Pathway Map Details

G-protein signaling_RAC1 in cellular process



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CDC42, P67-phox, PIP5KI, CYFIP2, HSPC300, 1,2-diacyl-glycerol 3-phosphate, WASF1(WAVE1), P47-phox, 1.6.3.1, NckAP1, Rac1, PAK2, Choline cytoplasm, P22-phox, RhoA, PAK3, GP91-phox, NAD(P)H, PARD6, BAIAP2, 3.1.4.4., PLD1, Phosphatidylcholine, Arp2/3, Actin cytoskeletal, PAK1, NCK1, WASF2, Cytochrome b-558, DBS, POR1, DMPK, PKC-zeta, MLK3(MAP3K11), O(,2), O(,2)('-)

Description:

RAC1 in cellular processes

Ras-related C3 botulinum toxin substrate 1 ( Rac1 ) is a member of the RAS superfamily of small GTPases. It plays an essential role in control of the cell polarity, actin cytoskeleton rearrangements, protein trafficking and directed motility in a vide variety of mammalian cells [1], [2].

GTP-bound Rac1 activates a large number of effector proteins and promotes various signaling pathways. p21 protein (Rac1/Rac)-activated kinases 1-3 ( PAK1, PAK2, PAK3 ) are known as downstream targets of Rac1. The association between the active GTP form of Rac1 and the PBD domain of PAK1-3 promotes PAK1-3 autophosphorylation and activation of Mitogen-activated protein kinases 8-10 ( JNK (MAPK 8-10) ) [3], [4], [5], [6], [7]. Rac1 can also activate JNK pathway via PAK- independent mechanism that involves binding and stimulation of Mitogen-activated protein kinase kinase kinase 11 ( MLK3(MAP3K11) ) [8], [9], [10].

Rac1 is a critical regulator of NADPH oxidase activity and assembly in phagocytic cells [11]. NADPH oxidase is a multisubunit complex that contains Cytochrome b-558, which is a heterodimer composed of the large Cytochrome b-245, beta polypeptide ( gp91-phox ) and small Cytochrome b-245, alpha polypeptide ( p22-phox ) subunits. Activation of the oxidase is controlled by the recruitment to the Cytochrome b-558 of such cytosolic regulatory proteins as Neutrophil cytosolic factors 1 and 2 ( p47-phox and p67-phox ) [11]. Rac1 interacts with p47-phox and p67-phox thus promoting activation of the NADPH oxidase [12], [13].

There are several known pathways through which Rac1 promotes remodeling of the cytoskeleton. One of these pathways is the stimulation by Rac1 of the actin polymerization by activation of WAS protein family, members 1 and 2 ( WASF1(WAVE1) and WASF2 ) [14], [2], [15]. Rac1 binds to NCK-associated protein 1 ( NckAP1 ) and Cytoplasmic FMR1 interacting protein 2 ( CYFIP2 ) and also promotes NCK adaptor protein 1 ( NCK1 ) binding to NckAP1. It inhibits NckAP1 and CYFIP2 binding to WASF1(WAVE1), and promotes release of the active complex of WASF1(WAVE1) and the Chromosome 3 open reading frame 10 ( HSPC300 ). Activated WASF1(WAVE1) stimulates Actin related protein 2/3 complex ( Arp2/3 ) that mediates Actin cytoskeletal polymerization [16]. In addition, Rac1 binds to BAI1-associated protein 2 ( BAIAP2 ) that in turn associates with WASF2. This stimulates Arp2/3 and leads to Actin cytoskeletal polymerization [17], [18], [15]. In addition, Rac1 modulates cytoskeleton remodeling by activating ADP-ribosylation factor interacting protein 2 ( POR1 ) and Phosphatidylinositol-4-phosphate 5-kinase, type 1 ( PIP5KI ) [19], [20], [21].

Rac1 can directly bind to Par-6 partitioning defective 6 homolog ( PARD6 ) that activates Protein kinase C, zeta ( PKC-zeta ). This leads to establishment of the cell polarity and promotes cellular transformation [22], [23], [24].

Activated Rac1 in turn can activate MCF.2 cell line derived transforming sequence-like ( DBS ), a common activator for CDC42 and RhoA [25].

Dystrophia myotonica-protein kinase ( DMPK ) and Phospholipase D1, phosphatidylcholine-specific ( PLD1 ) are also downstream targets of the Rac1 [26], [27].

References:

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    Rho GTPases: biochemistry and biology. Annual review of cell and developmental biology 2005;21:247-69
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    Human Ste20 homologue hPAK1 links GTPases to the JNK MAP kinase pathway. Current biology : CB 1996 May 1;6(5):598-605
  4. Joneson T, McDonough M, Bar-Sagi D, Van Aelst L
    RAC regulation of actin polymerization and proliferation by a pathway distinct from Jun kinase. Science (New York, N.Y.) 1996 Nov 22;274(5291):1374-6
  5. Knaus UG, Bokoch GM
    The p21Rac/Cdc42-activated kinases (PAKs). The international journal of biochemistry & cell biology 1998 Aug;30(8):857-62
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    BLNK required for coupling Syk to PLC gamma 2 and Rac1-JNK in B cells. Immunity 1999 Jan;10(1):117-25
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    The ups and downs of MEK kinase interactions. Cellular signalling 2001 Dec;13(12):863-75
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    Signaling from the small GTP-binding proteins Rac1 and Cdc42 to the c-Jun N-terminal kinase/stress-activated protein kinase pathway. A role for mixed lineage kinase 3/protein-tyrosine kinase 1, a novel member of the mixed lineage kinase family. The Journal of biological chemistry 1996 Nov 1;271(44):27225-8
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    The MAP kinase kinase kinase MLK2 co-localizes with activated JNK along microtubules and associates with kinesin superfamily motor KIF3. The EMBO journal 1998 Jan 2;17(1):149-58
  10. Lambert JM, Karnoub AE, Graves LM, Campbell SL, Der CJ
    Role of MLK3-mediated activation of p70 S6 kinase in Rac1 transformation. The Journal of biological chemistry 2002 Feb 15;277(7):4770-7
  11. Hordijk PL
    Regulation of NADPH oxidases: the role of Rac proteins. Circulation research 2006 Mar 3;98(4):453-62
  12. Diekmann D, Abo A, Johnston C, Segal AW, Hall A
    Interaction of Rac with p67phox and regulation of phagocytic NADPH oxidase activity. Science 1994 Jul 22;265(5171):531-3
  13. Zhao X, Carnevale KA, Cathcart MK
    Human monocytes use Rac1, not Rac2, in the NADPH oxidase complex. The Journal of biological chemistry 2003 Oct 17;278(42):40788-92
  14. Miki H, Suetsugu S, Takenawa T
    WAVE, a novel WASP-family protein involved in actin reorganization induced by Rac. The EMBO journal 1998 Dec 1;17(23):6932-41
  15. Suetsugu S, Kurisu S, Oikawa T, Yamazaki D, Oda A, Takenawa T
    Optimization of WAVE2 complex-induced actin polymerization by membrane-bound IRSp53, PIP(3), and Rac. The Journal of cell biology 2006 May 22;173(4):571-85
  16. Eden S, Rohatgi R, Podtelejnikov AV, Mann M, Kirschner MW
    Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck. Nature 2002 Aug 15;418(6899):790-3
  17. Miki H, Yamaguchi H, Suetsugu S, Takenawa T
    IRSp53 is an essential intermediate between Rac and WAVE in the regulation of membrane ruffling. Nature 2000 Dec 7;408(6813):732-5
  18. Miki H, Takenawa T
    WAVE2 serves a functional partner of IRSp53 by regulating its interaction with Rac. Biochemical and biophysical research communications 2002 Apr 26;293(1):93-9
  19. D'Souza-Schorey C, Boshans RL, McDonough M, Stahl PD, Van Aelst L
    A role for POR1, a Rac1-interacting protein, in ARF6-mediated cytoskeletal rearrangements. The EMBO journal 1997 Sep 1;16(17):5445-54
  20. Tolias KF, Hartwig JH, Ishihara H, Shibasaki Y, Cantley LC, Carpenter CL
    Type Ialpha phosphatidylinositol-4-phosphate 5-kinase mediates Rac-dependent actin assembly. Current biology : CB 2000 Feb 10;10(3):153-6
  21. Weernink PA, Meletiadis K, Hommeltenberg S, Hinz M, Ishihara H, Schmidt M, Jakobs KH
    Activation of type I phosphatidylinositol 4-phosphate 5-kinase isoforms by the Rho GTPases, RhoA, Rac1, and Cdc42. The Journal of biological chemistry 2004 Feb 27;279(9):7840-9
  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. Cheng L, Mahon GM, Kostenko EV, Whitehead IP
    Pleckstrin homology domain-mediated activation of the rho-specific guanine nucleotide exchange factor Dbs by Rac1. The Journal of biological chemistry 2004 Mar 26;279(13):12786-93
  26. Shimizu M, Wang W, Walch ET, Dunne PW, Epstein HF
    Rac-1 and Raf-1 kinases, components of distinct signaling pathways, activate myotonic dystrophy protein kinase. FEBS letters 2000 Jun 23;475(3):273-7
  27. Farquhar MJ, Powner DJ, Levine BA, Wright MH, Ladds G, Hodgkin MN
    Interaction of PLD1b with actin in antigen-stimulated mast cells. Cellular signalling 2007 Feb;19(2):349-58