Cytoskeleton remodeling - CDC42 in cellular processes

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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 [3], [12], [13], [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:

  1. Joberty G, Petersen C, Gao L, Macara IG
    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
  5. Bagrodia S, Cerione RA
    Pak to the future. Trends in cell biology 1999 Sep;9(9):350-5
  6. Jaffer ZM, Chernoff J
    p21-activated kinases: three more join the Pak. The international journal of biochemistry & cell biology 2002 Jul;34(7):713-7
  7. Jung JH, Traugh JA
    Regulation of the interaction of Pak2 with Cdc42 via autophosphorylation of serine 141. The Journal of biological chemistry 2005 Dec 2;280(48):40025-31
  8. Knaus UG, Bokoch GM
    The p21Rac/Cdc42-activated kinases (PAKs). The international journal of biochemistry & cell biology 1998 Aug;30(8):857-62
  9. Zhao J, Pei DS, Zhang QG, Zhang GY
    Down-regulation Cdc42 attenuates neuronal apoptosis through inhibiting MLK3/JNK3 cascade during ischemic reperfusion in rat hippocampus. Cellular signalling 2007 Apr;19(4):831-43
  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 2007 Jan 1;313(1):10-21
  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
  16. Symons M, Derry JM, Karlak B, Jiang S, Lemahieu V, Mccormick F, Francke U, Abo A
    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

  1. Joberty G, Petersen C, Gao L, Macara IG
    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
  5. Bagrodia S, Cerione RA
    Pak to the future. Trends in cell biology 1999 Sep;9(9):350-5
  6. Jaffer ZM, Chernoff J
    p21-activated kinases: three more join the Pak. The international journal of biochemistry & cell biology 2002 Jul;34(7):713-7
  7. Jung JH, Traugh JA
    Regulation of the interaction of Pak2 with Cdc42 via autophosphorylation of serine 141. The Journal of biological chemistry 2005 Dec 2;280(48):40025-31
  8. Knaus UG, Bokoch GM
    The p21Rac/Cdc42-activated kinases (PAKs). The international journal of biochemistry & cell biology 1998 Aug;30(8):857-62
  9. Zhao J, Pei DS, Zhang QG, Zhang GY
    Down-regulation Cdc42 attenuates neuronal apoptosis through inhibiting MLK3/JNK3 cascade during ischemic reperfusion in rat hippocampus. Cellular signalling 2007 Apr;19(4):831-43
  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 2007 Jan 1;313(1):10-21
  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
  16. Symons M, Derry JM, Karlak B, Jiang S, Lemahieu V, Mccormick F, Francke U, Abo A
    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

Target Details

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