G-protein signaling - Rac2 regulation pathway

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Rac2 regulation pathway

Ras-related C3 botulinum toxin substrate 2 (Rac2) belongs to family of small Rho guanosine triphosphatases (GTPases) and it is a critical signaling regulator in mammalian cells. Expression of Rac2 is restricted to cells of hematopoietic origin. It plays critical roles in a wide variety of primary hematopoietic cells, including the regulation of adhesion, migration, oxidase activity, and gene expression [1], [2], [3], [4], [5].

Main transcriptional activators of Rac2 promoter are Sp1 and Sp3 transcription factors (SP1 and SP3) [6]. Activation of Rac proteins is mediated by guanine nucleotide exchange factors (GEFs), main GEFs for Rac2 are T-cell lymphoma invasion and metastasis 1 (TIAM1) [7], Phosphatidylinositol 3,4,5-trisphosphate-dependent RAC exchanger 1 (PREX1) [8], [9] and Vav 1 guanine nucleotide exchange factor (VAV-1) [10] which is most efficient in inducing oxidase activity of Rac2 [5].

Rac2 is isoprenylated at its C-terminus by Geranylgeranyltransferase type I (GGTase-I), such modification may influence on Rac2 membrane transport from cytosol [11], [12].

Rac2 activity is inhibited by GTPase-activating proteins (GAPs), known GAPs for Rac2 are Breakpoint cluster region (BCR), Active BCR-related gene (ABR) [13], [14] and Rac GTPase activating protein 1 (RacGAP1) [15], [16].

Activated Rac2 interacts with several effectors which promote activation of important cellular pathways. It was shown that Rac2 can bind and activate Phosphoinositide-3-kinase, regulatory subunit 1 (PI3K reg class IA (p85)) [17]. Also, Rac2 stimulates Nitric oxide (NO) production by interacting with Nitric oxide synthase 2A (iNos) [18], [19]. In addition, Rac2 promotes Phospholipase C, beta 2 (PLC-beta 2) activation and 1,2-diacyl-glycerol (DAG) production [20].

Important effector of Rac2 is p21 protein (Cdc42/Rac)-activated kinase 1 (PAK1). Activated by Rac2, it stimulates activity of NADPH oxidase subunits [21].

NADPH oxidase is a multisubunit complex. It comprises of the Cytochrome b-558, which is a heterodimer composed of a large Cytochrome b-245, beta polypeptide (gp91-phox) and a small Cytochrome b-245, alpha polypeptide (p22-phox) subunit. Oxidase activation is controlled by the recruitment of cytosolic regulatory proteins to the Cytochrome b-558, including the Neutrophil cytosolic factors 1 and 2 (p47-phox and p67-phox) [5]. Rac2 is a critical regulator of NADPH oxidase activity and assembly in phagocytic cells [22], [23], [24]. Ezrin (VIL2(ezrin)) and Radixin (RDX (radixin)) bind to Rho GDP dissociation inhibitor (GDI) alpha (RhoGDI alpha) and remove it from binding with Rac2 in cytosol thus promoting Rac2 binding to p67-phox and translocation to plasma membrane [25], [26], [27], [28]. Rac2 also binds to NADPH oxidase activator 1 (NOXA1) which stimulates activity of p47-phox [29]. p47-phox and p67-phox bind to Cytochrome b-558 subunits and thus promote NADPH oxidase activation, Superoxide anion (O(2)(-)) production and initiation of oxidative stress [28], [30].

References:

  1. Roberts AW, Kim C, Zhen L, Lowe JB, Kapur R, Petryniak B, Spaetti A, Pollock JD, Borneo JB, Bradford GB, Atkinson SJ, Dinauer MC, Williams DA
    Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense. Immunity 1999 Feb;10(2):183-96
  2. Yang FC, Kapur R, King AJ, Tao W, Kim C, Borneo J, Breese R, Marshall M, Dinauer MC, Williams DA
    Rac2 stimulates Akt activation affecting BAD/Bcl-XL expression while mediating survival and actin function in primary mast cells. Immunity 2000 May;12(5):557-68
  3. Yang FC, Atkinson SJ, Gu Y, Borneo JB, Roberts AW, Zheng Y, Pennington J, Williams DA
    Rac and Cdc42 GTPases control hematopoietic stem cell shape, adhesion, migration, and mobilization. Proceedings of the National Academy of Sciences of the United States of America 2001 May 8;98(10):5614-8
  4. Gu Y, Byrne MC, Paranavitana NC, Aronow B, Siefring JE, D'Souza M, Horton HF, Quilliam LA, Williams DA
    Rac2, a hematopoiesis-specific Rho GTPase, specifically regulates mast cell protease gene expression in bone marrow-derived mast cells. Molecular and cellular biology 2002 Nov;22(21):7645-57
  5. Hordijk PL
    Regulation of NADPH oxidases: the role of Rac proteins. Circulation research 2006 Mar 3;98(4):453-62
  6. Ou X, Pollock J, Dinauer MC, Gharehbaghi-Schnell E, Skalnik DG
    Identification and functional characterization of the murine Rac2 gene promoter. DNA and cell biology 1999 Mar;18(3):253-63
  7. Haeusler LC, Blumenstein L, Stege P, Dvorsky R, Ahmadian MR
    Comparative functional analysis of the Rac GTPases. FEBS letters 2003 Dec 18;555(3):556-60
  8. Welch HC, Coadwell WJ, Ellson CD, Ferguson GJ, Andrews SR, Erdjument-Bromage H, Tempst P, Hawkins PT, Stephens LR
    P-Rex1, a PtdIns(3,4,5)P3- and Gbetagamma-regulated guanine-nucleotide exchange factor for Rac. Cell 2002 Mar 22;108(6):809-21
  9. Barber MA, Donald S, Thelen S, Anderson KE, Thelen M, Welch HC
    Membrane translocation of P-Rex1 is mediated by G protein betagamma subunits and phosphoinositide 3-kinase. The Journal of biological chemistry 2007 Oct 12;282(41):29967-76
  10. Ming W, Li S, Billadeau DD, Quilliam LA, Dinauer MC
    The Rac effector p67phox regulates phagocyte NADPH oxidase by stimulating Vav1 guanine nucleotide exchange activity. Molecular and cellular biology 2007 Jan;27(1):312-23
  11. Kinsella BT, Erdman RA, Maltese WA
    Carboxyl-terminal isoprenylation of ras-related GTP-binding proteins encoded by rac1, rac2, and ralA. The Journal of biological chemistry 1991 May 25;266(15):9786-94
  12. Lacy P, Mahmudi-Azer S, Bablitz B, Gilchrist M, Fitzharris P, Cheng D, Man SF, Bokoch GM, Moqbel R
    Expression and translocation of Rac2 in eosinophils during superoxide generation. Immunology 1999 Oct;98(2):244-52
  13. 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
  14. Heisterkamp N, Kaartinen V, van Soest S, Bokoch GM, Groffen J
    Human ABR encodes a protein with GAPrac activity and homology to the DBL nucleotide exchange factor domain. The Journal of biological chemistry 1993 Aug 15;268(23):16903-6
  15. Toure A, Dorseuil O, Morin L, Timmons P, Jegou B, Reibel L, Gacon G
    MgcRacGAP, a new human GTPase-activating protein for Rac and Cdc42 similar to Drosophila rotundRacGAP gene product, is expressed in male germ cells. The Journal of biological chemistry 1998 Mar 13;273(11):6019-23
  16. Tonozuka Y, Minoshima Y, Bao YC, Moon Y, Tsubono Y, Hatori T, Nakajima H, Nosaka T, Kawashima T, Kitamura T
    A GTPase-activating protein binds STAT3 and is required for IL-6-induced STAT3 activation and for differentiation of a leukemic cell line. Blood 2004 Dec 1;104(12):3550-7
  17. Bokoch GM, Vlahos CJ, Wang Y, Knaus UG, Traynor-Kaplan AE
    Rac GTPase interacts specifically with phosphatidylinositol 3-kinase. The Biochemical journal 1996 May 1;315 ( Pt 3):775-9
  18. Kone BC
    Protein-protein interactions controlling nitric oxide synthases. Acta physiologica Scandinavica 2000 Jan;168(1):27-31
  19. Kuncewicz T, Balakrishnan P, Snuggs MB, Kone BC
    Specific association of nitric oxide synthase-2 with Rac isoforms in activated murine macrophages. American journal of physiology. Renal physiology 2001 Aug;281(2):F326-36
  20. Snyder JT, Singer AU, Wing MR, Harden TK, Sondek J
    The pleckstrin homology domain of phospholipase C-beta2 as an effector site for Rac. The Journal of biological chemistry 2003 Jun 6;278(23):21099-104
  21. Martyn KD, Kim MJ, Quinn MT, Dinauer MC, Knaus UG
    p21-activated kinase (Pak) regulates NADPH oxidase activation in human neutrophils. Blood 2005 Dec 1;106(12):3962-9
  22. Abo A, Webb MR, Grogan A, Segal AW
    Activation of NADPH oxidase involves the dissociation of p21rac from its inhibitory GDP/GTP exchange protein (rhoGDI) followed by its translocation to the plasma membrane. The Biochemical journal 1994 Mar 15;298 Pt 3:585-91
  23. Kim C, Dinauer MC
    Rac2 is an essential regulator of neutrophil nicotinamide adenine dinucleotide phosphate oxidase activation in response to specific signaling pathways. Journal of immunology (Baltimore, Md. : 1950) 2001 Jan 15;166(2):1223-32
  24. Diebold BA, Bokoch GM
    Molecular basis for Rac2 regulation of phagocyte NADPH oxidase. Nature immunology 2001 Mar;2(3):211-5
  25. 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
  26. Bretscher A
    Regulation of cortical structure by the ezrin-radixin-moesin protein family. Current opinion in cell biology 1999 Feb;11(1):109-16
  27. Sagesser E
    [The snow crunches under the soles]. Krankenpflege. Soins infirmiers 2004;97(2):24-5
  28. Bokoch GM, Zhao T
    Regulation of the phagocyte NADPH oxidase by Rac GTPase. Antioxidants & redox signaling 2006 Sep-Oct;8(9-10):1533-48
  29. Takeya R, Ueno N, Kami K, Taura M, Kohjima M, Izaki T, Nunoi H, Sumimoto H
    Novel human homologues of p47phox and p67phox participate in activation of superoxide-producing NADPH oxidases. The Journal of biological chemistry 2003 Jul 4;278(27):25234-46
  30. Bokoch GM, Diebold BA
    Current molecular models for NADPH oxidase regulation by Rac GTPase. Blood 2002 Oct 15;100(8):2692-6

  1. Roberts AW, Kim C, Zhen L, Lowe JB, Kapur R, Petryniak B, Spaetti A, Pollock JD, Borneo JB, Bradford GB, Atkinson SJ, Dinauer MC, Williams DA
    Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense. Immunity 1999 Feb;10(2):183-96
  2. Yang FC, Kapur R, King AJ, Tao W, Kim C, Borneo J, Breese R, Marshall M, Dinauer MC, Williams DA
    Rac2 stimulates Akt activation affecting BAD/Bcl-XL expression while mediating survival and actin function in primary mast cells. Immunity 2000 May;12(5):557-68
  3. Yang FC, Atkinson SJ, Gu Y, Borneo JB, Roberts AW, Zheng Y, Pennington J, Williams DA
    Rac and Cdc42 GTPases control hematopoietic stem cell shape, adhesion, migration, and mobilization. Proceedings of the National Academy of Sciences of the United States of America 2001 May 8;98(10):5614-8
  4. Gu Y, Byrne MC, Paranavitana NC, Aronow B, Siefring JE, D'Souza M, Horton HF, Quilliam LA, Williams DA
    Rac2, a hematopoiesis-specific Rho GTPase, specifically regulates mast cell protease gene expression in bone marrow-derived mast cells. Molecular and cellular biology 2002 Nov;22(21):7645-57
  5. Hordijk PL
    Regulation of NADPH oxidases: the role of Rac proteins. Circulation research 2006 Mar 3;98(4):453-62
  6. Ou X, Pollock J, Dinauer MC, Gharehbaghi-Schnell E, Skalnik DG
    Identification and functional characterization of the murine Rac2 gene promoter. DNA and cell biology 1999 Mar;18(3):253-63
  7. Haeusler LC, Blumenstein L, Stege P, Dvorsky R, Ahmadian MR
    Comparative functional analysis of the Rac GTPases. FEBS letters 2003 Dec 18;555(3):556-60
  8. Welch HC, Coadwell WJ, Ellson CD, Ferguson GJ, Andrews SR, Erdjument-Bromage H, Tempst P, Hawkins PT, Stephens LR
    P-Rex1, a PtdIns(3,4,5)P3- and Gbetagamma-regulated guanine-nucleotide exchange factor for Rac. Cell 2002 Mar 22;108(6):809-21
  9. Barber MA, Donald S, Thelen S, Anderson KE, Thelen M, Welch HC
    Membrane translocation of P-Rex1 is mediated by G protein betagamma subunits and phosphoinositide 3-kinase. The Journal of biological chemistry 2007 Oct 12;282(41):29967-76
  10. Ming W, Li S, Billadeau DD, Quilliam LA, Dinauer MC
    The Rac effector p67phox regulates phagocyte NADPH oxidase by stimulating Vav1 guanine nucleotide exchange activity. Molecular and cellular biology 2007 Jan;27(1):312-23
  11. Kinsella BT, Erdman RA, Maltese WA
    Carboxyl-terminal isoprenylation of ras-related GTP-binding proteins encoded by rac1, rac2, and ralA. The Journal of biological chemistry 1991 May 25;266(15):9786-94
  12. Lacy P, Mahmudi-Azer S, Bablitz B, Gilchrist M, Fitzharris P, Cheng D, Man SF, Bokoch GM, Moqbel R
    Expression and translocation of Rac2 in eosinophils during superoxide generation. Immunology 1999 Oct;98(2):244-52
  13. 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
  14. Heisterkamp N, Kaartinen V, van Soest S, Bokoch GM, Groffen J
    Human ABR encodes a protein with GAPrac activity and homology to the DBL nucleotide exchange factor domain. The Journal of biological chemistry 1993 Aug 15;268(23):16903-6
  15. Toure A, Dorseuil O, Morin L, Timmons P, Jegou B, Reibel L, Gacon G
    MgcRacGAP, a new human GTPase-activating protein for Rac and Cdc42 similar to Drosophila rotundRacGAP gene product, is expressed in male germ cells. The Journal of biological chemistry 1998 Mar 13;273(11):6019-23
  16. Tonozuka Y, Minoshima Y, Bao YC, Moon Y, Tsubono Y, Hatori T, Nakajima H, Nosaka T, Kawashima T, Kitamura T
    A GTPase-activating protein binds STAT3 and is required for IL-6-induced STAT3 activation and for differentiation of a leukemic cell line. Blood 2004 Dec 1;104(12):3550-7
  17. Bokoch GM, Vlahos CJ, Wang Y, Knaus UG, Traynor-Kaplan AE
    Rac GTPase interacts specifically with phosphatidylinositol 3-kinase. The Biochemical journal 1996 May 1;315 ( Pt 3):775-9
  18. Kone BC
    Protein-protein interactions controlling nitric oxide synthases. Acta physiologica Scandinavica 2000 Jan;168(1):27-31
  19. Kuncewicz T, Balakrishnan P, Snuggs MB, Kone BC
    Specific association of nitric oxide synthase-2 with Rac isoforms in activated murine macrophages. American journal of physiology. Renal physiology 2001 Aug;281(2):F326-36
  20. Snyder JT, Singer AU, Wing MR, Harden TK, Sondek J
    The pleckstrin homology domain of phospholipase C-beta2 as an effector site for Rac. The Journal of biological chemistry 2003 Jun 6;278(23):21099-104
  21. Martyn KD, Kim MJ, Quinn MT, Dinauer MC, Knaus UG
    p21-activated kinase (Pak) regulates NADPH oxidase activation in human neutrophils. Blood 2005 Dec 1;106(12):3962-9
  22. Abo A, Webb MR, Grogan A, Segal AW
    Activation of NADPH oxidase involves the dissociation of p21rac from its inhibitory GDP/GTP exchange protein (rhoGDI) followed by its translocation to the plasma membrane. The Biochemical journal 1994 Mar 15;298 Pt 3:585-91
  23. Kim C, Dinauer MC
    Rac2 is an essential regulator of neutrophil nicotinamide adenine dinucleotide phosphate oxidase activation in response to specific signaling pathways. Journal of immunology (Baltimore, Md. : 1950) 2001 Jan 15;166(2):1223-32
  24. Diebold BA, Bokoch GM
    Molecular basis for Rac2 regulation of phagocyte NADPH oxidase. Nature immunology 2001 Mar;2(3):211-5
  25. 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
  26. Bretscher A
    Regulation of cortical structure by the ezrin-radixin-moesin protein family. Current opinion in cell biology 1999 Feb;11(1):109-16
  27. Sagesser E
    [The snow crunches under the soles]. Krankenpflege. Soins infirmiers 2004;97(2):24-5
  28. Bokoch GM, Zhao T
    Regulation of the phagocyte NADPH oxidase by Rac GTPase. Antioxidants & redox signaling 2006 Sep-Oct;8(9-10):1533-48
  29. Takeya R, Ueno N, Kami K, Taura M, Kohjima M, Izaki T, Nunoi H, Sumimoto H
    Novel human homologues of p47phox and p67phox participate in activation of superoxide-producing NADPH oxidases. The Journal of biological chemistry 2003 Jul 4;278(27):25234-46
  30. Bokoch GM, Diebold BA
    Current molecular models for NADPH oxidase regulation by Rac GTPase. Blood 2002 Oct 15;100(8):2692-6

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