Signal transduction pathways in chronic inflammatory autoimmune disease: Small GTPases

Open Rheumatology Journal

Volumn 6, Issue SPEC. ISSUE 2, 2012, Pages 259-272

  Reedquist, Kris A ^a   Tak, Paul P ^a  

^a UNIVERSITY OF AMSTERDAM   (Netherlands)

Author keywords

Farnesyltransferase inhibitors; GTPases; Matrix metalloproteinases; Systemic lupus erythematosus

Indexed keywords

4 AMINO 6 [2 [[4 (DIETHYLAMINO) 1 METHYLBUTYL]AMINO] 6 METHYL 4 PYRIMIDINYL] 2 METHYLQUINOLINE; ABATACEPT; ATORVASTATIN; CD28 ANTIGEN; CERIVASTATIN; FLUINDOSTATIN; GUANOSINE TRIPHOSPHATASE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; INTERLEUKIN 1BETA; INTERLEUKIN 6; INTERLEUKIN 8; INTERSTITIAL COLLAGENASE; K RAS PROTEIN; MITOGEN ACTIVATED PROTEIN KINASE; PITAVASTATIN; PROTEIN FARNESYLTRANSFERASE INHIBITOR; RAC1 PROTEIN; RAC2 PROTEIN; RAP PROTEIN; RAP1 PROTEIN; RAS PROTEIN; RHO GUANINE NUCLEOTIDE BINDING PROTEIN; RHO KINASE INHIBITOR; SIMVASTATIN; STRESS ACTIVATED PROTEIN KINASE; STROMELYSIN; T LYMPHOCYTE RECEPTOR; TUMOR NECROSIS FACTOR ALPHA; UNINDEXED DRUG; VITRONECTIN;

ARTHRALGIA; ARTHRITIS; AUTOIMMUNE DISEASE; CHRONIC INFLAMMATION; DRUG EFFICACY; DRUG TARGETING; GENETIC MANIPULATION; HUMAN; IMMUNOPHENOTYPING; NONHUMAN; PRIORITY JOURNAL; REVIEW; RHEUMATOID ARTHRITIS; SIGNAL TRANSDUCTION; SYSTEMIC LUPUS ERYTHEMATOSUS;

EID: 84870979274     PISSN: None     EISSN: 18743129     Source Type: Journal    
DOI: 10.2174/1874312901206010259     Document Type: Review

References (168)

1. Fassbender HG. Histomorphological basis of articular cartilage destruction in rheumatoid arthritis. Coll Relat Res 1983; 3: 141-55.
2. Fassbender HG. What destroys the joint in rheumatoid arthritis? Arch Orthop Trauma Surg 1998; 117: 2-7.
3. Mohr W, Beneke G, Mohing W. Proliferation of synovial lining cells and fibroblasts. Ann Rheum Dis 1975; 34: 219-24.
4. Lafyatis R, Remmers EF, Roberts AB, Yocum DE, Sporn MB, Wilder RL. Anchorage-independent growth of synoviocytes from arthritic and normal joints. Stimulation by exogenous plateletderived growth factor and inhibition by transforming growth factorbeta and retinoids. J Clin Invest 1989; 83: 1267-76.
5. Trabandt A, Aicher WK, Gay RE, et al. Expression of the collagenolytic and Ras-induced cysteine proteinase cathepsin L and proliferation-associated oncogenes in synovial cells of MRL/I mice and patients with rheumatoid arthritis. Matrix 1990; 10: 349-61.
6. Lefevre S, Knedla A, Tennie C, et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat Med 2009; 15: 1414-20.
7. Kasperkovitz PV, Timmer TC, Smeets TJ, et al. Fibroblast-like synoviocytes derived from patients with rheumatoid arthritis show the imprint of synovial tissue heterogeneity: evidence of a link between an increased myofibroblast-like phenotype and highinflammation synovitis. Arthritis Rheum 2005; 52: 430-41.
8. Tolboom TC, Pieterman E, van der Laan WH, et al. Invasive properties of fibroblast-like synoviocytes: correlation with growth characteristics and expression of MMP-1, MMP-3, and MMP-10. Ann Rheum Dis 2002; 61: 975-80.
9. Tolboom TC, van der Helm-Van Mil AH, Nelissen RG, Breedveld FC, Toes RE, Huizinga TW. Invasiveness of fibroblast-like synoviocytes is an individual patient characteristic associated with the rate of joint destruction in patients with rheumatoid arthritis. Arthritis Rheum 2005; 52: 1999-2002.
10. Gay S, Gay RE. Cellular basis and oncogene expression of rheumatoid joint destruction. Rheumatol Int 1989; 9: 105-13.
11. Firestein GS, Echeverri F, Yeo M, Zvaifler NJ, Green DR. Somatic mutations in the p53 tumor suppressor gene in rheumatoid arthritis synovium. Proc Natl Acad Sci USA 1997; 94: 10895-900.
12. Roivainen A, Jalava J, Pirila L, Yli-Jama T, Tiusanen H, Toivanen P. H-ras oncogene point mutations in arthritic synovium. Arthritis Rheum 1997; 40: 1636-43.
13. Roivainen A, Zhu F, Sipola E, Yli-Jama T, Toivanen P. Failure to verify H-ras mutations in arthritic synovium: comment on the article by Roivainen et al. Arthritis Rheum 2001; 44: 2705.
14. Klinman DM, Mushinski JF, Honda M, Ishigatsubo Y, Mountz JD, Raveche ES et al. Oncogene expression in autoimmune and normal peripheral blood mononuclear cells. J Exp Med 1986; 163: 1292-307.
15. Pap T, Franz JK, Hummel KM, Jeisy E, Gay R, Gay S. Activation of synovial fibroblasts in rheumatoid arthritis: lack of Expression of the tumour suppressor PTEN at sites of invasive growth and destruction. Arthritis Res 2000; 2: 59-64.
16. Tak PP, Smeets TJ, Boyle DL, et al. p53 overexpression in synovial tissue from patients with early and longstanding rheumatoid arthritis compared with patients with reactive arthritis and osteoarthritis. Arthritis Rheum 1999; 42: 948-53.
17. Tas SW, Remans PH, Reedquist KA, Tak PP. Signal transduction pathways and transcription factors as therapeutic targets in inflammatory disease: towards innovative antirheumatic therapy. Curr Pharm Des 2005; 11: 581-611.
18. Takai Y, Sasaki T, Matozaki T. Small GTP-binding proteins. Physiol Rev 2001; 81: 153-208.
19. Colicelli J. Human RAS superfamily proteins and related GTPases. Sci STKE 2004; 2004: RE13.
20. Fransson A, Ruusala A, Aspenstrom P. Atypical Rho GTPases have roles in mitochondrial homeostasis and apoptosis. J Biol Chem 2003; 278: 6495-502.
21. Berthold J, Schenkova K, Rivero F. Rho GTPases of the RhoBTB subfamily and tumorigenesis. Acta Pharmacol Sin 2008; 29: 285-95.
22. Bos JL, Rehmann H, Wittinghofer A. GEFs and GAPs: critical elements in the control of small G proteins. Cell 2007; 129: 865-77.
23. Esteban LM, Vicario-Abejon C, Fernandez-Salguero P, et al. Targeted genomic disruption of H-ras and N-ras, individually or in combination, reveals the dispensability of both loci for mouse growth and development. Mol Cell Biol 2001; 21: 1444-52.
24. Plowman SJ, Williamson DJ, O'Sullivan MJ, et al. While K-ras is essential for mouse development, expression of the K-ras 4A splice variant is dispensable. Mol Cell Biol 2003; 23: 9245-50.
25. Buday L, Downward J. Many faces of Ras activation. Biochim Biophys Acta 2008; 1786: 178-87.
26. Buday L, Downward J. Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Cell 1993; 73: 611-20.
27. Byrne JL, Paterson HF, Marshall CJ. p21Ras activation by the guanine nucleotide exchange factor Sos, requires the Sos/Grb2 interaction and a second ligand-dependent signal involving the Sos N-terminus. Oncogene 1996; 13: 2055-65.
28. Tognon CE, Kirk HE, Passmore LA, Whitehead IP, Der CJ, Kay RJ. Regulation of RasGRP via a phorbol ester-responsive C1 domain. Mol Cell Biol 1998; 18: 6995-7008.
29. Clyde-Smith J, Silins G, Gartside M, et al. Characterization of RasGRP2, a plasma membrane-targeted, dual specificity Ras/Rap exchange factor. J Biol Chem 2000; 275: 32260-7.
30. Lorenzo PS, Kung JW, Bottorff DA, Garfield SH, Stone JC, Blumberg PM. Phorbol esters modulate the ras exchange factor RasGRP3. Cancer Res 2001; 61: 943-9.
31. Katsoulotos GP, Qi M, Qi JC, et al. The diacylglycerol-dependent translocation of Ras guanine nucleotide-releasing protein 4 inside a human mast cell line results in substantial phenotypic changes, including expression of interleukin 13 receptor alpha 2. J Biol Chem 2008; 283: 1610-21.
32. Tian X, Feig LA. Basis for signaling specificity difference between Sos and Ras-GRF guanine nucleotide exchange factors. J Biol Chem 2001; 276: 47248-56.
33. Jones MK, Jackson JH. Ras-GRF activates Ha-Ras, but not N-Ras or K-Ras 4B, protein in vivo. J Biol Chem 1998; 273: 1782-7.
34. Brown MD, Sacks DB. Protein scaffolds in MAP kinase signalling. Cell Signal 2009; 21: 462-9.
35. Hawkins PT, Anderson KE, Davidson K, Stephens LR. Signalling through Class I PI3Ks in mammalian cells. Biochem Soc Trans 2006; 34: 647-62.
36. Hancock JF. Ras proteins: different signals from different locations. Nat Rev Mol Cell Biol 2003; 4: 373-84.
37. Yan J, Roy S, Apolloni A, Lane A, Hancock JF. Ras isoforms vary in their ability to activate Raf-1 and phosphoinositide 3-kinase. J Biol Chem 1998; 273: 24052-6.
38. Voice JK, Klemke RL, Le A, Jackson JH. Four human ras homologs differ in their abilities to activate Raf-1, induce transformation, and stimulate cell motility. J Biol Chem 1999; 274: 17164-70.
39. Castellano E, De Las RJ, Guerrero C, Santos E. Transcriptional networks of knockout cell lines identify functional specificities of H-Ras and N-Ras: significant involvement of N-Ras in biotic and defense responses. Oncogene 2007; 26: 917-33.
40. Castellano E, Guerrero C, Nunez A, De Las RJ, Santos E. Serumdependent transcriptional networks identify distinct functional roles for H-Ras and N-Ras during initial stages of the cell cycle. Genome Biol 2009; 10: R123.
41. Martinez-Salgado C, Fuentes-Calvo I, Garcia-Cenador B, Santos E, Lopez-Novoa JM. Involvement of H-and N-Ras isoforms in transforming growth factor-beta1-induced proliferation and in collagen and fibronectin synthesis. Exp Cell Res 2006; 312: 2093-106.
42. Genot E, Cantrell DA. Ras regulation and function in lymphocytes. Curr Opin Immunol 2000; 12: 289-94.
43. Perez dC, I, Diaz R, Malumbres M, et al. Mice deficient for N-ras: impaired antiviral immune response and T-cell function. Cancer Res 2003; 63: 1615-22.
44. Thomas R, Turner M, Cope AP. High avidity autoreactive T cells with a low signalling capacity through the T-cell receptor: central to rheumatoid arthritis pathogenesis? Arthritis Res Ther 2008; 10: 210.
45. Priatel JJ, Teh SJ, Dower NA, Stone JC, Teh HS. RasGRP1 transduces low-grade TCR signals which are critical for T cell development, homeostasis, and differentiation. Immunity 2002; 17: 617-27.
46. Layer K, Lin G, Nencioni A, et al. Autoimmunity as the consequence of a spontaneous mutation in Rasgrp1. Immunity 2003; 19: 243-55.
47. Priatel JJ, Chen X, Dhanji S, Abraham N, Teh HS. RasGRP1 transmits prodifferentiation TCR signaling that is crucial for CD4 T cell development. J Immunol 2006; 177: 1470-80.
48. Amsen D, Kruisbeek A, Bos JL, Reedquist K. Activation of the Ras-related GTPase Rap1 by thymocyte TCR engagement and during selection. Eur J Immunol 2000; 30: 2832-41.
49. Priatel JJ, Chen X, Zenewicz LA, et al. Chronic immunodeficiency in mice lacking RasGRP1 results in CD4 T cell immune activation and exhaustion. J Immunol 2007; 179: 2143-52.
50. Roivainen A, Soderstrom KO, Pirila L, et al. Oncoprotein expression in human synovial tissue: an immunohistochemical study of different types of arthritis. Br J Rheumatol 1996; 35: 933-42.
51. de LD, Vreijling J, Hartkamp LM, et al. Silencing the expression of Ras family GTPase homologues decreases inflammation and joint destruction in experimental arthritis. Am J Pathol 2010; 177: 3010-24.
52. Abreu JR, de LD, Sanders ME, et al. The Ras guanine nucleotide exchange factor RasGRF1 promotes matrix metalloproteinase-3 production in rheumatoid arthritis synovial tissue. Arthritis Res Ther 2009; 11: R121.
53. Remans PH, Gringhuis SI, van Laar JM, et al. Rap1 signaling is required for suppression of Ras-generated reactive oxygen species and protection against oxidative stress in T lymphocytes. J Immunol 2004; 173: 920-31.
54. Na HJ, Lee SJ, Kang YC, et al. Inhibition of farnesyltransferase prevents collagen-induced arthritis by down-regulation of inflammatory gene expression through suppression of p21(ras)-dependent NF-kappaB activation. J Immunol 2004; 173: 1276-83.
55. Philips MR, Cox AD. Geranylgeranyltransferase I as a target for anti-cancer drugs. J Clin Invest 2007; 117: 1223-5.
56. Abeles AM, Marjanovic N, Park J, et al. Protein isoprenylation regulates secretion of matrix metalloproteinase 1 from rheumatoid synovial fibroblasts: effects of statins and farnesyl and geranylgeranyl transferase inhibitors. Arthritis Rheum 2007; 56: 2840-53.
57. Pap T, Nawrath M, Heinrich J, et al. Cooperation of Ras-and c-Myc-dependent pathways in regulating the growth and invasiveness of synovial fibroblasts in rheumatoid arthritis. Arthritis Rheum 2004; 50: 2794-802.
58. Herrmann C, Horn G, Spaargaren M, Wittinghofer A. Differential interaction of the ras family GTP-binding proteins H-Ras, Rap1A, and R-Ras with the putative effector molecules Raf kinase and Ralguanine nucleotide exchange factor. J Biol Chem 1996; 271: 6794-800.
59. Yamamoto A, Fukuda A, Seto H, et al. Suppression of arthritic bone destruction by adenovirus-mediated dominant-negative Ras gene transfer to synoviocytes and osteoclasts. Arthritis Rheum 2003; 48: 2682-92.
60. Baouz S, Jacquet E, Bernardi A, Parmeggiani A. The N-terminal moiety of CDC25(Mm), a GDP/GTP exchange factor of Ras proteins, controls the activity of the catalytic domain. Modulation by calmodulin and calpain. J Biol Chem 1997; 272: 6671-6.
61. Zhu TN, He HJ, Kole S, et al. Filamin A-mediated down-regulation of the exchange factor Ras-GRF1 correlates with decreased matrix metalloproteinase-9 expression in human melanoma cells. J Biol Chem 2007; 282: 14816-26.
62. Remans PH, van Oosterhout M, Smeets TJ, et al. Intracellular free radical production in synovial T lymphocytes from patients with rheumatoid arthritis. Arthritis Rheum 2005; 52: 2003-9.
63. Kitasato H, Noda M, Akahoshi T, et al. Activated Ras modifies the proliferative response of rheumatoid synovial cells to TNF-alpha and TGF-alpha. Inflamm Res 2001; 50: 592-7.
64. Rapoport MJ, Mor A, Amit M, et al. Decreased expression of the p21ras stimulatory factor hSOS in PBMC from inactive SLE patients. Lupus 1999; 8: 24-8.
65. Rapoport MJ, Amit M, Aharoni D, et al. Constitutive up-regulated activity of MAP kinase is associated with down-regulated early p21Ras pathway in lymphocytes of SLE patients. J Autoimmun 2002; 19: 63-70.
66. Molad Y, Mit-Vasina M, Bloch O, Yona E, Rapoport MJ. Increased ERK and JNK activities correlate with disease activity in patients with systemic lupus erythematosus. Ann Rheum Dis 2010; 69: 175-80.
67. Gang C, Jiahui Y, Huaizhou W, Qing C, Dongbao Z, Qian S. Defects of mitogen-activated protein kinase in ICOS signaling pathway lead to CD4(+) and CD8(+) T-cell dysfunction in patients with active SLE. Cell Immunol 2009; 258: 83-9.
68. Cedeno S, Cifarelli DF, Blasini AM, et al. Defective activity of ERK-1 and ERK-2 mitogen-activated protein kinases in peripheral blood T lymphocytes from patients with systemic lupus erythematosus: potential role of altered coupling of Ras guanine nucleotide exchange factor hSos to adapter protein Grb2 in lupus T cells. Clin Immunol 2003; 106: 41-9.
69. Yasuda S, Stevens RL, Terada T, et al. Defective expression of Ras guanyl nucleotide-releasing protein 1 in a subset of patients with systemic lupus erythematosus. J Immunol 2007; 179: 4890-900.
70. Priatel JJ, Chen X, Huang YH, et al. RasGRP1 regulates antigeninduced developmental programming by naive CD8 T cells. J Immunol 2010; 184: 666-76.
71. Katzav A, Kloog Y, Korczyn AD, et al. Treatment of MRL/lpr mice, a genetic autoimmune model, with the Ras inhibitor, farnesylthiosalicylate (FTS). Clin Exp Immunol 2001; 126: 570-7.
72. Bos JL, de Rooij J, Reedquist KA. Rap1 signalling: adhering to new models. Nat Rev Mol Cell Biol 2001; 2: 369-77.
73. Lafuente EM, van Puijenbroek AA, Krause M, et al. RIAM, an Ena/VASP and Profilin ligand, interacts with Rap1-GTP and mediates Rap1-induced adhesion. Dev Cell 2004; 7: 585-95.
74. Han J, Lim CJ, Watanabe N, et al. Reconstructing and deconstructing agonist-induced activation of integrin alphaIIbbeta3. Curr Biol 2006; 16: 1796-806.
75. Menasche G, Kliche S, Chen EJ, Stradal TE, Schraven B, Koretzky G. RIAM links the ADAP/SKAP-55 signaling module to Rap1, facilitating T-cell-receptor-mediated integrin activation. Mol Cell Biol 2007; 27: 4070-81.
76. Katagiri K, Maeda A, Shimonaka M, Kinashi T. RAPL, a Rap1-binding molecule that mediates Rap1-induced adhesion through spatial regulation of LFA-1. Nat Immunol 2003; 4: 741-8.
77. Katagiri K, Imamura M, Kinashi T. Spatiotemporal regulation of the kinase Mst1 by binding protein RAPL is critical for lymphocyte polarity and adhesion. Nat Immunol 2006; 7: 919-28.
78. Price LS, Hajdo-Milasinovic A, Zhao J, Zwartkruis FJ, Collard JG, Bos JL. Rap1 regulates E-cadherin-mediated cell-cell adhesion. J Biol Chem 2004; 279: 35127-32.
79. Hogan C, Serpente N, Cogram P, et al. Rap1 regulates the formation of E-cadherin-based cell-cell contacts. Mol Cell Biol 2004; 24: 6690-700.
80. Hoshino T, Sakisaka T, Baba T, Yamada T, Kimura T, Takai Y. Regulation of E-cadherin endocytosis by nectin through afadin, Rap1, and p120ctn. J Biol Chem 2005; 280: 24095-103.
81. Raaijmakers JH, Bos JL. Specificity in Ras and Rap signaling. J Biol Chem 2008; 284: 10995-9.
82. Li L, Greenwald RJ, Lafuente EM, et al. Rap1-GTP is a negative regulator of Th cell function and promotes the generation of CD4+CD103+ regulatory T cells in vivo. J Immunol 2005; 175: 3133-9.
83. Li L, Kim J, Boussiotis VA. Rap1A regulates generation of T regulatory cells via LFA-1-dependent and LFA-1-independent mechanisms. Cell Immunol 2010; 266: 7-13.
84. Sebzda E, Bracke M, Tugal T, Hogg N, Cantrell DA. Rap1A positively regulates T cells via integrin activation rather than inhibiting lymphocyte signaling. Nat Immunol 2002; 3: 251-8.
85. Abreu JR, Krausz S, Dontje W, et al. Sustained T cell Rap1 signaling is protective in the collagen-induced arthritis model of rheumatoid arthritis. Arthritis Rheum 2010; 62: 3289-99.
86. Ishida D, Yang H, Masuda K, et al. Antigen-driven T cell anergy and defective memory T cell response via deregulated Rap1 activation in SPA-1-deficient mice. Proc Natl Acad Sci USA 2003; 100: 10919-24.
87. Ishida D, Su L, Tamura A, et al. Rap1 signal controls B cell receptor repertoire and generation of self-reactive B1a cells. Immunity 2006; 24: 417-27.
88. Li Y, Yan J, De P, et al. Rap1a null mice have altered myeloid cell functions suggesting distinct roles for the closely related Rap1a and 1b proteins. J Immunol 2007; 179: 8322-31.
89. Duchniewicz M, Zemojtel T, Kolanczyk M, Grossmann S, Scheele JS, Zwartkruis FJ. Rap1A-deficient T and B cells show impaired integrin-mediated cell adhesion. Mol Cell Biol 2006; 26: 643-53.
90. Chu H, Awasthi A, White GC, Chrzanowska-Wodnicka M, Malarkannan S. Rap1b regulates B cell development, homing, and T cell-dependent humoral immunity. J Immunol 2008; 181: 3373-83.
91. Dillon TJ, Carey KD, Wetzel SA, Parker DC, Stork PJ. Regulation of the small GTPase Rap1 and extracellular signal-regulated kinases by the costimulatory molecule CTLA-4. Mol Cell Biol 2005; 25: 4117-28.
92. Chrzanowska-Wodnicka M, Kraus AE, Gale D, White GC, Vansluys J. Defective angiogenesis, endothelial migration, proliferation, and MAPK signaling in Rap1b-deficient mice. Blood 2008; 111: 2647-56.
93. Katagiri K, Ueda Y, Tomiyama T, et al. Deficiency of Rap1-Binding Protein RAPL Causes Lymphoproliferative Disorders through Mislocalization of p27kip1. Immunity 2011; 34: 24-38.
94. Katagiri K, Ohnishi N, Kabashima K, et al. Crucial functions of the Rap1 effector molecule RAPL in lymphocyte and dendritic cell trafficking. Nat Immunol 2004; 5: 1045-51.
95. Ebisuno Y, Katagiri K, Katakai T, et al. Rap1 controls lymphocyte adhesion cascade and interstitial migration within lymph nodes in RAPL-dependent and-independent manners. Blood 2010; 115: 804-14.
96. Carmona G, Gottig S, Orlandi A, et al. Role of the small GTPase Rap1 for integrin activity regulation in endothelial cells and angiogenesis. Blood 2009; 113: 488-97.
97. Yan J, Li F, Ingram DA, Quilliam LA. Rap1a is a key regulator of fibroblast growth factor 2-induced angiogenesis and together with Rap1b controls human endothelial cell functions. Mol Cell Biol 2008; 28: 5803-10.
98. Remans PH, Wijbrandts CA, Sanders ME, et al. CTLA-4IG suppresses reactive oxygen species by preventing synovial adherent cell-induced inactivation of Rap1, a Ras family GTPASE mediator of oxidative stress in rheumatoid arthritis T cells. Arthritis Rheum 2006; 54: 3135-43.
99. Reedquist KA, Bos JL. Costimulation through CD28 suppresses T cell receptor-dependent activation of the Ras-like small GTPase Rap1 in human T lymphocytes. J Biol Chem 1998; 273: 4944-9.
100. Tatla S, Woodhead V, Foreman JC, Chain BM. The role of reactive oxygen species in triggering proliferation and IL-2 secretion in T cells. Free Radic Biol Med 1999; 26: 14-24.
101. Hehner SP, Breitkreutz R, Shubinsky G, et al. Enhancement of T cell receptor signaling by a mild oxidative shift in the intracellular thiol pool. J Immunol 2000; 165: 4319-28.
102. Wherry EJ, Ha SJ, Kaech SM, et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 2007; 27: 670-84.
103. Fuller MJ, Khanolkar A, Tebo AE, Zajac AJ. Maintenance, loss, and resurgence of T cell responses during acute, protracted, and chronic viral infections. J Immunol 2004; 172: 4204-14.
104. Katagiri K, Hattori M, Minato N, Kinashi T. Rap1 functions as a key regulator of T-cell and antigen-presenting cell interactions and modulates T-cell responses. Mol Cell Biol 2002; 22: 1001-15.
105. Gonzalo JA, Delaney T, Corcoran J, Goodearl A, Gutierrez-Ramos JC, Coyle AJ. Cutting edge: the related molecules CD28 and inducible costimulator deliver both unique and complementary signals required for optimal T cell activation. J Immunol 2001; 166: 1-5.
106. McAdam AJ, Greenwald RJ, Levin MA, et al. ICOS is critical for CD40-mediated antibody class switching. Nature 2001; 409: 102-5.
107. Kojima F, Kapoor M, Kawai S, Yang L, Aronoff DM, Crofford LJ. Prostaglandin E2 activates Rap1 via EP2/EP4 receptors and cAMPsignaling in rheumatoid synovial fibroblasts: involvement of Epac1 and PKA. Prostaglandins Other Lipid Mediat 2009; 89: 26-33.
108. Jaffe AB, Hall A. Rho GTPases: Biochemistry and biology. Annu Rev Cell Dev Biol 2005; 21: 247-69.
109. Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene 2007; 26: 3279-90.
110. Schiller MR. Coupling receptor tyrosine kinases to Rho GTPases--GEFs what's the link. Cell Signal 2006; 18: 1834-43.
111. Aittaleb M, Boguth CA, Tesmer JJ. Structure and function of heterotrimeric G protein-regulated Rho guanine nucleotide exchange factors. Mol Pharmacol 2010; 77: 111-25.
112. Tcherkezian J, Lamarche-Vane N. Current knowledge of the large RhoGAP family of proteins. Biol Cell 2007; 99: 67-86.
113. Mulloy JC, Cancelas JA, Filippi MD, Kalfa TA, Guo F, Zheng Y. Rho GTPases in hematopoiesis and hemopathies. Blood 2010; 115: 936-47.
114. Sugihara K, Nakatsuji N, Nakamura K, et al. Rac1 is required for the formation of three germ layers during gastrulation. Oncogene 1998; 17: 3427-33.
115. Croker BA, Handman E, Hayball JD, et al. Rac2-deficient mice display perturbed T-cell distribution and chemotaxis, but only minor abnormalities in T(H)1 responses. Immunol Cell Biol 2002; 80: 231-40.
116. Yu H, Leitenberg D, Li B, Flavell RA. Deficiency of small GTPase Rac2 affects T cell activation. J Exp Med 2001; 194: 915-26.
117. Guo F, Cancelas JA, Hildeman D, Williams DA, Zheng Y. Rac GTPase isoforms Rac1 and Rac2 play a redundant and crucial role in T-cell development. Blood 2008; 112: 1767-75.
118. Dumont C, Corsoni-Tadrzak A, Ruf S, et al. Rac GTPases play critical roles in early T-cell development. Blood 2009; 113: 3990-8.
119. Li B, Yu H, Zheng W, et al. Role of the guanosine triphosphatase Rac2 in T helper 1 cell differentiation. Science 2000; 288: 2219-22.
120. Walmsley MJ, Ooi SKT, Reynolds LF, et al. Critical roles for Rac1 and Rac2 GTPases in B cell development and signaling. Science 2003; 302: 459-62.
121. Croker BA, Tarlinton DM, Cluse LA, et al. The Rac2 guanosine triphosphatase regulates B lymphocyte antigen receptor responses and chemotaxis and is required for establishment of B-1a and marginal zone B lymphocytes. J Immunol 2002; 168: 3376-86.
122. Glogauer M, Marchal CC, Zhu F, et al. Rac1 deletion in mouse neutrophils has selective effects on neutrophil functions. J Immunol 2003; 170: 5652-7.
123. Sun CX, Downey GP, Zhu F, Koh AL, Thang H, Glogauer M. Rac1 is the small GTPase responsible for regulating the neutrophil chemotaxis compass. Blood 2004; 104: 3758-65.
124. Wells CM, Walmsley M, Ooi S, Tybulewicz V, Ridley AJ. Rac1-deficient macrophages exhibit defects in cell spreading and membrane ruffling but not migration. J Cell Sci 2004; 117: 1259-68.
125. Wheeler AP, Wells CM, Smith SD, et al. Rac1 and Rac2 regulate macrophage morphology but are not essential for migration. J Cell Sci 2006; 119: 2749-57.
126. Yamauchi A, Kim C, Li S, et al. Rac2-deficient murine macrophages have selective defects in superoxide production and phagocytosis of opsonized particles. J Immunol 2004; 173: 5971-9.
127. Benvenuti F, Hugues S, Walmsley M, et al. Requirement of Rac1 and Rac2 expression by mature dendritic cells for T cell priming. Science 2004; 305: 1150-3.
128. Wang Y, Lebowitz D, Sun C, Thang H, Grynpas MD, Glogauer M. Identifying the relative contributions of Rac1 and Rac2 to osteoclastogenesis. J Bone Miner Res 2008; 23: 260-70.
129. Fukui Y, Hashimoto O, Sanui T, et al. Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration. Nature 2001; 412: 826-31.
130. Gotoh K, Tanaka Y, Nishikimi A, et al. Differential requirement for DOCK2 in migration of plasmacytoid dendritic cells versus myeloid dendritic cells. Blood 2008; 111: 2973-6.
131. Kunisaki Y, Nishikimi A, Tanaka Y, et al. DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis. J Cell Biol 2006; 174: 647-52.
132. Galandrini R, Henning SW, Cantrell DA. Different functions of the GTPase Rho in prothymocytes and late pre-T cells. Immunity 1997; 7: 163-74.
133. Vielkind S, Gallagher-Gambarelli M, Gomez M, Hinton HJ, Cantrell DA. Integrin regulation by RhoA in thymocytes. J Immunol 2005; 175: 350-7.
134. Lou Z, Billadeau DD, Savoy DN, Schoon RA, Leibson PJ. A role for a RhoA/ROCK/LIM-kinase pathway in the regulation of cytotoxic lymphocytes. J Immunol 2001; 167: 5749-57.
135. Kamon H, Kawabe T, Kitamura H, et al. TRIF-GEFH1-RhoB pathway is involved in MHCII expression on dendritic cells that is critical for CD4 T-cell activation. EMBO J 2006; 25: 4108-19.
136. Ocana-Morgner C, Wahren C, Jessberger R. SWAP-70 regulates RhoA/RhoB-dependent MHCII surface localization in dendritic cells. Blood 2009; 113: 1474-82.
137. Gu Y, Chae HD, Siefring JE, Jasti AC, Hildeman DA, Williams DA. RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development. Nat Immunol 2006; 7: 1182-90.
138. Dorn T, Kuhn U, Bungartz G, et al. RhoH is important for positive thymocyte selection and T-cell receptor signaling. Blood 2007; 109: 2346-55.
139. Baker CM, Comrie WA, Hyun YM, et al. Opposing roles for RhoH GTPase during T-cell migration and activation. Proc Natl Acad Sci USA 2012; 109(26): 10474-9.
140. Oda H, Fujimoto M, Patrick MS, et al. RhoH plays critical roles in Fc epsilon RI-dependent signal transduction in mast cells. J Immunol 2009; 182: 957-62.
141. Szczur K, Xu H, Atkinson S, Zheng Y, Filippi MD. Rho GTPase CDC42 regulates directionality and random movement via distinct MAPK pathways in neutrophils. Blood 2006; 108: 4205-13.
142. Guo F, Velu CS, Grimes HL, Zheng Y. Rho GTPase Cdc42 is essential for B-lymphocyte development and activation. Blood 2009; 114: 2909-16.
143. Itzstein C, Coxon FP, Rogers MJ. The regulation of osteoclast function and bone resorption by small GTPases. Small Gtpases 2011; 2: 117-30.
144. Chan A, Akhtar M, Brenner M, Zheng Y, Gulko PS, Symons M. The GTPase Rac regulates the proliferation and invasion of fibroblast-like synoviocytes from rheumatoid arthritis patients. Mol Med 2007; 13: 297-304.
145. Zhang X, Glogauer M, Zhu F, Kim TH, Chiu B, Inman RD. Innate immunity and arthritis: neutrophil Rac and toll-like receptor 4 expression define outcomes in infection-triggered arthritis. Arthritis Rheum 2005; 52: 1297-304.
146. Abreu JR, Dontje W, Krausz S, et al. A Rac1 inhibitory peptide suppresses antibody production and paw swelling in the murine collagen-induced arthritis model of rheumatoid arthritis. Arthritis Res Ther 2010; 12: R2.
147. Abeles AM, Pillinger MH. Statins as antiinflammatory and immunomodulatory agents: a future in rheumatologic therapy? Arthritis Rheum 2006; 54: 393-407.
148. Connor AM, Berger S, Narendran A, Keystone EC. Inhibition of protein geranylgeranylation induces apoptosis in synovial fibroblasts. Arthritis Res Ther 2006; 8: R94.
149. Nagashima T, Okazaki H, Yudoh K, Matsuno H, Minota S. Apoptosis of rheumatoid synovial cells by statins through the blocking of protein geranylgeranylation: a potential therapeutic approach to rheumatoid arthritis. Arthritis Rheum 2006; 54: 579-86.
150. Xu H, Liu P, Liang L, et al. RhoA-mediated, tumor necrosis factor alpha-induced activation of NF-kappaB in rheumatoid synoviocytes: inhibitory effect of simvastatin. Arthritis Rheum 2006; 54: 3441-51.
151. Nakayamada S, Kurose H, Saito K, Mogami A, Tanaka Y. Small GTP-binding protein Rho-mediated signaling promotes proliferation of rheumatoid synovial fibroblasts. Arthritis Res Ther 2005; 7: R476-R484.
152. Lin H, Xiao Y, Chen G, et al. HMG-CoA reductase inhibitor simvastatin suppresses Toll-like receptor 2 ligand-induced activation of nuclear factor kappa B by preventing RhoA activation in monocytes from rheumatoid arthritis patients. Rheumatol Int 2011; 31(11): 1451-8.
153. He Y, Xu H, Liang L, et al. Antiinflammatory effect of Rho kinase blockade via inhibition of NF-kappaB activation in rheumatoid arthritis. Arthritis Rheum 2008; 58: 3366-76.
154. Leung BP, Sattar N, Crilly A, et al. A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol 2003; 170: 1524-30.
155. Palmer G, Chobaz V, Talabot-Ayer D, et al. Assessment of the efficacy of different statins in murine collagen-induced arthritis. Arthritis Rheum 2004; 50: 4051-9.
156. Fan H, Patel VA, Longacre A, Levine JS. Abnormal regulation of the cytoskeletal regulator Rho typifies macrophages of the major murine models of spontaneous autoimmunity. J Leukoc Biol 2006; 79: 155-65.
157. Lawman S, Mauri C, Jury EC, Cook HT, Ehrenstein MR. Atorvastatin inhibits autoreactive B cell activation and delays lupus development in New Zealand black/white F1 mice. J Immunol 2004; 173: 7641-6.
158. Salinas GF, Krausz S, Dontje W, et al. Sustained Rap1 activation in autoantigen-specific T lymphocytes attenuates experimental autoimmune encephalomyelitis. J Neuroimmunol 2012 [Epub ahead of print].
159. Greenwood J, Walters CE, Pryce G, et al. Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. FASEB J 2003; 17: 905-7.
160. Paintlia AS, Paintlia MK, Singh AK, Singh I. Inhibition of rho family functions by lovastatin promotes myelin repair in ameliorating experimental autoimmune encephalomyelitis. Mol Pharmacol 2008; 73: 1381-93.
161. Walters CE, Pryce G, Hankey DJ, et al. Inhibition of Rho GTPases with protein prenyltransferase inhibitors prevents leukocyte recruitment to the central nervous system and attenuates clinical signs of disease in an animal model of multiple sclerosis. J Immunol 2002; 168: 4087-94.
162. Cope AP, Londei M, Chu NR, et al. Chronic exposure to tumor necrosis factor (TNF) in vitro impairs the activation of T cells through the T cell receptor/CD3 complex; reversal in vivo by anti-TNF antibodies in patients with rheumatoid arthritis. J Clin Invest 1994; 94: 749-60.
163. Isomaki P, Panesar M, Annenkov A, et al. Prolonged exposure of T cells to TNF down-regulates TCR zeta and expression of the TCR/CD3 complex at the cell surface. J Immunol 2001; 166: 5495-507.
164. Abreu JR, Grabiec AM, Krausz S, et al. The presumed hyporesponsive behavior of rheumatoid arthritis T lymphocytes can be attributed to spontaneous ex vivo apoptosis rather than defects in T cell receptor signaling. J Immunol 2009; 183: 621-30.
165. Enserink JM, Christensen AE, de RJ, et al. A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK. Nat Cell Biol 2002; 4: 901-6.
166. Nishikimi A, Uruno T, Duan X, et al. Blockade of Inflammatory Responses by a Small-Molecule Inhibitor of the Rac Activator DOCK2. Chem Biol 2012; 19: 488-97.
167. Schmidt S, Diriong S, Mery J, Fabbrizio E, Debant A. Identification of the first Rho-GEF inhibitor, TRIPalpha, which targets the RhoA-specific GEF domain of Trio. FEBS Lett 2002; 523: 35-42.
168. Gao Y, Dickerson JB, Guo F, Zheng J, Zheng Y. Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci USA 2004; 101: 7618-23.