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:
- 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
- Erickson JW, Cerione RA
Multiple roles for Cdc42 in cell regulation.
Current opinion in cell biology 2001 Apr;13(2):153-7
- 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
- Cerione RA
Cdc42: new roads to travel.
Trends in cell biology 2004 Mar;14(3):127-32
- Bagrodia S, Cerione RA
Pak to the future.
Trends in cell biology 1999 Sep;9(9):350-5
- 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
- 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
- Knaus UG, Bokoch GM
The p21Rac/Cdc42-activated kinases (PAKs).
The international journal of biochemistry & cell biology 1998 Aug;30(8):857-62
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Carlier MF, Ducruix A, Pantaloni D
Signalling to actin: the Cdc42-N-WASP-Arp2/3 connection.
Chemistry & biology 1999 Sep;6(9):R235-40
- 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
- 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
- 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
- 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
- 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
- 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
- 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