CoChat
Sign Up
Cited by 539Protein Kinase Regulation and GTPase SignalingCellular Mechanics and InteractionsCellular transport and secretion

Rho GTPase signaling complexes in cell migration and invasion

Open access
Lawson, Campbell D., Ridley, Anne J.·2018·Journal of Cell Biology
DOI 10.1083/jcb.201612069PMC PMC5800797
Open this paper in CoChat — free accountOpen PDF

Abstract

Cell migration is dependent on the dynamic formation and disassembly of actin filament–based structures, including lamellipodia, filopodia, invadopodia, and membrane blebs, as well as on cell–cell and cell–extracellular matrix adhesions. These processes all involve Rho family small guanosine triphosphatases (GTPases), which are regulated by the opposing actions of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Rho GTPase activity needs to be precisely tuned at distinct cellular locations to enable cells to move in response to different environments and stimuli. In this review, we focus on the ability of RhoGEFs and RhoGAPs to form complexes with diverse binding partners, and describe how this influences their ability to control localized GTPase activity in the context of migration and invasion.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1083/jcb.201612069

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Y-27632 is an inhibitor of Rho-associated protein kinase (ROCK), a kinase acting downstream of RhoA.

    “Treatment with Y-27632, an inhibitor of Rho-associated protein kinase (ROCK), a kinase acting downstream of RhoA 50-52 , had no strong effect on actin organization or cell shape in these conditions (Fig. 2a,c,e and Extended Data Fig. 2a-f), in agreement with serum starvation reducing the baseline RhoA activity.”

    From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [51]

    The Rho-specific GEF complexes section identifies ROCK as a RHOA effector, supporting the downstream relationship. Our copy does not identify Y-27632 as a ROCK inhibitor (searched: “Y-27632” and “Y-27632 inhibitor of ROCK”). The citing paper’s observation about actin organization and cell shape is not part of the claim attributed to this source. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Phosphorylated myosin light chain (p-MLC) is a downstream target of RhoA signalling.

    “myosin light chain (p-MLC), a downstream target of RhoA signalling 51”

    From Taxane-induced conformational changes in the microtubule lattice activate GEF-H1-dependent RhoA signalling (2026) · cites this paper as [51]

    The Rho-specific GEF complexes section says that GEF-H1 activates RHOA to increase actomyosin contractility. That supports a downstream effect of RhoA signalling, but our copy does not identify phosphorylated myosin light chain (p-MLC) as that downstream target; searches for “myosin light chain” and “MLC phosphorylation” did not find it. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 106

  1. Aittaleb M., Boguth C.A., and Tesmer J.J. 2010 Structure and function of heterotrimeric G protein-regulated Rho guanine nucleotide exchange factors. Mol. Pharmacol. 77: 111– 125. 10.1124/mol.109.061234 19880753 PMC2812070 · DOI
  2. Arthur W.T., and Burridge K. 2001 RhoA inactivation by p190RhoGAP regulates cell spreading and migration by promoting membrane protrusion and polarity. Mol. Biol. Cell. 12: 2711– 2720. 10.1091/mbc.12.9.2711 11553710 PMC59706 · DOI
  3. Arthur W.T., Petch L.A., and Burridge K. 2000 Integrin engagement suppresses RhoA activity via a c-Src-dependent mechanism. Curr. Biol. 10: 719– 722. 10.1016/S0960-9822(00)00537-6 10873807 · DOI
  4. Bartolomé R.A., Díaz-Martínez M., Coló G.P., Arellano-Sánchez N., Torres-Ayuso P., Kleinovink J.W., Mérida I., and Teixidó J. 2014 A Blk-p190RhoGAP signaling module downstream of activated Gα13 functionally opposes CXCL12-stimulated RhoA activation and cell invasion. Cell. Signal. 26: 2551– 2561. 10.1016/j.cellsig.2014.07.008 25025568 · DOI
  5. Basile J.R., Barac A., Zhu T., Guan K.L., and Gutkind J.S. 2004 Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B. Cancer Res. 64: 5212– 5224. 10.1158/0008-5472.CAN-04-0126 15289326 · DOI
  6. Binamé F., Bidaud-Meynard A., Magnan L., Piquet L., Montibus B., Chabadel A., Saltel F., Lagrée V., and Moreau V. 2016 Cancer-associated mutations in the protrusion-targeting region of p190RhoGAP impact tumor cell migration. J. Cell Biol. 214: 859– 873. 10.1083/jcb.201601063 27646271 PMC5037408 · DOI
  7. Blumberg P.M., Kedei N., Lewin N.E., Yang D., Czifra G., Pu Y., Peach M.L., and Marquez V.E. 2008 Wealth of opportunity - the C1 domain as a target for drug development. Curr. Drug Targets. 9: 641– 652. 10.2174/138945008785132376 18691011 PMC3420355 · DOI
  8. Bos J.L., Rehmann H., and Wittinghofer A. 2007 GEFs and GAPs: critical elements in the control of small G proteins. Cell. 129: 865– 877. 10.1016/j.cell.2007.05.018 17540168 · DOI · Paper page
  9. Braun A.C., and Olayioye M.A. 2015 Rho regulation: DLC proteins in space and time. Cell. Signal. 27: 1643– 1651. 10.1016/j.cellsig.2015.04.003 25889896 · DOI
  10. Bravo-Cordero J.J., Oser M., Chen X., Eddy R., Hodgson L., and Condeelis J. 2011 A novel spatiotemporal RhoC activation pathway locally regulates cofilin activity at invadopodia. Curr. Biol. 21: 635– 644. 10.1016/j.cub.2011.03.039 21474314 PMC3081966 · DOI
  11. Bravo-Cordero J.J., Sharma V.P., Roh-Johnson M., Chen X., Eddy R., Condeelis J., and Hodgson L. 2013 Spatial regulation of RhoC activity defines protrusion formation in migrating cells. J. Cell Sci. 126: 3356– 3369. 10.1242/jcs.123547 23704350 PMC3730245 · DOI
  12. Bustos R.I., Forget M.A., Settleman J.E., and Hansen S.H. 2008 Coordination of Rho and Rac GTPase function via p190B RhoGAP. Curr. Biol. 18: 1606– 1611. 10.1016/j.cub.2008.09.019 18948007 PMC4084715 · DOI
  13. Cao X., Voss C., Zhao B., Kaneko T., and Li S.S. 2012 Differential regulation of the activity of deleted in liver cancer 1 (DLC1) by tensins controls cell migration and transformation. Proc. Natl. Acad. Sci. USA. 109: 1455– 1460. 10.1073/pnas.1114368109 22307599 PMC3277110 · DOI
  14. Cao X., Kaneko T., Li J.S., Liu A.D., Voss C., and Li S.S. 2015 A phosphorylation switch controls the spatiotemporal activation of Rho GTPases in directional cell migration. Nat. Commun. 6: 7721 10.1038/ncomms8721 26166433 PMC4510974 · DOI
  15. Carmona G., Perera U., Gillett C., Naba A., Law A.L., Sharma V.P., Wang J., Wyckoff J., Balsamo M., Mosis F., 2016 Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE. Oncogene. 35: 5155– 5169. 10.1038/onc.2016.47 26996666 PMC5031503 · DOI
  16. Casalou C., Faustino A., and Barral D.C. 2016 Arf proteins in cancer cell migration. Small GTPases. 7: 270– 282. 10.1080/21541248.2016.1228792 27589148 PMC5129889 · DOI
  17. Chávez-Vargas L., Adame-García S.R., Cervantes-Villagrana R.D., Castillo-Kauil A., Bruystens J.G., Fukuhara S., Taylor S.S., Mochizuki N., Reyes-Cruz G., and Vázquez-Prado J. 2016 Protein kinase A (PKA) type I interacts with P-Rex1, a Rac guanine nucleotide exchange factor: effect on PKA localization and P-Rex1 signaling. J. Biol. Chem. 291: 6182– 6199. 10.1074/jbc.M115.712216 26797121 PMC4813559 · DOI
  18. Connolly B.A., Rice J., Feig L.A., and Buchsbaum R.J. 2005 Tiam1-IRSp53 complex formation directs specificity of rac-mediated actin cytoskeleton regulation. Mol. Cell. Biol. 25: 4602– 4614. 10.1128/MCB.25.11.4602-4614.2005 15899863 PMC1140638 · DOI
  19. Coutinho-Budd J., Ghukasyan V., Zylka M.J., and Polleux F. 2012 The F-BAR domains from srGAP1, srGAP2 and srGAP3 regulate membrane deformation differently. J. Cell Sci. 125: 3390– 3401. 10.1242/jcs.098962 22467852 PMC3516379 · DOI
  20. De Pascalis C., and Etienne-Manneville S. 2017 Single and collective cell migration: the mechanics of adhesions. Mol. Biol. Cell. 28: 1833– 1846. 10.1091/mbc.E17-03-0134 28684609 PMC5541834 · DOI
  21. Diamantopoulou Z., White G., Fadlullah M.Z.H., Dreger M., Pickering K., Maltas J., Ashton G., MacLeod R., Baillie G.S., Kouskoff V., 2017 TIAM1 Antagonizes TAZ/YAP Both in the Destruction Complex in the Cytoplasm and in the Nucleus to Inhibit Invasion of Intestinal Epithelial Cells. Cancer Cell. 31: 621– 634. 28416184 PMC5425402
  22. Donnelly S.K., Cabrera R., Mao S.P.H., Christin J.R., Wu B., Guo W., Bravo-Cordero J.J., Condeelis J.S., Segall J.E., and Hodgson L. 2017 Rac3 regulates breast cancer invasion and metastasis by controlling adhesion and matrix degradation. J. Cell Biol. 216: 4331– 4349. 10.1083/jcb.201704048 29061650 PMC5716284 · DOI
  23. Dubash A.D., Wennerberg K., García-Mata R., Menold M.M., Arthur W.T., and Burridge K. 2007 A novel role for Lsc/p115 RhoGEF and LARG in regulating RhoA activity downstream of adhesion to fibronectin. J. Cell Sci. 120: 3989– 3998. 10.1242/jcs.003806 17971419 · DOI
  24. Endris V., Haussmann L., Buss E., Bacon C., Bartsch D., and Rappold G. 2011 SrGAP3 interacts with lamellipodin at the cell membrane and regulates Rac-dependent cellular protrusions. J. Cell Sci. 124: 3941– 3955. 10.1242/jcs.077081 22159416 · DOI
  25. Fine N., Dimitriou I.D., Rullo J., Sandí M.J., Petri B., Haitsma J., Ibrahim H., La Rose J., Glogauer M., Kubes P., 2016 GEF-H1 is necessary for neutrophil shear stress-induced migration during inflammation. J. Cell Biol. 215: 107– 119. 10.1083/jcb.201603109 27738004 PMC5057286 · DOI
  26. Foxall E., Pipili A., Jones G.E., and Wells C.M. 2016 Significance of kinase activity in the dynamic invadosome. Eur. J. Cell Biol. 95: 483– 492. 10.1016/j.ejcb.2016.07.002 27465307 · DOI
  27. Frank S.R., and Hansen S.H. 2008 The PIX-GIT complex: a G protein signaling cassette in control of cell shape. Semin. Cell Dev. Biol. 19: 234– 244. 10.1016/j.semcdb.2008.01.002 18299239 PMC2394276 · DOI
  28. Frank S.R., Köllmann C.P., van Lidth de Jeude J.F., Thiagarajah J.R., Engelholm L.H., Frödin M., and Hansen S.H. 2017 The focal adhesion-associated proteins DOCK5 and GIT2 comprise a rheostat in control of epithelial invasion. Oncogene. 36: 1816– 1828. 10.1038/onc.2016.345 27669437 PMC5366285 · DOI
  29. Friedl P., and Mayor R. 2017 Tuning Collective Cell Migration by Cell-Cell Junction Regulation. Cold Spring Harb. Perspect. Biol. 9: a029199 10.1101/cshperspect.a029199 28096261 PMC5378050 · DOI
  30. Fritz R.D., and Pertz O. 2016 The dynamics of spatio-temporal Rho GTPase signaling: formation of signaling patterns. F1000Res. 5: Faculty Rev–749 10.12688/f1000research.7370.1 PMC4847568 27158467 · DOI
  31. Gadea G., and Blangy A. 2014 Dock-family exchange factors in cell migration and disease. Eur. J. Cell Biol. 93: 466– 477. 10.1016/j.ejcb.2014.06.003 25022758 · DOI · Paper page
  32. Goicoechea S.M., Awadia S., and Garcia-Mata R. 2014 I’m coming to GEF you: Regulation of RhoGEFs during cell migration. Cell Adhes. Migr. 8: 535– 549. 10.4161/cam.28721 PMC4594598 25482524 · DOI
  33. Grimsley C.M., Kinchen J.M., Tosello-Trampont A.C., Brugnera E., Haney L.B., Lu M., Chen Q., Klingele D., Hengartner M.O., and Ravichandran K.S. 2004 Dock180 and ELMO1 proteins cooperate to promote evolutionarily conserved Rac-dependent cell migration. J. Biol. Chem. 279: 6087– 6097. 10.1074/jbc.M307087200 14638695 · DOI · Paper page
  34. Guilluy C., Swaminathan V., Garcia-Mata R., O’Brien E.T., Superfine R., and Burridge K. 2011 The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins. Nat. Cell Biol. 13: 722– 727. 10.1038/ncb2254 21572419 PMC3107386 · DOI
  35. Haga R.B., and Ridley A.J. 2016 Rho GTPases: Regulation and roles in cancer cell biology. Small GTPases. 7: 207– 221. 10.1080/21541248.2016.1232583 27628050 PMC5129894 · DOI
  36. Haynie D.T. 2014 Molecular physiology of the tensin brotherhood of integrin adaptor proteins. Proteins. 82: 1113– 1127. 10.1002/prot.24560 24634006 · DOI
  37. Heasman S.J., Carlin L.M., Cox S., Ng T., and Ridley A.J. 2010 Coordinated RhoA signaling at the leading edge and uropod is required for T cell transendothelial migration. J. Cell Biol. 190: 553– 563. 10.1083/jcb.201002067 20733052 PMC2928012 · DOI
  38. Hernández-Negrete I., Carretero-Ortega J., Rosenfeldt H., Hernández-García R., Calderón-Salinas J.V., Reyes-Cruz G., Gutkind J.S., and Vázquez-Prado J. 2007 P-Rex1 links mammalian target of rapamycin signaling to Rac activation and cell migration. J. Biol. Chem. 282: 23708– 23715. 10.1074/jbc.M703771200 17565979 · DOI
  39. Hernández-Vásquez M.N., Adame-García S.R., Hamoud N., Chidiac R., Reyes-Cruz G., Gratton J.P., Côté J.F., and Vázquez-Prado J. 2017 Cell adhesion controlled by adhesion G protein-coupled receptor GPR124/ADGRA2 is mediated by a protein complex comprising intersectins and Elmo-Dock. J. Biol. Chem. 292: 12178– 12191. 10.1074/jbc.M117.780304 28600358 PMC5519368 · DOI
  40. Hodge R.G., and Ridley A.J. 2016 Regulating Rho GTPases and their regulators. Nat. Rev. Mol. Cell Biol. 17: 496– 510. 10.1038/nrm.2016.67 27301673 · DOI
  41. Hordijk P.L., ten Klooster J.P., van der Kammen R.A., Michiels F., Oomen L.C., and Collard J.G. 1997 Inhibition of invasion of epithelial cells by Tiam1-Rac signaling. Science. 278: 1464– 1466. 10.1126/science.278.5342.1464 9367959 · DOI
  42. Iwanicki M.P., Vomastek T., Tilghman R.W., Martin K.H., Banerjee J., Wedegaertner P.B., and Parsons J.T. 2008 FAK, PDZ-RhoGEF and ROCKII cooperate to regulate adhesion movement and trailing-edge retraction in fibroblasts. J. Cell Sci. 121: 895– 905. 10.1242/jcs.020941 18303050 · DOI
  43. Jacquemet G., Green D.M., Bridgewater R.E., von Kriegsheim A., Humphries M.J., Norman J.C., and Caswell P.T. 2013 a RCP-driven α5β1 recycling suppresses Rac and promotes RhoA activity via the RacGAP1-IQGAP1 complex. J. Cell Biol. 202: 917– 935. 10.1083/jcb.201302041 24019536 PMC3776348 · DOI
  44. Jacquemet G., Morgan M.R., Byron A., Humphries J.D., Choi C.K., Chen C.S., Caswell P.T., and Humphries M.J. 2013 b Rac1 is deactivated at integrin activation sites through an IQGAP1-filamin-A-RacGAP1 pathway. J. Cell Sci. 126: 4121– 4135. 10.1242/jcs.121988 23843620 PMC3772387 · DOI
  45. Katoh H., and Negishi M. 2003 RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo. Nature. 424: 461– 464. 10.1038/nature01817 12879077 · DOI
  46. Kim E.K., Yun S.J., Ha J.M., Kim Y.W., Jin I.H., Yun J., Shin H.K., Song S.H., Kim J.H., Lee J.S., 2011 Selective activation of Akt1 by mammalian target of rapamycin complex 2 regulates cancer cell migration, invasion, and metastasis. Oncogene. 30: 2954– 2963. 10.1038/onc.2011.22 21339740 · DOI
  47. Kiyokawa E., Hashimoto Y., Kobayashi S., Sugimura H., Kurata T., and Matsuda M. 1998 a Activation of Rac1 by a Crk SH3-binding protein, DOCK180. Genes Dev. 12: 3331– 3336. 10.1101/gad.12.21.3331 9808620 PMC317231 · DOI
  48. Kiyokawa E., Hashimoto Y., Kurata T., Sugimura H., and Matsuda M. 1998 b Evidence that DOCK180 up-regulates signals from the CrkII-p130(Cas) complex. J. Biol. Chem. 273: 24479– 24484. 10.1074/jbc.273.38.24479 9733740 · DOI
  49. Koubek E.J., and Santy L.C. 2016 ARF1 and ARF6 regulate recycling of GRASP/Tamalin and the Rac1-GEF Dock180 during HGF-induced Rac1 activation. Small GTPases. 1– 18. 10.1080/21541248.2016.1219186 PMC5927479 27562622 · DOI
  50. Kutys M.L., and Yamada K.M. 2014 An extracellular-matrix-specific GEF-GAP interaction regulates Rho GTPase crosstalk for 3D collagen migration. Nat. Cell Biol. 16: 909– 917. 10.1038/ncb3026 25150978 PMC4150836 · DOI
  51. Lahoz A., and Hall A. 2013 A tumor suppressor role for srGAP3 in mammary epithelial cells. Oncogene. 32: 4854– 4860. 10.1038/onc.2012.489 23108406 · DOI
  52. Laurin M., and Côté J.F. 2014 Insights into the biological functions of Dock family guanine nucleotide exchange factors. Genes Dev. 28: 533– 547. 10.1101/gad.236349.113 24637113 PMC3967044 · DOI · Paper page
  53. Lawson C.D., and Burridge K. 2014 The on-off relationship of Rho and Rac during integrin-mediated adhesion and cell migration. Small GTPases. 5: e27958 10.4161/sgtp.27958 24607953 PMC4114617 · DOI
  54. Li H., Yang L., Fu H., Yan J., Wang Y., Guo H., Hao X., Xu X., Jin T., and Zhang N. 2013 Association between Gαi2 and ELMO1/Dock180 connects chemokine signalling with Rac activation and metastasis. Nat. Commun. 4: 1706 10.1038/ncomms2680 23591873 PMC3644068 · DOI
  55. Li L., Guris D.L., Okura M., and Imamoto A. 2003 Translocation of CrkL to focal adhesions mediates integrin-induced migration downstream of Src family kinases. Mol. Cell. Biol. 23: 2883– 2892. 10.1128/MCB.23.8.2883-2892.2003 12665586 PMC152569 · DOI
  56. Lim Y., Lim S.T., Tomar A., Gardel M., Bernard-Trifilo J.A., Chen X.L., Uryu S.A., Canete-Soler R., Zhai J., Lin H., 2008 PyK2 and FAK connections to p190Rho guanine nucleotide exchange factor regulate RhoA activity, focal adhesion formation, and cell motility. J. Cell Biol. 180: 187– 203. 10.1083/jcb.200708194 18195107 PMC2213606 · DOI
  57. Ma X., Zhao Y., Daaka Y., and Nie Z. 2012 Acute activation of β2-adrenergic receptor regulates focal adhesions through βArrestin2- and p115RhoGEF protein-mediated activation of RhoA. J. Biol. Chem. 287: 18925– 18936. 10.1074/jbc.M112.352260 22500016 PMC3365927 · DOI
  58. Mack N.A., and Georgiou M. 2014 The interdependence of the Rho GTPases and apicobasal cell polarity. Small GTPases. 5: 10 10.4161/21541248.2014.973768 25469537 PMC4601375 · DOI
  59. Manser E., Loo T.H., Koh C.G., Zhao Z.S., Chen X.Q., Tan L., Tan I., Leung T., and Lim L. 1998 PAK kinases are directly coupled to the PIX family of nucleotide exchange factors. Mol. Cell. 1: 183– 192. 10.1016/S1097-2765(00)80019-2 9659915 · DOI
  60. Marei H., Carpy A., Woroniuk A., Vennin C., White G., Timpson P., Macek B., and Malliri A. 2016 Differential Rac1 signalling by guanine nucleotide exchange factors implicates FLII in regulating Rac1-driven cell migration. Nat. Commun. 7: 10664 10.1038/ncomms10664 26887924 PMC4759627 · DOI
  61. Mayeenuddin L.H., and Garrison J.C. 2006 Phosphorylation of P-Rex1 by the cyclic AMP-dependent protein kinase inhibits the phosphatidylinositiol (3,4,5)-trisphosphate and Gbetagamma-mediated regulation of its activity. J. Biol. Chem. 281: 1921– 1928. 10.1074/jbc.M506035200 16301320 · DOI
  62. Mikelis C.M., Palmby T.R., Simaan M., Li W., Szabo R., Lyons R., Martin D., Yagi H., Fukuhara S., Chikumi H., 2013 PDZ-RhoGEF and LARG are essential for embryonic development and provide a link between thrombin and LPA receptors and Rho activation. J. Biol. Chem. 288: 12232– 12243. 10.1074/jbc.M112.428599 23467409 PMC3636907 · DOI
  63. Miller N.L., Lawson C., Kleinschmidt E.G., Tancioni I., Uryu S., and Schlaepfer D.D. 2013 A non-canonical role for Rgnef in promoting integrin-stimulated focal adhesion kinase activation. J. Cell Sci. 126: 5074– 5085. 10.1242/jcs.135509 24006257 PMC3820247 · DOI
  64. Miller N.L., Kleinschmidt E.G., and Schlaepfer D.D. 2014 RhoGEFs in cell motility: novel links between Rgnef and focal adhesion kinase. Curr. Mol. Med. 14: 221– 234. 10.2174/1566524014666140128110339 24467206 PMC4075329 · DOI
  65. Mitin N., Roberts P.J., Chenette E.J., and Der C.J. 2012 Posttranslational lipid modification of Rho family small GTPases. Methods Mol. Biol. 827: 87– 95. 10.1007/978-1-61779-442-1_6 22144269 · DOI
  66. Mori M., Saito K., and Ohta Y. 2014 ARHGAP22 localizes at endosomes and regulates actin cytoskeleton. PLoS One. 9: e100271 10.1371/journal.pone.0100271 24933155 PMC4059726 · DOI
  67. Nayal A., Webb D.J., Brown C.M., Schaefer E.M., Vicente-Manzanares M., and Horwitz A.R. 2006 Paxillin phosphorylation at Ser273 localizes a GIT1-PIX-PAK complex and regulates adhesion and protrusion dynamics. J. Cell Biol. 173: 587– 589. 10.1083/jcb.200509075 16717130 PMC2063867 · DOI
  68. Nicholas N.S., Pipili A., Lesjak M.S., Ameer-Beg S.M., Geh J.L., Healy C., MacKenzie Ross A.D., Parsons M., Nestle F.O., Lacy K.E., and Wells C.M. 2016 PAK4 suppresses PDZ-RhoGEF activity to drive invadopodia maturation in melanoma cells. Oncotarget. 7: 70881– 70897. 27765920 PMC5342596
  69. Nishimura T., Yamaguchi T., Kato K., Yoshizawa M., Nabeshima Y., Ohno S., Hoshino M., and Kaibuchi K. 2005 PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nat. Cell Biol. 7: 270– 277. 10.1038/ncb1227 15723051 · DOI
  70. Nola S., Sebbagh M., Marchetto S., Osmani N., Nourry C., Audebert S., Navarro C., Rachel R., Montcouquiol M., Sans N., 2008 Scrib regulates PAK activity during the cell migration process. Hum. Mol. Genet. 17: 3552– 3565. 10.1093/hmg/ddn248 18716323 · DOI
  71. Ohta Y., Hartwig J.H., and Stossel T.P. 2006 FilGAP, a Rho- and ROCK-regulated GAP for Rac binds filamin A to control actin remodelling. Nat. Cell Biol. 8: 803– 814. 10.1038/ncb1437 16862148 · DOI
  72. Osmani N., Vitale N., Borg J.P., and Etienne-Manneville S. 2006 Scrib controls Cdc42 localization and activity to promote cell polarization during astrocyte migration. Curr. Biol. 16: 2395– 2405. 10.1016/j.cub.2006.10.026 17081755 · DOI · Paper page
  73. Paluch E.K., and Raz E. 2013 The role and regulation of blebs in cell migration. Curr. Opin. Cell Biol. 25: 582– 590. 10.1016/j.ceb.2013.05.005 23786923 PMC3989058 · DOI
  74. Patel M., Chiang T.C., Tran V., Lee F.J., and Côté J.F. 2011 The Arf family GTPase Arl4A complexes with ELMO proteins to promote actin cytoskeleton remodeling and reveals a versatile Ras-binding domain in the ELMO proteins family. J. Biol. Chem. 286: 38969– 38979. 10.1074/jbc.M111.274191 21930703 PMC3234722 · DOI
  75. Paterson E.K., and Courtneidge S.A. 2017 Invadosomes are coming: new insights into function and disease relevance. FEBS J. 10.1111/febs.14123 PMC6029861 28548369 · DOI
  76. Pegtel D.M., Ellenbroek S.I., Mertens A.E., van der Kammen R.A., de Rooij J., and Collard J.G. 2007 The Par-Tiam1 complex controls persistent migration by stabilizing microtubule-dependent front-rear polarity. Curr. Biol. 17: 1623– 1634. 10.1016/j.cub.2007.08.035 17825562 · DOI
  77. Perrot V., Vazquez-Prado J., and Gutkind J.S. 2002 Plexin B regulates Rho through the guanine nucleotide exchange factors leukemia-associated Rho GEF (LARG) and PDZ-RhoGEF. J. Biol. Chem. 277: 43115– 43120. 10.1074/jbc.M206005200 12183458 · DOI
  78. Plutoni C., Bazellieres E., Le Borgne-Rochet M., Comunale F., Brugues A., Séveno M., Planchon D., Thuault S., Morin N., Bodin S., 2016 P-cadherin promotes collective cell migration via a Cdc42-mediated increase in mechanical forces. J. Cell Biol. 212: 199– 217. 10.1083/jcb.201505105 26783302 PMC4738379 · DOI
  79. Radu M., Semenova G., Kosoff R., and Chernoff J. 2014 PAK signalling during the development and progression of cancer. Nat. Rev. Cancer. 14: 13– 25. 10.1038/nrc3645 24505617 PMC4115244 · DOI
  80. Rajagopal S., Ji Y., Xu K., Li Y., Wicks K., Liu J., Wong K.W., Herman I.M., Isberg R.R., and Buchsbaum R.J. 2010 Scaffold proteins IRSp53 and spinophilin regulate localized Rac activation by T-lymphocyte invasion and metastasis protein 1 (TIAM1). J. Biol. Chem. 285: 18060– 18071. 10.1074/jbc.M109.051490 20360004 PMC2878567 · DOI
  81. Razidlo G.L., Schroeder B., Chen J., Billadeau D.D., and McNiven M.A. 2014 Vav1 as a central regulator of invadopodia assembly. Curr. Biol. 24: 86– 93. 10.1016/j.cub.2013.11.013 24332539 PMC3917499 · DOI
  82. Ridley A.J. 2001 Rho GTPases and cell migration. J. Cell Sci. 114: 2713– 2722. 11683406
  83. Ridley A.J. 2015 Rho GTPase signalling in cell migration. Curr. Opin. Cell Biol. 36: 103– 112. 10.1016/j.ceb.2015.08.005 26363959 PMC4728192 · DOI
  84. Rosenberg B.J., Gil-Henn H., Mader C.C., Halo T., Yin T., Condeelis J., Machida K., Wu Y.I., and Koleske A.J. 2017 Phosphorylated cortactin recruits Vav2 guanine nucleotide exchange factor to activate Rac3 and promote invadopodial function in invasive breast cancer cells. Mol. Biol. Cell. 28: 1347– 1360. 10.1091/mbc.E16-12-0885 28356423 PMC5426849 · DOI
  85. Rossman K.L., Der C.J., and Sondek J. 2005 GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat. Rev. Mol. Cell Biol. 6: 167– 180. 10.1038/nrm1587 15688002 · DOI · Paper page
  86. Saito K., Ozawa Y., Hibino K., and Ohta Y. 2012 FilGAP, a Rho/Rho-associated protein kinase-regulated GTPase-activating protein for Rac, controls tumor cell migration. Mol. Biol. Cell. 23: 4739– 4750. 10.1091/mbc.E12-04-0310 23097497 PMC3521682 · DOI
  87. Sanz-Moreno V., Gadea G., Ahn J., Paterson H., Marra P., Pinner S., Sahai E., and Marshall C.J. 2008 Rac activation and inactivation control plasticity of tumor cell movement. Cell. 135: 510– 523. 10.1016/j.cell.2008.09.043 18984162 · DOI
  88. Schaefer A., Reinhard N.R., and Hordijk P.L. 2014 Toward understanding RhoGTPase specificity: structure, function and local activation. Small GTPases. 5: 6 10.4161/21541248.2014.968004 25483298 PMC4601309 · DOI
  89. Semprucci E., Tocci P., Cianfrocca R., Sestito R., Caprara V., Veglione M., Castro V.D., Spadaro F., Ferrandina G., Bagnato A., and Rosanò L. 2016 Endothelin A receptor drives invadopodia function and cell motility through the β-arrestin/PDZ-RhoGEF pathway in ovarian carcinoma. Oncogene. 35: 3432– 3442. 10.1038/onc.2015.403 26522724 · DOI
  90. Soderling S.H., Binns K.L., Wayman G.A., Davee S.M., Ong S.H., Pawson T., and Scott J.D. 2002 The WRP component of the WAVE-1 complex attenuates Rac-mediated signalling. Nat. Cell Biol. 4: 970– 975. 10.1038/ncb886 12447388 · DOI
  91. Tachibana M., Kiyokawa E., Hara S., Iemura S., Natsume T., Manabe T., and Matsuda M. 2009 Ankyrin repeat domain 28 (ANKRD28), a novel binding partner of DOCK180, promotes cell migration by regulating focal adhesion formation. Exp. Cell Res. 315: 863– 876. 10.1016/j.yexcr.2008.12.005 19118547 · DOI
  92. Tomar A., Lim S.T., Lim Y., and Schlaepfer D.D. 2009 A FAK-p120RasGAP-p190RhoGAP complex regulates polarity in migrating cells. J. Cell Sci. 122: 1852– 1862. 10.1242/jcs.046870 19435801 PMC2684836 · DOI
  93. Vincent A., Berthel E., Dacheux E., Magnard C., and Venezia N.L. 2016 BRCA1 affects protein phosphatase 6 signalling through its interaction with ANKRD28. Biochem. J. 473: 949– 960. 10.1042/BJ20150797 27026398 · DOI
  94. Wang S., Watanabe T., Matsuzawa K., Katsumi A., Kakeno M., Matsui T., Ye F., Sato K., Murase K., Sugiyama I., 2012 Tiam1 interaction with the PAR complex promotes talin-mediated Rac1 activation during polarized cell migration. J. Cell Biol. 199: 331– 345. 10.1083/jcb.201202041 23071154 PMC3471226 · DOI
  95. Ward J.D., Ha J.H., Jayaraman M., and Dhanasekaran D.N. 2015 LPA-mediated migration of ovarian cancer cells involves translocalization of Gαi2 to invadopodia and association with Src and β-pix. Cancer Lett. 356(2 Pt B): 382– 391. 10.1016/j.canlet.2014.09.030 25451317 PMC4821470 · DOI
  96. Welch H.C. 2015 Regulation and function of P-Rex family Rac-GEFs. Small GTPases. 6: 49– 70. 10.4161/21541248.2014.973770 25961466 PMC4601503 · DOI
  97. Wennerberg K., Forget M.A., Ellerbroek S.M., Arthur W.T., Burridge K., Settleman J., Der C.J., and Hansen S.H. 2003 Rnd proteins function as RhoA antagonists by activating p190 RhoGAP. Curr. Biol. 13: 1106– 1115. 10.1016/S0960-9822(03)00418-4 12842009 PMC6918695 · DOI
  98. White D.T., McShea K.M., Attar M.A., and Santy L.C. 2010 GRASP and IPCEF promote ARF-to-Rac signaling and cell migration by coordinating the association of ARNO/cytohesin 2 with Dock180. Mol. Biol. Cell. 21: 562– 571. 10.1091/mbc.E09-03-0217 20016009 PMC2820421 · DOI
  99. Wilson E., Leszczynska K., Poulter N.S., Edelmann F., Salisbury V.A., Noy P.J., Bacon A., Rappoport J.Z., Heath J.K., Bicknell R., and Heath V.L. 2014 RhoJ interacts with the GIT-PIX complex and regulates focal adhesion disassembly. J. Cell Sci. 127: 3039– 3051. 10.1242/jcs.140434 24928894 PMC4106786 · DOI
  100. Wuertenberger S., and Groemping Y. 2015 A single PXXP motif in the C-terminal region of srGAP3 mediates binding to multiple SH3 domains. FEBS Lett. 589: 1156– 1163. 10.1016/j.febslet.2015.03.014 25819436 · DOI
  101. Yamaguchi H., Lorenz M., Kempiak S., Sarmiento C., Coniglio S., Symons M., Segall J., Eddy R., Miki H., Takenawa T., and Condeelis J. 2005 Molecular mechanisms of invadopodium formation: The role of the N-WASP-Arp2/3 complex pathway and cofilin. J. Cell Biol. 168: 441– 452. 10.1083/jcb.200407076 15684033 PMC2171731 · DOI
  102. Yang Y., Marcello M., Endris V., Saffrich R., Fischer R., Trendelenburg M.F., Sprengel R., and Rappold G. 2006 MEGAP impedes cell migration via regulating actin and microtubule dynamics and focal complex formation. Exp. Cell Res. 312: 2379– 2393. 10.1016/j.yexcr.2006.04.001 16730001 · DOI
  103. Yoshimura Y., and Miki H. 2011 Dynamic regulation of GEF-H1 localization at microtubules by Par1b/MARK2. Biochem. Biophys. Res. Commun. 408: 322– 328. 10.1016/j.bbrc.2011.04.032 21513698 · DOI · Paper page
  104. Zaritsky A., Tseng Y.Y., Rabadán M.A., Krishna S., Overholtzer M., Danuser G., and Hall A. 2017 Diverse roles of guanine nucleotide exchange factors in regulating collective cell migration. J. Cell Biol. 216: 1543– 1556. 10.1083/jcb.201609095 28512143 PMC5461017 · DOI
  105. Zhou W., Li X., and Premont R.T. 2016 Expanding functions of GIT Arf GTPase-activating proteins, PIX Rho guanine nucleotide exchange factors and GIT-PIX complexes. J. Cell Sci. 129: 1963– 1974. 10.1242/jcs.179465 27182061 PMC6518221 · DOI
  106. Zuo Y., Oh W., and Frost J.A. 2014 Controlling the switches: Rho GTPase regulation during animal cell mitosis. Cell. Signal. 26: 2998– 3006. 10.1016/j.cellsig.2014.09.022 25286227 PMC4293258 · DOI

Cited by

Sorted by citations

Authors
Lawson, C. D., & Ridley, A. J.
Affiliations
King's College London (GB)
Corresponding author
Ridley, Anne J.
ORCID
Venue
Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2017-12-12
Volume
217
Issue
2
Pages
447-457
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
DOI
10.1083/jcb.201612069
PMC
PMC5800797
OpenAlex
W2775062021
Cited by
539
References
5
Citations by year
2026: 37 · 2025: 44 · 2024: 71 · 2023: 69 · 2022: 63 · 2021: 89 · 2020: 94 · 2019: 47 · 2018: 25
FWCI
4.24
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (acceptedVersion, cc-by-nc-sa)
  • Bristol Research (University of Bristol) (acceptedVersion, cc-by-nc-sa)
  • Explore Bristol Research (submittedVersion, cc-by-nc-sa)
Funders
Cancer Research UK (C6620/A15961)
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 › Cellular Mechanics and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
Rho GTPases, RhoGEF, RhoGAP, cell migration, cell invasion, signaling complexes, actin cytoskeleton, lamellipodia, filopodia, invadopodia, membrane blebs, cell-matrix adhesion, cell-cell adhesion, guanine nucleotide exchange factor, GTPase-activating protein
MeSH terms
Animals, Cell Movement, Humans, Signal Transduction, rho GTP-Binding Proteins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review