G-protein signaling - RhoA regulation pathway

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RhoA regulation pathway

Ras homolog gene family, member A (RhoA) is a member of a family of small GTPases. Rho GTPases control multiple cellular processes, including actin and microtubule dynamics, gene expression, the cell cycle, cell polarity and membrane transport, through their ability to bind to numerous downstream effectors, which lead to diverse parallel downstream signaling pathways [1], [2].

There are three classes of regulatory proteins that affect the activation state of RhoA molecules: guanine nucleotide exchange factors (GEFs) thatpromote exchange of GTP for GDP; GTPase-activating proteins (GAPs) that enhance the intrinsic GTP-hydrolysis activity, leading to GTPase inactivation; and guaninenucleotide-dissociation inhibitors (GDIs) that bind to prenylated GDP-bound Rho proteins and allow translocation between membranes and the cytosol [2], [3].

RhoA pathway can be activated by different signaling events that lead to various Rho GEFs activation. Insulin-like growth factor 1 (IGF-1) signaling promotes activation of Insulin-like growth factor 1 receptor (IGF-1 receptor) that forms a complex with Rho guanine nucleotide exchange factor (GEF) 12 (LARG) [4]. G-proteins alpha-q/11 and G-protein alpha-12 family can also associate with LARG thus promoting RhoA activation [5], [6], [7], [8]. Activated RhoA may stimulate PTK2 protein tyrosine kinase 2 (FAK1) that phosphorylates LARG, thereby enhancing the activation of RhoA [9], [10]. In addition, G-protein alpha-12 family can activate RhoA by stimulating Rho guanine nucleotide exchange factor (GEF) 1 (ARHGEF1(p115RhoGEF)) [11], [12]. Ephrin-A receptors, activated by Ephrin-A, associate with Neuronal guanine nucleotide exchange factor (Ephexin), which stimulates activity of RhoA [13].

Activated Ras-related C3 botulinum toxin substrate 1 (Rac1) by stimulation MCF.2 cell line derived transforming sequence-like (DBS) activity promotes RhoA activation [14], [15]. RAP1, GTP-GDP dissociation stimulator 1 (Rap1GDS1) bound with Kinesin-associated protein 3 (KAP3) also activates RhoA [16]. Epithelial cell transforming sequence 2 oncogene (ECT2), Rho/rac guanine nucleotide exchange factor (GEF) 2 (ARHGEF2) and Rho guanine nucleotide exchange factor (GEF) 3 (ARHGEF3) are known GEFs for RhoA [17], [18], [19].

Geranylgeranylation by Geranylgeranyltransferase type I (GGTase-I) is also essential for RhoA biological activity [20]. BMX non-receptor tyrosine kinase (BMX) binding to RhoA modulates its activity [21].

There are several known GAPs which negatively regulate RhoA: Myosin IXb [22], Rho GTPase activating protein 26 (GRAF) [23], Rho GTPase activating protein 1 (RhoGAP1) [24] and Rho GTPase-activating protein (p200RhoGAP) stimulated by FYN oncogene related to SRC, FGR, YES (Fyn) [25].

Rho GDP dissociation inhibitors (GDIs) alpha, beta and gamma (RhoGDI alpha, LyGDI, and RhoGDI gamma) bind to RhoA and negatively modulate its activation. GDIs may also be critical for RhoA cellular compartmentalization [26], [27].

Once activated, the GTPases bind to a spectrum of effectors to stimulate downstream signaling pathways. Binding of RhoA to key effectors Rho-associated coiled-coil containing protein kinase 1 (ROCK), Diaphanous homolog 1 (DIA1) and Rhophilin Rho GTPase binding protein 1 (Rhophilin 1) leads to actin polymerization and cytoskeleton rearrangements, Protein kinase N1 (PRK1) is a RhoA effector involved in endosomal trafficking. [1], [28]. Also, RhoA can directly bind and activate Phospholipase D1 phosphatidylcholine-specific (PLD1) [29], [30], [31].

References:

  1. Schwartz M
    Rho signalling at a glance. Journal of cell science 2004 Nov 1;117(Pt 23):5457-8
  2. Buchsbaum RJ
    Rho activation at a glance. Journal of cell science 2007 Apr 1;120(Pt 7):1149-52
  3. Longenecker K, Read P, Derewenda U, Dauter Z, Liu X, Garrard S, Walker L, Somlyo AV, Nakamoto RK, Somlyo AP, Derewenda ZS
    How RhoGDI binds Rho. Acta crystallographica. Section D, Biological crystallography 1999 Sep;55(Pt 9):1503-15
  4. Taya S, Inagaki N, Sengiku H, Makino H, Iwamatsu A, Urakawa I, Nagao K, Kataoka S, Kaibuchi K
    Direct interaction of insulin-like growth factor-1 receptor with leukemia-associated RhoGEF. The Journal of cell biology 2001 Nov 26;155(5):809-20
  5. Nielsen B
    Old dialysis membranes: yet another culprit in dialysis treatment. Artificial organs 2000 Oct;24(10):765-6
  6. Chikumi H, Vazquez-Prado J, Servitja JM, Miyazaki H, Gutkind JS
    Potent activation of RhoA by Galpha q and Gq-coupled receptors. The Journal of biological chemistry 2002 Jul 26;277(30):27130-4
  7. Booden MA, Siderovski DP, Der CJ
    Leukemia-associated Rho guanine nucleotide exchange factor promotes G alpha q-coupled activation of RhoA. Molecular and cellular biology 2002 Jun;22(12):4053-61
  8. Sternweis PC, Carter AM, Chen Z, Danesh SM, Hsiung YF, Singer WD
    Regulation of Rho guanine nucleotide exchange factors by G proteins. Advances in protein chemistry 2007;74:189-228
  9. Chikumi H, Fukuhara S, Gutkind JS
    Regulation of G protein-linked guanine nucleotide exchange factors for Rho, PDZ-RhoGEF, and LARG by tyrosine phosphorylation: evidence of a role for focal adhesion kinase. The Journal of biological chemistry 2002 Apr 5;277(14):12463-73
  10. Torsoni AS, Marin TM, Velloso LA, Franchini KG
    RhoA/ROCK signaling is critical to FAK activation by cyclic stretch in cardiac myocytes. American journal of physiology. Heart and circulatory physiology 2005 Oct;289(4):H1488-96
  11. Kozasa T, Jiang X, Hart MJ, Sternweis PM, Singer WD, Gilman AG, Bollag G, Sternweis PC
    p115 RhoGEF, a GTPase activating protein for Galpha12 and Galpha13. Science (New York, N.Y.) 1998 Jun 26;280(5372):2109-11
  12. Mao J, Yuan H, Xie W, Wu D
    Guanine nucleotide exchange factor GEF115 specifically mediates activation of Rho and serum response factor by the G protein alpha subunit Galpha13. Proceedings of the National Academy of Sciences of the United States of America 1998 Oct 27;95(22):12973-6
  13. Shamah SM, Lin MZ, Goldberg JL, Estrach S, Sahin M, Hu L, Bazalakova M, Neve RL, Corfas G, Debant A, Greenberg ME
    EphA receptors regulate growth cone dynamics through the novel guanine nucleotide exchange factor ephexin. Cell 2001 Apr 20;105(2):233-44
  14. Horii Y, Beeler JF, Sakaguchi K, Tachibana M, Miki T
    A novel oncogene, ost, encodes a guanine nucleotide exchange factor that potentially links Rho and Rac signaling pathways. The EMBO journal 1994 Oct 17;13(20):4776-86
  15. 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
  16. Shimizu K, Kawabe H, Minami S, Honda T, Takaishi K, Shirataki H, Takai Y
    SMAP, an Smg GDS-associating protein having arm repeats and phosphorylated by Src tyrosine kinase. The Journal of biological chemistry 1996 Oct 25;271(43):27013-7
  17. Tatsumoto T, Xie X, Blumenthal R, Okamoto I, Miki T
    Human ECT2 is an exchange factor for Rho GTPases, phosphorylated in G2/M phases, and involved in cytokinesis. The Journal of cell biology 1999 Nov 29;147(5):921-8
  18. Kristelly R, Gao G, Tesmer JJ
    Structural determinants of RhoA binding and nucleotide exchange in leukemia-associated Rho guanine-nucleotide exchange factor. The Journal of biological chemistry 2004 Nov 5;279(45):47352-62
  19. Chang YC, Nalbant P, Birkenfeld J, Chang ZF, Bokoch GM
    GEF-H1 couples nocodazole-induced microtubule disassembly to cell contractility via RhoA. Molecular biology of the cell 2008 May;19(5):2147-53
  20. Allal C, Favre G, Couderc B, Salicio S, Sixou S, Hamilton AD, Sebti SM, Lajoie-Mazenc I, Pradines A
    RhoA prenylation is required for promotion of cell growth and transformation and cytoskeleton organization but not for induction of serum response element transcription. The Journal of biological chemistry 2000 Oct 6;275(40):31001-8
  21. Kim O, Yang J, Qiu Y
    Selective activation of small GTPase RhoA by tyrosine kinase Etk through its pleckstrin homology domain. The Journal of biological chemistry 2002 Aug 16;277(33):30066-71
  22. Post PL, Bokoch GM, Mooseker MS
    Human myosin-IXb is a mechanochemically active motor and a GAP for rho. Journal of cell science 1998 Apr;111 ( Pt 7):941-50
  23. Longenecker KL, Zhang B, Derewenda U, Sheffield PJ, Dauter Z, Parsons JT, Zheng Y, Derewenda ZS
    Structure of the BH domain from graf and its implications for Rho GTPase recognition. The Journal of biological chemistry 2000 Dec 8;275(49):38605-10
  24. Zhang B, Zheng Y
    Regulation of RhoA GTP hydrolysis by the GTPase-activating proteins p190, p50RhoGAP, Bcr, and 3BP-1. Biochemistry 1998 Apr 14;37(15):5249-57
  25. Taniguchi S, Liu H, Nakazawa T, Yokoyama K, Tezuka T, Yamamoto T
    p250GAP, a neural RhoGAP protein, is associated with and phosphorylated by Fyn. Biochemical and biophysical research communications 2003 Jun 20;306(1):151-5
  26. Adra CN, Manor D, Ko JL, Zhu S, Horiuchi T, Van Aelst L, Cerione RA, Lim B
    RhoGDIgamma: a GDP-dissociation inhibitor for Rho proteins with preferential expression in brain and pancreas. Proceedings of the National Academy of Sciences of the United States of America 1997 Apr 29;94(9):4279-84
  27. Michaelson D, Silletti J, Murphy G, D'Eustachio P, Rush M, Philips MR
    Differential localization of Rho GTPases in live cells: regulation by hypervariable regions and RhoGDI binding. The Journal of cell biology 2001 Jan 8;152(1):111-26
  28. Watanabe G, Saito Y, Madaule P, Ishizaki T, Fujisawa K, Morii N, Mukai H, Ono Y, Kakizuka A, Narumiya S
    Protein kinase N (PKN) and PKN-related protein rhophilin as targets of small GTPase Rho. Science (New York, N.Y.) 1996 Feb 2;271(5249):645-8
  29. Yamazaki M, Zhang Y, Watanabe H, Yokozeki T, Ohno S, Kaibuchi K, Shibata H, Mukai H, Ono Y, Frohman MA, Kanaho Y
    Interaction of the small G protein RhoA with the C terminus of human phospholipase D1. The Journal of biological chemistry 1999 Mar 5;274(10):6035-8
  30. Walker SJ, Brown HA
    Specificity of Rho insert-mediated activation of phospholipase D1. The Journal of biological chemistry 2002 Jul 19;277(29):26260-7
  31. Su W, Chardin P, Yamazaki M, Kanaho Y, Du G
    RhoA-mediated Phospholipase D1 signaling is not required for the formation of stress fibers and focal adhesions. Cellular signalling 2006 Apr;18(4):469-78

  1. Schwartz M
    Rho signalling at a glance. Journal of cell science 2004 Nov 1;117(Pt 23):5457-8
  2. Buchsbaum RJ
    Rho activation at a glance. Journal of cell science 2007 Apr 1;120(Pt 7):1149-52
  3. Longenecker K, Read P, Derewenda U, Dauter Z, Liu X, Garrard S, Walker L, Somlyo AV, Nakamoto RK, Somlyo AP, Derewenda ZS
    How RhoGDI binds Rho. Acta crystallographica. Section D, Biological crystallography 1999 Sep;55(Pt 9):1503-15
  4. Taya S, Inagaki N, Sengiku H, Makino H, Iwamatsu A, Urakawa I, Nagao K, Kataoka S, Kaibuchi K
    Direct interaction of insulin-like growth factor-1 receptor with leukemia-associated RhoGEF. The Journal of cell biology 2001 Nov 26;155(5):809-20
  5. Nielsen B
    Old dialysis membranes: yet another culprit in dialysis treatment. Artificial organs 2000 Oct;24(10):765-6
  6. Chikumi H, Vazquez-Prado J, Servitja JM, Miyazaki H, Gutkind JS
    Potent activation of RhoA by Galpha q and Gq-coupled receptors. The Journal of biological chemistry 2002 Jul 26;277(30):27130-4
  7. Booden MA, Siderovski DP, Der CJ
    Leukemia-associated Rho guanine nucleotide exchange factor promotes G alpha q-coupled activation of RhoA. Molecular and cellular biology 2002 Jun;22(12):4053-61
  8. Sternweis PC, Carter AM, Chen Z, Danesh SM, Hsiung YF, Singer WD
    Regulation of Rho guanine nucleotide exchange factors by G proteins. Advances in protein chemistry 2007;74:189-228
  9. Chikumi H, Fukuhara S, Gutkind JS
    Regulation of G protein-linked guanine nucleotide exchange factors for Rho, PDZ-RhoGEF, and LARG by tyrosine phosphorylation: evidence of a role for focal adhesion kinase. The Journal of biological chemistry 2002 Apr 5;277(14):12463-73
  10. Torsoni AS, Marin TM, Velloso LA, Franchini KG
    RhoA/ROCK signaling is critical to FAK activation by cyclic stretch in cardiac myocytes. American journal of physiology. Heart and circulatory physiology 2005 Oct;289(4):H1488-96
  11. Kozasa T, Jiang X, Hart MJ, Sternweis PM, Singer WD, Gilman AG, Bollag G, Sternweis PC
    p115 RhoGEF, a GTPase activating protein for Galpha12 and Galpha13. Science (New York, N.Y.) 1998 Jun 26;280(5372):2109-11
  12. Mao J, Yuan H, Xie W, Wu D
    Guanine nucleotide exchange factor GEF115 specifically mediates activation of Rho and serum response factor by the G protein alpha subunit Galpha13. Proceedings of the National Academy of Sciences of the United States of America 1998 Oct 27;95(22):12973-6
  13. Shamah SM, Lin MZ, Goldberg JL, Estrach S, Sahin M, Hu L, Bazalakova M, Neve RL, Corfas G, Debant A, Greenberg ME
    EphA receptors regulate growth cone dynamics through the novel guanine nucleotide exchange factor ephexin. Cell 2001 Apr 20;105(2):233-44
  14. Horii Y, Beeler JF, Sakaguchi K, Tachibana M, Miki T
    A novel oncogene, ost, encodes a guanine nucleotide exchange factor that potentially links Rho and Rac signaling pathways. The EMBO journal 1994 Oct 17;13(20):4776-86
  15. 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
  16. Shimizu K, Kawabe H, Minami S, Honda T, Takaishi K, Shirataki H, Takai Y
    SMAP, an Smg GDS-associating protein having arm repeats and phosphorylated by Src tyrosine kinase. The Journal of biological chemistry 1996 Oct 25;271(43):27013-7
  17. Tatsumoto T, Xie X, Blumenthal R, Okamoto I, Miki T
    Human ECT2 is an exchange factor for Rho GTPases, phosphorylated in G2/M phases, and involved in cytokinesis. The Journal of cell biology 1999 Nov 29;147(5):921-8
  18. Kristelly R, Gao G, Tesmer JJ
    Structural determinants of RhoA binding and nucleotide exchange in leukemia-associated Rho guanine-nucleotide exchange factor. The Journal of biological chemistry 2004 Nov 5;279(45):47352-62
  19. Chang YC, Nalbant P, Birkenfeld J, Chang ZF, Bokoch GM
    GEF-H1 couples nocodazole-induced microtubule disassembly to cell contractility via RhoA. Molecular biology of the cell 2008 May;19(5):2147-53
  20. Allal C, Favre G, Couderc B, Salicio S, Sixou S, Hamilton AD, Sebti SM, Lajoie-Mazenc I, Pradines A
    RhoA prenylation is required for promotion of cell growth and transformation and cytoskeleton organization but not for induction of serum response element transcription. The Journal of biological chemistry 2000 Oct 6;275(40):31001-8
  21. Kim O, Yang J, Qiu Y
    Selective activation of small GTPase RhoA by tyrosine kinase Etk through its pleckstrin homology domain. The Journal of biological chemistry 2002 Aug 16;277(33):30066-71
  22. Post PL, Bokoch GM, Mooseker MS
    Human myosin-IXb is a mechanochemically active motor and a GAP for rho. Journal of cell science 1998 Apr;111 ( Pt 7):941-50
  23. Longenecker KL, Zhang B, Derewenda U, Sheffield PJ, Dauter Z, Parsons JT, Zheng Y, Derewenda ZS
    Structure of the BH domain from graf and its implications for Rho GTPase recognition. The Journal of biological chemistry 2000 Dec 8;275(49):38605-10
  24. Zhang B, Zheng Y
    Regulation of RhoA GTP hydrolysis by the GTPase-activating proteins p190, p50RhoGAP, Bcr, and 3BP-1. Biochemistry 1998 Apr 14;37(15):5249-57
  25. Taniguchi S, Liu H, Nakazawa T, Yokoyama K, Tezuka T, Yamamoto T
    p250GAP, a neural RhoGAP protein, is associated with and phosphorylated by Fyn. Biochemical and biophysical research communications 2003 Jun 20;306(1):151-5
  26. Adra CN, Manor D, Ko JL, Zhu S, Horiuchi T, Van Aelst L, Cerione RA, Lim B
    RhoGDIgamma: a GDP-dissociation inhibitor for Rho proteins with preferential expression in brain and pancreas. Proceedings of the National Academy of Sciences of the United States of America 1997 Apr 29;94(9):4279-84
  27. Michaelson D, Silletti J, Murphy G, D'Eustachio P, Rush M, Philips MR
    Differential localization of Rho GTPases in live cells: regulation by hypervariable regions and RhoGDI binding. The Journal of cell biology 2001 Jan 8;152(1):111-26
  28. Watanabe G, Saito Y, Madaule P, Ishizaki T, Fujisawa K, Morii N, Mukai H, Ono Y, Kakizuka A, Narumiya S
    Protein kinase N (PKN) and PKN-related protein rhophilin as targets of small GTPase Rho. Science (New York, N.Y.) 1996 Feb 2;271(5249):645-8
  29. Yamazaki M, Zhang Y, Watanabe H, Yokozeki T, Ohno S, Kaibuchi K, Shibata H, Mukai H, Ono Y, Frohman MA, Kanaho Y
    Interaction of the small G protein RhoA with the C terminus of human phospholipase D1. The Journal of biological chemistry 1999 Mar 5;274(10):6035-8
  30. Walker SJ, Brown HA
    Specificity of Rho insert-mediated activation of phospholipase D1. The Journal of biological chemistry 2002 Jul 19;277(29):26260-7
  31. Su W, Chardin P, Yamazaki M, Kanaho Y, Du G
    RhoA-mediated Phospholipase D1 signaling is not required for the formation of stress fibers and focal adhesions. Cellular signalling 2006 Apr;18(4):469-78

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