Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Rac GTPase

  • Diamantis G. Konstantinidis
  • Theodosia A. Kalfa
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_597

Synonyms

 Rac1: Ras-related C3 botulinum toxin substrate 1; migration-inducing gene 5 protein (MIG5); RAS-like protein TC25

 Rac2: Ras-related C3 botulinum toxin substrate 2

 Rac3: Ras-related C3 botulinum toxin substrate 3

 RhoG: Ras homology growth-related; ARGH

Historical Background and Taxonomy

Rac GTPases comprise one of the eight subfamilies of the Rho (Ras homology) GTPases family, itself a subgroup of the Ras superfamily of small G proteins (Burridge and Wennerberg 2004). They were first identified as a substrate for the bacterial C3-like transferases that block Rho by ADP-ribosylation (hence their name, Ras-related C3 botulinum toxin substrate 1–3), although the C3-like transferases act on Rac rather inefficiently. More effective are the large clostridial cytotoxins (with prototypes the Clostridium difficile toxin A and B) which glycosylate Rac at Thr35, inhibiting its functions by preventing effector coupling (Aktories et al. 2000). Rac GTPases are preferred targets for...

This is a preview of subscription content, log in to check access.

References

  1. Aktories K, Schmidt G, Just I. Rho GTPases as targets of bacterial protein toxins. Biol Chem. 2000;381:421–6.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Alan JK, Lundquist EA. Mutationally activated Rho GTPases in cancer. Small GTPases. 2013;4(3):159–63.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Aslan JE, McCarty OJT. Rho GTPases in platelet function. J Thromb Haemost. 2013;11(1):35–46.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Bishop AL, Hall A. Rho GTPases and their effector proteins. Biochem J. 2000;348(Pt 2):241–55.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Bosco EE, Mulloy JC, Zheng Y. Rac1 GTPase: a “Rac” of all trades. Cell Mol Life Sci. 2009;66:370–4.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Burridge K, Wennerberg K. Rho and Rac take center stage. Cell. 2004;116(2):167–79.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Cancelas JA, Lee AW, Prabhakar R, Stringer KF, Zheng Y, Williams DA. Rac GTPases differentially integrate signals regulating hematopoietic stem cell localization. Nat Med. 2005;11:886–91.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Carrizzo A, Forte M, Lembo M, Formisano L, Puca AA, Vecchione C. Rac1 as a new therapeutic target in cerebro and cardiovascular diseases. Current Drug Targets. 2014;15(13):1231–46.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Cho YJ, Zhang B, Kaartinen V, Haataja L, de Curtis I, Groffen J, Heisterkamp N. Generation of rac3 null mutant mice: role of Rac3 in Bcr/Abl-caused lymphoblastic leukemia. Mol Cell Biol. 2005;25:5777–85.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature. 2002;420:629–35.PubMedPubMedCentralCrossRefGoogle Scholar
  11. George A, Pushkaran S, Konstantinidis DG, Koochaki S, Malik P, Mohandas N, Zheng Y, Joiner CH, Kalfa TA. Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease. Blood. 2013;121(11):2099–107.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Gu Y, Filippi MD, Cancelas JA, Siefring JE, Williams EP, Jasti AC, Harris CE, Lee AW, Prabhakar R, Atkinson SJ, Kwiatkowski DJ, Williams DA. Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases. Science. 2003;302:445–9.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Goggs R, Harper MMT, Pope RJ, Savage JS, Williams CM, Mundell SJ, Heesom KJ, Bass M, Mellor H, Poole AW. RhoG protein regulates platelet granule secretion and thrombus formation in mice. J Biol Chem. 2013;288(47):34217–29.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Hall A. Rho GTPases and the actin cytoskeleton. Science. 1998;279:509–14.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Heasman SJ, Ridley AJ. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol. 2008;9:690–701.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Hordijk PL. Regulation of NADPH oxidases: the role of Rac proteins. Circ Res. 2006;98:453–62.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Ji P, Jayapal SR, Lodish HF. Enucleation of cultured mouse fetal erythroblasts requires Rac GTPases and mDia2. Nat Cell Biol. 2008;10:314–21.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Kalfa TA, Pushkaran S, Mohandas N, Hartwig JH, Fowler VM, Johnson JF, Joiner CH, Williams DA, Zheng Y. Rac GTPases regulate the morphology and deformability of the erythrocyte cytoskeleton. Blood. 2006;108:3637–45.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Kalfa TA, Pushkaran S, Zhang X, Johnson JF, Pan D, Daria D, Geiger H, Cancelas JA, Williams DA, Zheng Y. Rac1 and Rac2 GTPases are necessary for early erythropoietic expansion in the bone marrow but not in the spleen. Haematologica. 2010;95:27–35.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Katoh H, Negishi M. RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo. Nature. 2003;424(24):461–4.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Konstantinidis DG, Pushkaran S, Johnson JF, Cancelas JA, Manganaris S, Harris CE, Williams DA, Zheng Y, Kalfa TA. Signaling and cytoskeletal requirements in erythroblast enucleation. Blood. 2012; 119(25): 6118–27.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Mulloy JC, Cancelas JA, Filippi MD, Kalfa TA, Guo F, Zheng Y. Rho GTPases in hematopoiesis and hemopathies. Blood. 2010;115:936–47.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Schumacher S, Franke K. miR-124-regulated RhoG. A conductor of neuronal process complexity. Small GTPases. 2013;4(1):42–6.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Schwartz M. Rho signalling at a glance. J Cell Sci. 2004;117:5457–8.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Thomas EK, Cancelas JA, Chae HD, Cox AD, Keller PJ, Perrotti D, Neviani P, Druker BJ, Setchell KD, Zheng Y, Harris CE, Williams DA. Rac guanosine triphosphatases represent integrating molecular therapeutic targets for BCR-ABL-induced myeloproliferative disease. Cancer Cell. 2007;12:467–78.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Wang L, Zheng Y. Cell type-specific functions of Rho GTPases revealed by gene targeting in mice. Trends Cell Biol. 2007;17:58–64.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Wang Z, Pedersen E, Basse A, Lefever T, Peyrollier K, Kapoor S, Mei Q, Karlsson R, Chrostek-Grashoff A, Brakebusch C. Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation in vivo. Oncogene. 2010;29:3362–73.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Westwick JK, Lambert QT, Clark GJ, Symons M, Van Aelst L, Pestell RG, Der CJ. Rac regulation of transformation, gene expression, and actin organization by multiple, PAK-independent pathways. Mol Cell Biol. 1997;17:1324–35.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Williams DA, Tao W, Yang F, Kim C, Gu Y, Mansfield P, Levine JE, Petryniak B, Derrow CW, Harris C, Jia B, Zheng Y, Ambruso DR, Lowe JB, Atkinson SJ, Dinauer MC, Boxer L. Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency. Blood. 2000;96:1646–54.PubMedPubMedCentralGoogle Scholar
  30. Wittmann T, Waterman-Storer CM. Spatial regulation of CLASP affinity for microtubules by Rac1 and GSK3β in migrating epithelial cells. J Cell Biol. 2005;169(6):929–39.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Diamantis G. Konstantinidis
    • 1
  • Theodosia A. Kalfa
    • 1
  1. 1.Cancer and Blood Diseases InstituteCincinnati Children’s Hospital Medical Center and University of Cincinnati College of MedicineCincinnatiUSA