabin) [5], [6], Epithelial cell transforming sequence 2 oncogene (ECT2) [7], SPATA13 spermatogenesis associated 13 (ASEF2) [8], Dedicators of cytokinesis 6, 9 and 11 (DOCK6, Zizimin 1, DOCK11) [9], [10], [11], MCF.2 cell line derived transforming sequence-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 is enhanced upon Tyrosine kinase, non-receptor, 2 (ACK1)-dependent phosphorylation [15], [16].

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) [17], Rho GTPase activating protein 17 (Rich1) [18], CDC42 GTPase-activating protein (CDGAP) [19], Breakpoint cluster region (BCR) [20], Active BCR-related gene (ABR) [21], RalA binding protein 1 (RalBP1) [22] and Chimerin (chimaerin) 2 (B-chimaerin), activated by 1,2-diacyl-glycerol (DAG) [23]. 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 [24]. Rho GTPase activating protein 5 (RhoGAP5) GAP activity is abrogated 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 E1B 19kDa 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 and Caspase-3, promote proteosomal degradation of LyGDI [30], [31], while binding of ERM protein Ezrin (VIL2 (ezrin)) removes RhoGDI alpha from binding with CDC42 leading to its activation [32].

References:

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