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Cited by 56Protein Kinase Regulation and GTPase SignalingMicrotubule and mitosis dynamicsCellular Mechanics and Interactions

Regulation and functions of the RhoA regulatory guanine nucleotide exchange factor GEF-H1

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Joo, Emily, Olson, Michael F·2021·Small GTPases
DOI 10.1080/21541248.2020.1840889PMC PMC8583009
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Abstract

and its human orthologue RhoB, membership in the Rho GTPase family has grown to 20 proteins, with representatives in all eukaryotic species. These GTPases are molecular switches that cycle between active (GTP bound) and inactivate (GDP bound) states. The exchange of GDP for GTP on Rho GTPases is facilitated by guanine exchange factors (GEFs). Approximately 80 Rho GEFs have been identified to date, and only a few GEFs associate with microtubules. The guanine nucleotide exchange factor H1, GEF-H1, is a unique GEF that associates with microtubules and is regulated by the polymerization state of microtubule networks. This review summarizes the regulation and functions of GEF-H1 and discusses the roles of GEF-H1 in human diseases.

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  • Human GEFH1 is a multidomain protein belonging to the Dbl homology family of Rho-GTPase activators.

    “Human GEFH1 is a multidomain protein belonging to the diffuse B cell lymphoma (Dbl) homology family of Rho-GTPase activators.”

    From Structural basis of microtubule-mediated signal transduction (2026) · cites this paper as [25]

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  1. [1]Madaule P, Axel R. A novel ras-related gene family. Cell. 1985; 41(1): 31– 40. 3888408
  2. [2]Mackay DJ, Hall A. Rho GTPases. J Biol Chem. 1998; 273(33): 20685– 20688. 9694808
  3. [3]Olson MF. Rho GTPases, their post-translational modifications, disease-associated mutations and pharmacological inhibitors. Small GTPases. 2018; 9(3): 203– 215. 27548350 PMC5927519
  4. [4]Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature. 2002; 420(6916): 629– 635. 12478284
  5. [5]Heasman SJ, Ridley AJ. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol. 2008; 9(9): 690– 701. 18719708
  6. [6]Jaffe AB, Hall A. Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol. 2005; 21(1): 247– 269. 16212495
  7. [7]Hodge RG, Ridley AJ. Regulating Rho GTPases and their regulators. Nat Rev Mol Cell Bio. 2016; 17(8): 496– 510. 27301673
  8. [8]Bos JL, Rehmann H, Wittinghofer A. GEFs and GAPs: critical elements in the control of small G proteins. Cell. 2007; 129(5): 865– 877. 17540168
  9. [9]Rossman KL, Der CJ, Sondek J. GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Bio. 2005; 6: 167 180. 15688002
  10. [10]Maldonado MDM, Medina JI, Velazquez L, et al. Targeting rac and Cdc42 GEFs in metastatic cancer. Frontiers Cell Dev Biol. 2020; 8: 201. PMC7156542 32322580
  11. [11]Meller N, Merlot S, Guda C. CZH proteins: a new family of Rho-GEFs. J Cell Sci. 2005; 118(21): 4937– 4946. 16254241
  12. [12]Whitehead I, Kirk H, Tognon C, et al. Expression cloning of lfc, a novel oncogene with structural similarities to guanine nucleotide exchange factors and to the regulatory region of protein kinase C. J Biol Chem. 1995; 270(31): 18388– 18395. 7629163
  13. [13]Ren Y, Li R, Zheng Y, et al. Cloning and characterization of GEF-H1, a microtubule-associated guanine nucleotide exchange factor for rac and rho GTPases. J Biol Chem. 1998; 273(52): 34954– 34960. 9857026
  14. [14]Fort P, Blangy A. The evolutionary landscape of Dbl-like RhoGEF families: adapting eukaryotic cells to environmental signals. Genome Biol Evol. 2017; 9(6): 1471– 1486. 28541439 PMC5499878
  15. [15]Callow MG, Zozulya S, Gishizky ML, et al. PAK4 mediates morphological changes through the regulation of GEF-H1. J Cell Sci. 2005; 118: 1861– 1872. 15827085
  16. [17]Glaven JA, Whitehead IP, Nomanbhoy T, et al. Lfc and Lsc oncoproteins represent two new guanine nucleotide exchange factors for the Rho GTP-binding protein. J Biol Chem. 1996; 271(44): 27374– 27381. 8910315
  17. [18]Benais-Pont G, Punn A, Flores-Maldonado C, et al. Identification of a tight junction–associated guanine nucleotide exchange factor that activates Rho and regulates paracellular permeability. J Cell Biol. 2003; 160(5): 729– 740. 12604587 PMC2173357
  18. [19]Gao Y, Xing J, Streuli M, et al. Trp 56 of Rac1 Specifies Interaction with a Subset of Guanine Nucleotide Exchange Factors. J Biol Chem. 2001; 276(50): 47530– 47541. 11595749
  19. [20]Tonami K, Kurihara Y, Arima S, et al. Calpain-6, a microtubule-stabilizing protein, regulates Rac1 activity and cell motility through interaction with GEF-H1. J Cell Sci. 2011; 124(8): 1214– 1223. 21406564
  20. [21]Waheed F, Dan Q, Amoozadeh Y, et al. Central role of the exchange factor GEF-H1 in TNF-α–induced sequential activation of Rac, ADAM17/TACE, and RhoA in tubular epithelial cells. Mol Biol Cell. 2013; 24(7): 1068– 1082. 23389627 PMC3608494
  21. [23]Birkenfeld J, Nalbant P, Yoon S-H, et al. Cellular functions of GEF-H1, a microtubule-regulated Rho-GEF: is altered GEF-H1 activity a crucial determinant of disease pathogenesis? Trends Cell Biol. 2008; 18(5): 210 219. 18394899
  22. [24]Glaven JA, Whitehead I, Bagrodia S, et al. The Dbl-related protein, lfc, localizes to microtubules and mediates the activation of rac signaling pathways in cells. J Biol Chem. 1999; 274(4): 2279– 2285. 9890991
  23. [25]Birkenfeld J, Nalbant P, Bohl BP, et al. GEF-H1 modulates localized rhoa activation during cytokinesis under the control of mitotic kinases. Dev Cell. 2007; 12(5): 699– 712. 17488622 PMC1965589
  24. [26]Meiri D, Marshall C, Greeve M, et al. Mechanistic insight into the microtubule and actin cytoskeleton coupling through dynein-dependent RhoGEF inhibition. Mol Cell. 2012; 45(5): 642 655. 22405273
  25. [27]Siesser PF, Motolese M, Walker MP, et al. FAM123A binds to microtubules and inhibits the guanine nucleotide exchange factor ARHGEF2 to decrease actomyosin contractility. Sci Signal. 2012; 5(240): ra64– ra64. 22949735 PMC3733483
  26. [28]Eitaki M, Yamamori T, Meike S, et al. Vincristine enhances amoeboid-like motility via GEF-H1/RhoA/ROCK/Myosin light chain signaling in MKN45 cells. BMC Cancer. 2012; 12(1): 469. 23057787 PMC3522013
  27. [29]Kratzer E, Tian Y, Sarich N, et al. Oxidative stress contributes to lung injury and barrier dysfunction via microtubule destabilization. Am J Resp Cell Mol. 2012; 47: 688– 697. PMC3547103 22842495
  28. [30]Pan Y-R, Chen -C-C, Chan Y-T, et al. STAT3-coordinated migration facilitates the dissemination of diffuse large B-cell lymphomas. Nat Commun. 2018; 9(1): 3696. 30209389 PMC6135800
  29. [31]Nagae S, Meng W, Takeichi M. Non‐centrosomal microtubules regulate F‐actin organization through the suppression of GEF‐H1 activity. Genes Cells. 2013; 18: 387– 396. 23432781
  30. [32]Samereier M, Schleicher M, Roth H, et al. EB1 contributes to proper front-to-back polarity in neutrophil-like HL-60 cells. Eur J Cell Biol. 2017; 96(2): 143– 153. 28132723
  31. [33]Zenke FT, Krendel M, DerMardirossian C, et al. p21-activated Kinase 1 phosphorylates and regulates 14–3–3 Binding to GEF–H1, a microtubule-localized rho exchange factor. J Biol Chem. 2004; 279(18): 18392– 18400. 14970201
  32. [34]Guillemot L, Paschoud S, Jond L, et al. Paracingulin regulates the activity of Rac1 and RhoA GTPases by recruiting Tiam1 and GEF-H1 to epithelial junctions. Mol Biol Cell. 2008; 19(10): 4442– 4453. 18653465 PMC2555940
  33. [35]Aijaz S, D’Atri F, Citi S, et al. Binding of GEF-H1 to the tight junction-associated adaptor cingulin results in inhibition of Rho signaling and G1/S phase transition. Dev Cell. 2005; 8: 777– 786. 15866167
  34. [36]Boulter E, Estrach S, Tissot FS, et al. Cell metabolism regulates integrin mechanosensing via an SLC3A2-dependent sphingolipid biosynthesis pathway. Nat Commun. 2018; 9(1): 4862. 30451822 PMC6242995
  35. [37]Fujishiro S-H, Tanimura S, Mure S, et al. ERK1/2 phosphorylate GEF-H1 to enhance its guanine nucleotide exchange activity toward RhoA. Biochem Biophys Res Commun. 2008; 368(1): 162– 167. 18211802
  36. [38]Kakiashvili E, Speight P, Waheed F, et al. GEF-H1 mediates tumor necrosis factor-α-induced rho activation and myosin phosphorylation role in the regulation of tubular paracellular permeability. J Biol Chem. 2009; 284(17): 11454– 11466. 19261619 PMC2670151
  37. [39]von Thun A, Preisinger C, Rath O, et al. Extracellular signal-regulated kinase regulates RhoA activation and tumor cell plasticity by inhibiting guanine exchange factor H1 activity. Mol Cell Biol. 2013; 33(22): 4526– 4537. 24043311 PMC3838172
  38. [40]Yamahashi Y, Saito Y, Murata-Kamiya N, et al. Polarity-regulating kinase partitioning-defective 1b (PAR1b) phosphorylates guanine nucleotide exchange factor H1 (GEF-H1) to regulate RhoA-dependent actin cytoskeletal reorganization. J Biol Chem. 2011; 286(52): 44576– 44584. 22072711 PMC3248009
  39. [41]Meiri D, Greeve MA, Brunet A, et al. Modulation of Rho guanine exchange factor lfc activity by protein kinase a-mediated phosphorylation▿. Mol Cell Biol. 2009; 29(21): 5963– 5973. 19667072 PMC2772734
  40. [42]Sandí M-J, Marshall CB, Balan M, et al. MARK3-mediated phosphorylation of ARHGEF2 couples microtubules to the actin cytoskeleton to establish cell polarity. Sci Signal. 2017; 10(503): eaan3286. 29089450 PMC6504561
  41. [44]Dubois F, Keller M, Calvayrac O, et al. RASSF1A suppresses the invasion and metastatic potential of human non–small cell lung cancer cells by inhibiting YAP activation through the GEF-H1/RhoB pathway. Cancer Res. 2016; 76(6): 1627– 1640. 26759237
  42. [45]Jiu Y, Peränen J, Schaible N, et al. Vimentin intermediate filaments control actin stress fiber assembly through GEF-H1 and RhoA. J Cell Sci. 2017; 130(5): jcs.196881. PMC5358333 28096473
  43. [46]Baltussen LL, Negraes PD, Silvestre M, et al. Chemical genetic identification of CDKL5 substrates reveals its role in neuronal microtubule dynamics. Embo J. 2018; 37(24). DOI: 10.15252/embj.201899763 PMC6293278 30266824 · DOI
  44. [47]Takano T, Wu M, Nakamuta S, et al. Discovery of long-range inhibitory signaling to ensure single axon formation. Nat Commun. 2017; 8(1): 33. 28652571 PMC5484694
  45. [48]Yoshimura Y, Miki H. Dynamic regulation of GEF-H1 localization at microtubules by Par1b/MARK2. Biochem Biophys Res Commun. 2011; 408(2): 322– 328. 21513698
  46. [49]Azoitei ML, Noh J, Marston DJ, et al. Spatiotemporal dynamics of GEF-H1 activation controlled by microtubule- and Src-mediated pathwaysSpatiotemporal dynamics of GEF-H1 activation. J Cell Biol. 2019; 218(9): 3077– 3097. 31420453 PMC6719461
  47. [50]Lauffenburger DA, Horwitz AF. Cell migration: a physically integrated molecular process. Cell. 1996; 84(3): 359– 369. 8608589
  48. [51]Yamada KM, Sixt M. Mechanisms of 3D cell migration. Nat Rev Mol Cell Biol. 2019; 20(12): 738– 752. 31582855
  49. [52]Trepat X, Chen Z, Jacobson K. Cell migration. Compr Physiol. 2012; 2: 2369– 2392. 23720251 PMC4457291
  50. [53]Friedl P, Wolf K. Plasticity of cell migration: a multiscale tuning model. J Cell Biol. 2010; 188(1): 11– 19. 19951899 PMC2812848
  51. [54]Ridley AJ, Schwartz MA, Burridge K, et al. Cell migration: integrating signals from front to back. Science. 2003; 302(5651): 1704– 1709. 14657486
  52. [55]Lawson CD, Ridley AJ. Rho GTPase signaling complexes in cell migration and invasion. J Cell Biol. 2018; 217(2): 447– 457. 29233866 PMC5800797
  53. [56]Fine N, Dimitriou ID, Rullo J, et al. GEF-H1 is necessary for neutrophil shear stress–induced migration during inflammation. J Cell Biol. 2016; 215(1): 107– 119. 27738004 PMC5057286
  54. [57]Heasman SJ, Carlin LM, Cox S, et al. Coordinated RhoA signaling at the leading edge and uropod is required for T cell transendothelial migration. J Cell Biol. 2010; 190(4): 553 563. 20733052 PMC2928012
  55. [58]Hind LE, Vincent WJ, Huttenlocher A. Leading from the Back: the role of the uropod in neutrophil polarization and migration. Dev Cell. 2016; 38(2): 161– 169. 27459068 PMC4982870
  56. [59]Huang I-H, Hsiao C-T, Wu J-C, et al. GEF-H1 controls focal adhesion signaling that regulates mesenchymal stem cell lineage commitment. J Cell Sci. 2014; 127(19): 4186– 4200. 25107365 PMC4179489
  57. [60]Guilluy C, Swaminathan V, Garcia-Mata R, et al. The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins. Nature Cell Biol. 2011; 13(6): 722. 21572419 PMC3107386
  58. [61]Rafiq NBM, Nishimura Y, Plotnikov SV, et al. A mechano-signalling network linking microtubules, myosin IIA filaments and integrin-based adhesions. Nat Mater. 2019; 18: 638– 649. 31114072
  59. [62]Fine N, Dimitriou ID, Rottapel R. Go with the flow: GEF-H1 mediated shear stress mechanotransduction in neutrophils. Small GTPases. 2017; 11: 1– 9. PMC6959313 29188751
  60. [63]Yoshida T, Tsujioka M, Honda S, et al. Autophagy suppresses cell migration by degrading GEF-H1, a RhoA GEF. Oncotarget. 2015; 7(23): 34420– 34429. PMC5085165 27120804
  61. [64]Bar-Sagi D, Hall A. Ras and Rho GTPases a family reunion. Cell. 2000; 103(2): 227– 238. 11057896
  62. [65]Olson MF, Paterson HF, Marshall CJ. Signals from Ras and Rho GTPases interact to regulate expression of p21Waf1/Cip1. Nature. 1998; 394(6690): 295– 299. 9685162
  63. [66]Prendergast GC, Khosravi-Far R, Solski PA, et al. Critical role of Rho in cell transformation by oncogenic Ras. Oncogene. 1995; 10: 2289– 2296. 7784077
  64. [67]Nie M, Aijaz S, San IVLC, et al. The Y‐box factor ZONAB/DbpA associates with GEF‐H1/Lfc and mediates Rho‐stimulated transcription. EMBO Rep. 2009; 10(10): 1125– 1131. 19730435 PMC2738780
  65. [68]Varma H, Yamamoto A, Sarantos MR, et al. Mutant huntingtin alters cell fate in response to microtubule depolymerization via the GEF-H1-RhoA-ERK pathway. J Biol Chem. 2010; 285(48): 37445– 37457. 20858895 PMC2988350
  66. [70]Claperon A, Therrien M. KSR and CNK: two scaffolds regulating RAS-mediated RAF activation. Oncogene. 2007; 26: 3143– 3158. 17496912
  67. [71]Tsapara A, Luthert P, Greenwood J, et al. The RhoA activator GEF-H1/Lfc Is a transforming growth factor-β target gene and effector that regulates α-smooth muscle actin expression and cell migration. Mol Biol Cell. 2010; 21(6): 860– 870. 20089843 PMC2836967
  68. [72]Chen H, Gao F, He M, et al. Long‐Read RNA sequencing identifies alternative splice variants in hepatocellular carcinoma and tumor‐specific isoforms. Hepatology. 2019; 70(3): 1011– 1025. 30637779 PMC6766942
  69. [73]Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000; 100(1): 57– 70. 10647931
  70. [74]Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144(5): 646– 674. 21376230
  71. [75]Osborne LD, Li GZ, How T, et al. TGF-β regulates LARG and GEF-H1 during EMT to impact stiffening response to force and cell invasion. Mol Biol Cell. 2014; 25(22): mbc.E14–05–1015. PMC4230614 25143398
  72. [77]Massague J. TGFbeta signalling in context. Nat Rev Mol Cell Biol. 2012; 13: 616– 630. 22992590 PMC4027049
  73. [78]Colak S, Ten Dijke P, Targeting TG. F-beta signaling in cancer. Trends Cancer. 2017; 3(1): 56– 71. 28718426
  74. [79]Pickup MW, Mouw JK, Weaver VM. The extracellular matrix modulates the hallmarks of cancer. EMBO Rep. 2014; 15: 1243– 1253. 25381661 PMC4264927
  75. [80]Gao Y, Smith E, Ker E, et al. Role of RhoA-specific guanine exchange factors in regulation of endomitosis in megakaryocytes. Dev Cell. 2012; 22(3): 573– 584. 22387001 PMC3306542
  76. [82]Ridgway LD, Wetzel MD, Marchetti D. Heparanase modulates Shh and Wnt3a signaling in human medulloblastoma cells. Exp Ther Med. 2010; 2(2): 229– 237. PMC3063606 21442027
  77. [83]Ridgway LD, Wetzel MD, Marchetti D. Modulation of GEF‐H1 Induced Signaling by Heparanase in Brain Metastatic Melanoma Cells. J Cell Biochem. 2010; 111: 1299– 1309. 20803552 PMC3007595
  78. [84]Ridgway LD, Wetzel MD, Ngo JA, et al. Heparanase-Induced GEF-H1 signaling regulates the cytoskeletal dynamics of brain metastatic breast cancer cells. Mol Cancer Res. 2012; 10(6): 689– 702. 22513363 PMC5524200
  79. [85]Shiba Y, Randazzo PA. GEFH1 binds ASAP1 and regulates podosome formation. Biochem Bioph Res Commun. 2011; 406(4): 574– 579.. PMC3065500 21352810
  80. [86]Mizuarai S, Yamanaka K, Kotani H. Mutant p53 induces the GEF-H1 oncogene, a guanine nucleotide exchange factor-H1 for RhoA, resulting in accelerated cell proliferation in tumor cells. Cancer Res. 2006; 66(12): 6319– 6326. 16778209
  81. [87]Cheng IKC, Tsang BC, Lai KP, et al. GEF‐H1 over‐expression in hepatocellular carcinoma promotes cell motility via activation of RhoA signalling. J Pathol. 2012; 228(4): 575– 585. 22847784
  82. [88]Cao J, Yang T, Tang D, et al. Increased expression of GEF-H1 promotes colon cancer progression by RhoA signaling. Pathol Res Pract. 2019; 215(5): 1012– 1019. 30846413
  83. [89]Guo B, Hui Q, Zhang Y, et al. miR-194 is a negative regulator of GEF-H1 pathway in melanoma. Oncol Rep. 2016; 36(4): 2412– 2420. 27573550
  84. [90]Kent OA, Sandi M-J, Rottapel R. Co-dependency between KRAS addiction and ARHGEF2 promotes an adaptive escape from MAPK pathway inhibition. Small GTPases. 2017; 10: 1– 8. PMC6748365 28656876
  85. [91]Zuber J, Tchernitsa OI, Hinzmann B, et al. A genome-wide survey of RAS transformation targets. Nat Genet. 2000; 24(2): 144– 152. 10655059
  86. [92]Cerione RA, Zheng Y. The Dbl family of oncogenes. Curr Opin Cell Biol. 1996; 8(2): 216– 222. 8791419
  87. [93]Brecht M, Steenvoorden ACM, Collard JG, et al. Activation of gef‐h1, a guanine nucleotide exchange factor for RhoA, by DNA transfection. Int J Cancer. 2005; 113(4): 533– 540. 15455375
  88. [94]Kurozumi K, Nakano Y, Ishida J, et al. High-grade glioneuronal tumor with an ARHGEF2–NTRK1 fusion gene. Brain Tumor Pathol. 2019; 36(3): 121– 128. 31011918
  89. [95]Punt J, Jones PP, Kuby J, et al. Kuby immunology. Eighth edition ed. W.H. Freeman; 2019.
  90. [96]Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011; 34(5): 637– 650. 21616434
  91. [97]Yoneyama M, Onomoto K, Jogi M, et al. Viral RNA detection by RIG-I-like receptors. Curr Opin Immunol. 2015; 32: 48– 53. 25594890
  92. [98]Philpott DJ, Sorbara MT, Robertson SJ, et al. NOD proteins: regulators of inflammation in health and disease. Nat Rev Immunol. 2014; 14(1): 9– 23. 24336102
  93. [99]Colonne PM, Winchell CG, Voth DE. Hijacking host cell highways: manipulation of the host actin cytoskeleton by obligate intracellular bacterial pathogens. Front Cell Infect Microbiol. 2016; 6: 107. 27713866 PMC5031698
  94. [100]Mostowy S, Shenoy AR. The cytoskeleton in cell-autonomous immunity: structural determinants of host defence. Nat Rev Immunol. 2015; 15: 559– 573. 26292640 PMC4869833
  95. [101]Samarin SN, Ivanov AI, Flatau G, et al. Rho/ Rho-associated kinase-ii signaling mediates disassembly of epithelial apical junctions. Mol Biol Cell. 2007; 18(9): 3429– 3439. 17596509 PMC1951751
  96. [102]Schossleitner K, Rauscher S, Groger M, et al. Evidence that cingulin regulates endothelial barrier function in vitro and in vivo. Arterioscler Thromb Vasc Biol. 2016; 36: 647– 654. 26821949
  97. [103]Birukova AA, Adyshev D, Gorshkov B, et al. GEF-H1 is involved in agonist-induced human pulmonary endothelial barrier dysfunction. Am J Physiol Lung Cell Mol Physiol. 2006; 290(3): L540– L548. 16257999
  98. [105]Chiang H-S, Zhao Y, Song J-H, et al. GEF-H1 controls microtubule-dependent sensing of nucleic acids for antiviral host defenses. Nat Immunol. 2014; 15(1): 63– 71. 24270516 PMC4066330
  99. [106]Lund JM, Alexopoulou L, Sato A, et al. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc Natl Acad Sci USA. 2004; 101(15): 5598– 5603. 15034168 PMC397437
  100. [107]Alexopoulou L, Holt AC, Medzhitov R, et al. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001; 413(6857): 732– 738. 11607032
  101. [108]Zhao Y, Zagani R, Park S-M, et al. Microbial recognition by GEF-H1 controls IKKε mediated activation of IRF5. Nat Commun. 2019; 10(1): 1349. 30902986 PMC6430831
  102. [109]Barbieri JT, Riese MJ, Aktories K. Bacterial toxins that modify the actin cytoskeleton. Annu Rev Cell Dev Biol. 2002; 18(1): 315– 344. 12142277
  103. [110]Fukazawa A, Alonso C, Kurachi K, et al. GEF-H1 mediated control of NOD1 dependent NF-κB activation by shigella effectors. PLoS Pathog. 2008; 4(11): e1000228. 19043560 PMC2583055
  104. [111]Matsuzawa T, Kuwae A, Yoshida S, et al. Enteropathogenic Escherichia coli activates the RhoA signaling pathway via the stimulation of GEF‐H1. Embo J. 2004; 23(17): 3570– 3582. 15318166 PMC516631
  105. [112]Hiyoshi H, Okada R, Matsuda S, et al. Interaction between the type III effector VopO and GEF-H1 activates the RhoA-rock pathway. PLoS Pathog. 2015; 11: e1004694. 25738744 PMC4349864
  106. [113]Guo F, Tang J, Zhou Z, et al. GEF-H1-RhoA signaling pathway mediates LPS-induced NF-κB transactivation and IL-8 synthesis in endothelial cells. Mol Immunol. 2012; 50(1–2): 98– 107. 22226472
  107. [114]Guo F, Xing Y, Zhou Z, et al. Guanine-nucleotide exchange factor H1 mediates lipopolysaccharide-induced interleukin 6 and tumor necrosis factor &agr; expression in endothelial cells via activation of nuclear factor κB. Shock. 2012; 37(5): 531– 538. 22301607
  108. [115]Tian Y, Gawlak G, O’Donnell JJ, et al. Modulation of endothelial inflammation by low and high magnitude cyclic stretch. PLoS One. 2016; 11(4): e0153387. 27128976 PMC4851399
  109. [116]Mambetsariev I, Tian Y, Wu T, et al. Stiffness-activated GEF-H1 expression exacerbates LPS-induced lung inflammation. PLoS One. 2014; 9(4): e92670. 24739883 PMC3989185
  110. [117]Waheed F, Speight P, Kawai G, et al. Extracellular signal-regulated kinase and GEF-H1 mediate depolarization-induced Rho activation and paracellular permeability increase. Am J Physiol Cell Physiol. 2010; 298(6): C1376– C1387. 20237148 PMC3226803
  111. [118]Kakiashvili E, Dan Q, Vandermeer M, et al. The epidermal growth factor receptor mediates tumor necrosis factor-α-induced activation of the ERK/GEF-H1/RhoA pathway in tubular epithelium. J Biol Chem. 2011; 286(11): 9268– 9279. 21212278 PMC3059019
  112. [119]Dan Q, Shi Y, Rabani R, et al. Claudin-2 suppresses GEF-H1, RHOA, and MRTF, thereby impacting proliferation and profibrotic phenotype of tubular cells. J Biol Chem. 2019; 294(42): 15446– 15465. 31481470 PMC6802501
  113. [120]Martin-Martin N, Dan Q, Amoozadeh Y, et al. RhoA and Rho kinase mediate cyclosporine A and sirolimus-induced barrier tightening in renal proximal tubular cells. Int J Biochem Cell Biol. 2012; 44(1): 178– 188. 22062948
  114. [121]Birukova AA, Fu P, Xing J, et al. Mechanotransduction by GEF-H1 as a novel mechanism of ventilator-induced vascular endothelial permeability. Am J Physiol Lung Cell Mol Physiol. 2010; 298(6): L837– L848. 20348280 PMC2886610
  115. [122]Tian X, Tian Y, Gawlak G, et al. Control of vascular permeability by atrial natriuretic peptide via a GEF-H1-dependent mechanism. J Biol Chem. 2014; 289(8): 5168– 5183. 24352660 PMC3931074
  116. [123]Tian Y, Mambetsariev I, Sarich N, et al. Role of microtubules in attenuation of PepG-induced vascular endothelial dysfunction by atrial natriuretic peptide. Biochim Biophys Acta Mol Basis Dis. 2015; 1852(1): 104– 119. PMC4268173 25445540
  117. [124]Stenmark H. Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol. 2009; 10: 513– 525. 19603039
  118. [125]Wu H, Rossi G, Brennwald P. The ghost in the machine: small GTPases as spatial regulators of exocytosis. Trends Cell Biol. 2008; 18(9): 397– 404. 18706813 PMC6521695
  119. [126]Feig LA. Ral-GTPases: approaching their 15 minutes of fame. Trends Cell Biol. 2003; 13(8): 419– 425. 12888294
  120. [127]Pathak R, Delorme-Walker VD, Howell MC, et al. The microtubule-associated rho activating factor GEF-H1 interacts with exocyst complex to regulate vesicle traffic. Dev Cell. 2012; 23(2): 397 411. 22898781 PMC3422510
  121. [128]Biondini M, Duclos G, Meyer-Schaller N, et al. RalB regulates contractility-driven cancer dissemination upon TGFβ stimulation via the RhoGEF GEF-H1. Sci Rep. 2015; 5(1): 11759. 26152517 PMC4495419
  122. [129]Sáez JJ, Diaz J, Ibañez J, et al. The exocyst controls lysosome secretion and antigen extraction at the immune synapse of B cells. J Cell Biol. 2019; 218(7): 2247– 2264. 31197029 PMC6605794
  123. [130]Eisler SA, Curado F, Link G, et al. A Rho signaling network links microtubules to PKD controlled carrier transport to focal adhesions. eLife. 2018; 7: e35907. 30028295 PMC6070338
  124. [132]Ryan XP, Alldritt J, Svenning P, et al. The Rho-specific GEF Lfc interacts with neurabin and spinophilin to regulate dendritic spine morphology. Neuron. 2005; 47: 85– 100. 15996550
  125. [133]Nakahata Y, Yasuda R. Plasticity of spine structure: local signaling, translation and cytoskeletal reorganization. Front Synaptic Neurosci. 2018; 10: 29. 30210329 PMC6123351
  126. [134]Gauthier-Fisher A, Lin DC, Greeve M, et al. Lfc and Tctex-1 regulate the genesis of neurons from cortical precursor cells. Nat Neurosci. 2009; 12: 735– 744. 19448628
  127. [135]Noctor SC, Martinez-Cerdeno V, Ivic L, et al. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat Neurosci. 2004; 7(2): 136– 144. 14703572
  128. [136]Luo T, Roman P, Liu C, et al. Upregulation of the GEF-H1 pathway after transient cerebral ischemia. Exp Neurol. 2015; 263: 306– 313. 25447939 PMC4262550
  129. [137]Ravindran E, Hu H, Yuzwa SA, et al. Homozygous ARHGEF2 mutation causes intellectual disability and midbrain-hindbrain malformation. PLoS Genet. 2017; 13: e1006746. 28453519 PMC5428974
  130. [138]Fritzlar S, White PA, Mackenzie JM. The microtubule-associated innate immune sensor GEF-H1 does not influence mouse norovirus replication in murine macrophages. Viruses. 2019; 11(1): 47. PMC6356845 30634661
  131. [140]Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013; 6: pl1. 23550210 PMC4160307

Cited by

Sorted by citations

Authors
Joo, E., & Olson, M. F.
Affiliations
Toronto Metropolitan University (CA)
Corresponding author
Olson, Michael F
ORCID
Olson, Michael F
Venue
Small GTPases
Publisher
Informa UK Limited
Published
2020-10-30
Volume
12
Issue
5-6
Pages
358-371
ISSN
  • 2154-1248 (ISSN-L)
  • 2154-1256
DOI
10.1080/21541248.2020.1840889
PMC
PMC8583009
OpenAlex
W3096083543
Cited by
56
References
9
Citations by year
2026: 9 · 2025: 16 · 2024: 10 · 2023: 7 · 2022: 11 · 2021: 3
FWCI
0.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Small GTPases (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Canada Research Chairs (950–231665)
  • Canadian Institutes of Health Research (PJT-169125, PJT–169106)
  • Natural Sciences and Engineering Research Council of Canada (RGPIN–2020–05388)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Keywords
GEF-H1, RhoB, Rho GTPases, guanine nucleotide exchange factor, microtubule association, microtubule assembly, RhoA, GTPase regulation, molecular switches, human disease
MeSH terms
Animals, Disease, Gene Expression Regulation, Humans, Microtubules, Rho Guanine Nucleotide Exchange Factors

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