Pathway Map Details

G-protein signaling_Regulation of CDC42 activity



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VIL2 (ezrin), LyGDI, DAG, ASEF2, p120GAP, FGD1, ECT2, RHG7, DBL, DOCK6, B-chimaerin, RhoGDI gamma, Fyn, DOCK11 , CDC42, DEF6, RhoGDI alpha, BCR, CDGAP, Zizimin 1, Caspase-3, DBS, ACK1, RalBP1, ABR, Caspase-1, RhoGAP5, NIP2, Rich1, Frabin, p200RhoGAP, RhoGAP1, FGFR1

Description:

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:

  1. Cerione RA
    Cdc42: new roads to travel. Trends in cell biology 2004 Mar;14(3):127-32
  2. Etienne-Manneville S
    Cdc42--the centre of polarity. Journal of cell science 2004 Mar 15;117(Pt 8):1291-300
  3. Heasman SJ, Ridley AJ
    Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nature reviews. Molecular cell biology 2008 Sep;9(9):690-701
  4. Denhardt DT
    Signal-transducing protein phosphorylation cascades mediated by Ras/Rho proteins in the mammalian cell: the potential for multiplex signalling. The Biochemical journal 1996 Sep 15;318 ( Pt 3):729-47
  5. Ikeda W, Nakanishi H, Tanaka Y, Tachibana K, Takai Y
    Cooperation of Cdc42 small G protein-activating and actin filament-binding activities of frabin in microspike formation. Oncogene 2001 Jun 14;20(27):3457-63
  6. Hayakawa M, Kitagawa H, Miyazawa K, Kitagawa M, Kikugawa K
    The FWD1/beta-TrCP-mediated degradation pathway establishes a 'turning off switch' of a Cdc42 guanine nucleotide exchange factor, FGD1. Genes to cells : devoted to molecular & cellular mechanisms 2005 Mar;10(3):241-51
  7. Tatsumoto T, Xie X, Blumenthal R, Okamoto I, Miki T
    Human ECT2 is an exchange factor for Rho GTPases, phosphorylated in G2/M phases, and involved in cytokinesis. The Journal of cell biology 1999 Nov 29;147(5):921-8
  8. Hamann MJ, Lubking CM, Luchini DN, Billadeau DD
    Asef2 Functions as a Cdc42 Exchange Factor and is Stimulated by the Release of an Autoinhibitory Module From a Concealed C-Terminal Activation Element. Molecular and cellular biology 2006 Dec 4;
  9. Meller N, Irani-Tehrani M, Ratnikov BI, Paschal BM, Schwartz MA
    The novel Cdc42 guanine nucleotide exchange factor, zizimin1, dimerizes via the Cdc42-binding CZH2 domain. The Journal of biological chemistry 2004 Sep 3;279(36):37470-6
  10. Lin Q, Yang W, Baird D, Feng Q, Cerione RA
    Identification of a DOCK180-related guanine nucleotide exchange factor that is capable of mediating a positive feedback activation of Cdc42. The Journal of biological chemistry 2006 Nov 17;281(46):35253-62
  11. Miyamoto Y, Yamauchi J, Sanbe A, Tanoue A
    Dock6, a Dock-C subfamily guanine nucleotide exchanger, has the dual specificity for Rac1 and Cdc42 and regulates neurite outgrowth. Experimental cell research 2006 Dec 6;
  12. Rossman KL, Worthylake DK, Snyder JT, Siderovski DP, Campbell SL, Sondek J
    A crystallographic view of interactions between Dbs and Cdc42: PH domain-assisted guanine nucleotide exchange. The EMBO journal 2002 Mar 15;21(6):1315-26
  13. Mavrakis KJ, McKinlay KJ, Jones P, Sablitzky F
    DEF6, a novel PH-DH-like domain protein, is an upstream activator of the Rho GTPases Rac1, Cdc42, and RhoA. Experimental cell research 2004 Apr 1;294(2):335-44
  14. Zhang B, Zhang Y, Wang Z, Zheng Y
    The role of Mg2+ cofactor in the guanine nucleotide exchange and GTP hydrolysis reactions of Rho family GTP-binding proteins. The Journal of biological chemistry 2000 Aug 18;275(33):25299-307
  15. Kato J, Kaziro Y, Satoh T
    Activation of the guanine nucleotide exchange factor Dbl following ACK1-dependent tyrosine phosphorylation. Biochemical and biophysical research communications 2000 Feb 5;268(1):141-7
  16. Kato-Stankiewicz J, Ueda S, Kataoka T, Kaziro Y, Satoh T
    Epidermal growth factor stimulation of the ACK1/Dbl pathway in a Cdc42 and Grb2-dependent manner. Biochemical and biophysical research communications 2001 Jun 8;284(2):470-7
  17. Wong CM, Lee JM, Ching YP, Jin DY, Ng IO
    Genetic and epigenetic alterations of DLC-1 gene in hepatocellular carcinoma. Cancer research 2003 Nov 15;63(22):7646-51
  18. Wells CD, Fawcett JP, Traweger A, Yamanaka Y, Goudreault M, Elder K, Kulkarni S, Gish G, Virag C, Lim C, Colwill K, Starostine A, Metalnikov P, Pawson T
    A Rich1/Amot Complex Regulates the Cdc42 GTPase and Apical-Polarity Proteins in Epithelial Cells. Cell 2006 May 5;125(3):535-48
  19. Tcherkezian J, Triki I, Stenne R, Danek EI, Lamarche-Vane N
    The human orthologue of CdGAP is a phosphoprotein and a GTPase-activating protein for Cdc42 and Rac1 but not RhoA. Biology of the cell / under the auspices of the European Cell Biology Organization 2006 Aug;98(8):445-56
  20. Chuang TH, Xu X, Kaartinen V, Heisterkamp N, Groffen J, Bokoch GM
    Abr and Bcr are multifunctional regulators of the Rho GTP-binding protein family. Proceedings of the National Academy of Sciences of the United States of America 1995 Oct 24;92(22):10282-6
  21. Tan EC, Leung T, Manser E, Lim L
    The human active breakpoint cluster region-related gene encodes a brain protein with homology to guanine nucleotide exchange proteins and GTPase-activating proteins. The Journal of biological chemistry 1993 Dec 25;268(36):27291-8
  22. Jullien-Flores V, Dorseuil O, Romero F, Letourneur F, Saragosti S, Berger R, Tavitian A, Gacon G, Camonis JH
    Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity. The Journal of biological chemistry 1995 Sep 22;270(38):22473-7
  23. Yang C, Kazanietz MG
    Chimaerins: GAPs that bridge diacylglycerol signalling and the small G-protein Rac. The Biochemical journal 2007 Apr 1;403(1):1-12
  24. Nakazawa T, Watabe AM, Tezuka T, Yoshida Y, Yokoyama K, Umemori H, Inoue A, Okabe S, Manabe T, Yamamoto T
    p250GAP, a novel brain-enriched GTPase-activating protein for Rho family GTPases, is involved in the N-methyl-d-aspartate receptor signaling. Molecular biology of the cell 2003 Jul;14(7):2921-34
  25. Burbelo PD, Miyamoto S, Utani A, Brill S, Yamada KM, Hall A, Yamada Y
    p190-B, a new member of the Rho GAP family, and Rho are induced to cluster after integrin cross-linking. The Journal of biological chemistry 1995 Dec 29;270(52):30919-26
  26. Kulkarni SV, Gish G, van der Geer P, Henkemeyer M, Pawson T
    Role of p120 Ras-GAP in directed cell movement. The Journal of cell biology 2000 Apr 17;149(2):457-70
  27. Low BC, Lim YP, Lim J, Wong ES, Guy GR
    Tyrosine phosphorylation of the Bcl-2-associated protein BNIP-2 by fibroblast growth factor receptor-1 prevents its binding to Cdc42GAP and Cdc42. The Journal of biological chemistry 1999 Nov 12;274(46):33123-30
  28. Adra CN, Manor D, Ko JL, Zhu S, Horiuchi T, Van Aelst L, Cerione RA, Lim B
    RhoGDIgamma: a GDP-dissociation inhibitor for Rho proteins with preferential expression in brain and pancreas. Proceedings of the National Academy of Sciences of the United States of America 1997 Apr 29;94(9):4279-84
  29. Gorvel JP, Chang TC, Boretto J, Azuma T, Chavrier P
    Differential properties of D4/LyGDI versus RhoGDI: phosphorylation and rho GTPase selectivity. FEBS letters 1998 Jan 30;422(2):269-73
  30. Kwon KB, Park EK, Ryu DG, Park BH
    D4-GDI is cleaved by caspase-3 during daunorubicin-induced apoptosis in HL-60 cells. Experimental & molecular medicine 2002 Mar 31;34(1):32-7
  31. Shao W, Yeretssian G, Doiron K, Hussain SN, Saleh M
    The caspase-1 digestome identifies the glycolysis pathway as a target during infection and septic shock. The Journal of biological chemistry 2007 Oct 24;
  32. Takahashi K, Sasaki T, Mammoto A, Takaishi K, Kameyama T, Tsukita S, Takai Y
    Direct interaction of the Rho GDP dissociation inhibitor with ezrin/radixin/moesin initiates the activation of the Rho small G protein. The Journal of biological chemistry 1997 Sep 12;272(37):23371-5