Pathway maps

Cytoskeleton remodeling_CDC42 in cellular processes
Cytoskeleton remodeling_CDC42 in cellular processes

Object List (links open in MetaCore):

PAK1, COPG2, CEP3, Arp2/3, CDC42, Destrin, LIMK2, c-Raf-1, Actin cytoskeletal, PAK3, N-WASP, MLK3(MAP3K11), PKC-zeta, PARD6, CEP2, LIMK1, Cofilin, WASP, PAK2, SPEC1, MRCKalpha, PAK4

Description

CDC42 in cellular processes

Cell division cycle 42 ( CDC42 ) is a member of the RAS superfamily of small GTPases and plays an essential role in control of cell polarity, actin cytoskeleton rearrangements, protein trafficking and directed cell movements in a vide variety of mammalian cells [1], [2], [3], [4]. CDC42 is activated by GEFs (Guanine Nucleotide Exchange Factors), and repressed by GAPs (GTPase- Activating Proteins).

GTP-bound CDC42 activates a large number of effector proteins and promotes different signaling pathways. p21 protein (Cdc42/Rac)-activated kinases 1-4 ( PAK1, PAK2, PAK3, PAK4 ) are known downstream targets of CDC42 [5], [6]. The association between the active GTP form of CDC42 and the PBD domain of PAK1-4 promotes PAK1-4 autophosphorylation [7]. All four PAKs are capable to promote Mitogen-activated protein kinases 8-10 ( JNK (MAPK 8-10) ) signaling activation that leads to cytoskeletal rearrangements and cell motility [8].

CDC42 can activate JNK pathway also by binding and stimulation of Mitogen-activated protein kinase kinase kinase 11 ( MLK3(MAP3K11) ) [9].

Binding of CDC42 small effector 1 ( SPEC1 ) to CDC42 suppresses CDC42 -induced JNK activation and cytoskeleton remodeling [10], [11].

CDC42 promotes changes in actin cytoskeleton by several pathways. CDC42 activates PAK1, PAK4 and CDC42 binding protein kinase alpha ( MRCKalpha ) which phosphorylate LIM domain kinases 1 and 2 ( LIMK1 and LIMK2 ) and they subsequently phosphorylate and inhibit Cofilin and Destrin (actin depolymerizing factor) ( Destrin ). This leads to actin polymerization and stimulation of filopodia and stress fibers formation [12], [13], [3], [14].

PAK3 stimulated by CDC42 induces v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 ) signaling [15].

CDC42 induces actin cytoskeleton changes also by activating Wiskott-Aldrich syndrome ( WASP ) and Wiskott-Aldrich syndrome-like ( N-WASP ) [16], [17], which binds to Actin related protein 2/3 complex ( Arp2/3 ) and this leads to Actin cytoskeletal polymerization and filopodia formation [18], [19].

And finally, CDC42 promotes cytoskeleton remodeling by binding to CDC42 effector proteins 2 and 3 ( CEP2 and CEP3 ) [20], [21].

CDC42 can directly bind to Par-6 partitioning defective 6 homolog ( PARD6 ) which activates Protein kinase C, zeta ( PKC-zeta ), and this leads to establishment of cell polarity and promotes cellular transformation [22], [23], [24]. Also CDC42 induces cellular transformation by associating with the Coatomer protein complex, subunit gamma 2 ( COPG2 ) [25].

References:

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    The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42. Nature cell biology 2000 Aug;2(8):531-9
  2. Erickson JW, Cerione RA
    Multiple roles for Cdc42 in cell regulation. Current opinion in cell biology 2001 Apr;13(2):153-7
  3. Sumi T, Matsumoto K, Shibuya A, Nakamura T
    Activation of LIM kinases by myotonic dystrophy kinase-related Cdc42-binding kinase alpha. The Journal of biological chemistry 2001 Jun 22;276(25):23092-6
  4. Cerione RA
    Cdc42: new roads to travel. Trends in cell biology 2004 Mar;14(3):127-32
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  10. Pirone DM, Fukuhara S, Gutkind JS, Burbelo PD
    SPECs, small binding proteins for Cdc42. The Journal of biological chemistry 2000 Jul 28;275(30):22650-6
  11. Ching KH, Kisailus AE, Burbelo PD
    Biochemical characterization of distinct regions of SPEC molecules and their role in phagocytosis. Experimental cell research 2006 Sep 20;
  12. Edwards DC, Sanders LC, Bokoch GM, Gill GN
    Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics. Nature cell biology 1999 Sep;1(5):253-9
  13. Sumi T, Matsumoto K, Takai Y, Nakamura T
    Cofilin phosphorylation and actin cytoskeletal dynamics regulated by rho- and Cdc42-activated LIM-kinase 2. The Journal of cell biology 1999 Dec 27;147(7):1519-32
  14. Dan C, Kelly A, Bernard O, Minden A
    Cytoskeletal changes regulated by the PAK4 serine/threonine kinase are mediated by LIM kinase 1 and cofilin. The Journal of biological chemistry 2001 Aug 24;276(34):32115-21
  15. Sun H, King AJ, Diaz HB, Marshall MS
    Regulation of the protein kinase Raf-1 by oncogenic Ras through phosphatidylinositol 3-kinase, Cdc42/Rac and Pak. Current biology : CB 2000 Mar 9;10(5):281-4
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    Wiskott-Aldrich syndrome protein, a novel effector for the GTPase CDC42Hs, is implicated in actin polymerization. Cell 1996 Mar 8;84(5):723-34
  17. Torres E, Rosen MK
    Protein-tyrosine kinase and GTPase signals cooperate to phosphorylate and activate Wiskott-Aldrich syndrome protein (WASP)/neuronal WASP. The Journal of biological chemistry 2006 Feb 10;281(6):3513-20
  18. Carlier MF, Ducruix A, Pantaloni D
    Signalling to actin: the Cdc42-N-WASP-Arp2/3 connection. Chemistry & biology 1999 Sep;6(9):R235-40
  19. Welch MD
    The world according to Arp: regulation of actin nucleation by the Arp2/3 complex. Trends in cell biology 1999 Nov;9(11):423-7
  20. Joberty G, Perlungher RR, Macara IG
    The Borgs, a new family of Cdc42 and TC10 GTPase-interacting proteins. Molecular and cellular biology 1999 Oct;19(10):6585-97
  21. Hirsch DS, Pirone DM, Burbelo PD
    A new family of Cdc42 effector proteins, CEPs, function in fibroblast and epithelial cell shape changes. The Journal of biological chemistry 2001 Jan 12;276(2):875-83
  22. Qiu RG, Abo A, Steven Martin G
    A human homolog of the C. elegans polarity determinant Par-6 links Rac and Cdc42 to PKCzeta signaling and cell transformation. Current biology : CB 2000 Jun 15;10(12):697-707
  23. Lin D, Edwards AS, Fawcett JP, Mbamalu G, Scott JD, Pawson T
    A mammalian PAR-3-PAR-6 complex implicated in Cdc42/Rac1 and aPKC signalling and cell polarity. Nature cell biology 2000 Aug;2(8):540-7
  24. Johansson A, Driessens M, Aspenstrom P
    The mammalian homologue of the Caenorhabditis elegans polarity protein PAR-6 is a binding partner for the Rho GTPases Cdc42 and Rac1. Journal of cell science 2000 Sep;113 ( Pt 18):3267-75
  25. Wu WJ, Erickson JW, Lin R, Cerione RA
    The gamma-subunit of the coatomer complex binds Cdc42 to mediate transformation. Nature 2000 Jun 15;405(6788):800-4