Advertisement

Molecular and Cellular Biochemistry

, Volume 334, Issue 1–2, pp 99–103 | Cite as

A new Rac/PAK/GC/cGMP signaling pathway

  • Dagang Guo
  • J. Jillian Zhang
  • Xin-Yun Huang
Article

Abstract

Guanosine 3′,5′-cyclic monophosphate (cGMP) and small GTPase Rac are critical regulators of cell functions. Recently, Rac has been shown to use its downstream effector p21-activated kinase (PAK) to directly activate transmembrane guanylyl cyclases (GCs). This novel Rac/PAK/GC/cGMP signaling pathway bridges Rac and cGMP, and provides a general molecular mechanism for diverse receptors to regulate physiological functions such as cell migration through elevating the cellular cGMP level.

Keywords

Guanylyl cyclase Rac PAK cGMP 

Notes

Acknowledgments

Research projects on guanylyl cyclases in our laboratory were supported by a grant from the NIH (GM84191).

References

  1. 1.
    Lucas KA, Pitari GM, Kazerounian S, Ruiz-Stewart I, Park J, Schulz S, Chepenik KP, Waldman SA (2000) Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev 52(3):375–414PubMedGoogle Scholar
  2. 2.
    Hofmann F, Feil R, Kleppisch T, Schlossmann J (2006) Function of cGMP-dependent protein kinases as revealed by gene deletion. Physiol Rev 86:1–23CrossRefPubMedGoogle Scholar
  3. 3.
    Sanders LC, Matsumura F, Bokoch GM, de Lanerolle P (1999) Inhibition of myosin light chain kinase by p21-activated kinase. Science 283(5410):2083–2085CrossRefPubMedGoogle Scholar
  4. 4.
    Finn JT, Grunwald ME, Yau KW (1996) Cyclic nucleotide-gated ion channels: an extended family with diverse functions. Annu Rev Physiol 58:395–426CrossRefPubMedGoogle Scholar
  5. 5.
    Leinders-Zufall T, Cockerham RE, Michalakis S, Biel M, Garbers DL, Reed RR, Zufall F, Munger SD (2007) Contribution of the receptor guanylyl cyclase GC-D to chemosensory function in the olfactory epithelium. Proc Natl Acad Sci 104(36):14507–14512CrossRefPubMedGoogle Scholar
  6. 6.
    Duda T, Sharma RK (2008) ONE-GC membrane guanylate cyclase, a trimodal odorant signal transducer. Biochem Biophys Res Commun 367:440–445CrossRefPubMedGoogle Scholar
  7. 7.
    Sun L, Wang H, Hu J, Han J, Matsunami H, Luo M (2009) Guanylyl cyclase-D in the olfactory CO2 neurons is activated by bicarbonate. Proc Natl Acad Sci 106(6):2041–2046CrossRefPubMedGoogle Scholar
  8. 8.
    Guo D, Zhang J, Huang XY (2009) Stimulation of guanylyl cyclase-D by bicarbonate. Biochemistry 48:4417–4422CrossRefPubMedGoogle Scholar
  9. 9.
    Raftopoulou M, Hall A (2004) Cell migration: Rho GTPases lead the way. Dev Biol 265(1):23–32CrossRefPubMedGoogle Scholar
  10. 10.
    Burridge K, Wennerberg K (2004) Rho and Rac take center stage. Cell 116:167–179CrossRefPubMedGoogle Scholar
  11. 11.
    Bar-Sagi D, Hall A (2000) Ras and Rho GTPases: a family reunion. Cell 103:227–238CrossRefPubMedGoogle Scholar
  12. 12.
    Carter JH, Douglass LE, Deddens JA, Colligan BM, Bhatt TR, Pemberton JO, Konicek S, Hom J, Marshall M, Graff JR (2004) Pak-1 expression increases with progression of colorectal carcinomas to metastasis. Clin Cancer Res 10:3448–3456CrossRefPubMedGoogle Scholar
  13. 13.
    Edwards DC, Sanders LC, Bokoch GG, Gill GN (1999) Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics. Nat Cell Biol 1:253–259CrossRefPubMedGoogle Scholar
  14. 14.
    Manser E, Huang HY, Loo TH, Chen XQ, Dong JM, Leung T, Lim L (1997) Expression of constitutively active alpha-PAK reveals effects of the kinase on actin and focal complexes. Mol Cell Biol 17(3):1129–1143PubMedGoogle Scholar
  15. 15.
    Müller-Taubenberger A, Bretschneider T, Faix J, Konzok A, Simmeth E, Weber I (2002) Differential localization of the Dictyostelium kinase DPAKa during cytokinesis and cell migration. J Mus Res Cell Motil 23(7–8):751–763CrossRefGoogle Scholar
  16. 16.
    Vadlamudi RK, Adam L, Wang RA, Mandal M, Nguyen D, Sahin A, Chernoff J, Hung MC, Kumar R (2000) Regulatable expression of p21-activated kinase-1 promotes anchorage-independent growth and abnormal organization of mitotic spindles in human epithelial breast cancer cells. J Biol Chem 275:36238–36244CrossRefPubMedGoogle Scholar
  17. 17.
    Lei M, Lu W, Meng W, Parrini MC, Eck MJ, Mayer BJ, Harrison SC (2000) Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch. Cell 102(3):387–397CrossRefPubMedGoogle Scholar
  18. 18.
    Guo D, Tan YC, Wang D, Madhusoodanan KS, Zheng Y, Maack T, Zhang JJ, Huang XY (2007) A Rac-cGMP signaling pathway. Cell 128:341–355CrossRefPubMedGoogle Scholar
  19. 19.
    Sauzeau V, Le Jeune H, Cario-Toumaniantz C, Smolenski A, Lohmann SM, Bertoglio J, Chardin P, Pacaud P, Loirand G (2000) Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitization of contraction in vascular smooth muscle. J Biol Chem 275(28):21722–21729CrossRefPubMedGoogle Scholar
  20. 20.
    Butt E, Gambaryan S, Göttfert N, Galler A, Marcus K, Meyer HE (2003) Actin binding of human LIM and SH3 protein is regulated by cGMP- and cAMP-dependent protein kinase phosphorylation on serine 146. J Biol Chem 278:15601–15607CrossRefPubMedGoogle Scholar
  21. 21.
    Bosgraaf L, Russcher H, Smith JL, Wessels D, Soll DR, Van Haastert PJ (2002) A novel cGMP signalling pathway mediating myosin phosphorylation and chemotaxis in Dictyostelium. EMBO J 21:4560–4570CrossRefPubMedGoogle Scholar
  22. 22.
    Veltman DM, Roelofs J, Engel R, Visser AJ, Van Haastert PJ (2005) Activation of soluble guanylyl cyclase at the leading edge during Dictyostelium chemotaxis. Mol Biol Cell 16:976–983CrossRefPubMedGoogle Scholar
  23. 23.
    Kook H, Itoh H, Choi BS, Sawada N, Doi K, Hwang TJ, Kim KK, Arai H, Baik YH, Lee S, Rivero F, Park KC, Huang E, Funamoto S, Firtel RA (2004) Dictyostelium PAKc is required for proper chemotaxis. Mol Biol Cell 15(12):5456–5469CrossRefGoogle Scholar
  24. 24.
    Ikeda M, Kohno M, Takeda T (1995) Inhibition by cardiac natriuretic peptides of rat vascular endothelial cell migration. Hypertension 26:401–405PubMedGoogle Scholar
  25. 25.
    Nakao K (2003) Physiological concentration of atrial natriuretic peptides induces endothelial regeneration in vitro. Am J Physiol Heart Circ Physiol 284:H1388–H1397PubMedGoogle Scholar
  26. 26.
    Zhang S et al (2003) Insulin-stimulated cyclic guanosine monophosphate inhibits vascular smooth muscle cell migration by inhibiting Ca/calmodulin-dependent protein kinase II. Circulation 107:1539–1544CrossRefPubMedGoogle Scholar
  27. 27.
    Kumada T, Lakshmana MK, Komuro H (2006) Reversal of neuronal migration in a mouse model of fetal alcohol syndrome by controlling second-messenger signalings. J Neurosci 26(3):742–756CrossRefPubMedGoogle Scholar
  28. 28.
    Song H, Ming G, He Z, Lehmann M, McKerracher L, Tessier-Lavigne M, Poo M (1998) Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science 281:1515–1518CrossRefPubMedGoogle Scholar
  29. 29.
    Ayoob JC, Yu HH, Terman JR, Kolodkin AL (2004) The Drosophila receptor guanylyl cyclase Gyc76C is required for semaphorin-1a-plexin A-mediated axonal repulsion. J Neurosci 24:6639–6649CrossRefPubMedGoogle Scholar
  30. 30.
    Hou Y, Ye RD, Browning DD (2004) Activation of the small GTPase Rac1 by cGMP-dependent protein kinase. Cell Signal 16:1061–1069PubMedGoogle Scholar
  31. 31.
    Frost JA, Khokhlatchev A, Stippec S, White MA, Cobb MH (1998) Differential effects of PAK1-activating mutations reveal activity-dependent and -independent effects on cytoskeletal regulation. J Biol Chem 273(43):28191–28198CrossRefPubMedGoogle Scholar
  32. 32.
    Pirruccello M, Sondermann H, Pelton JG, Pellicena P, Hoelz A, Chernoff J, Wemmer DE, Kuriyan J (2006) A dimeric kinase assembly underlying autophosphorylation in the p21 activated kinases. J Mol Biol 361:312–326CrossRefPubMedGoogle Scholar
  33. 33.
    Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J (2006) An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 125:1137–1149CrossRefPubMedGoogle Scholar
  34. 34.
    Ridley AJ, Hall A (1992) The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70(3):389–399CrossRefPubMedGoogle Scholar
  35. 35.
    Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A (1992) The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70(3):401–410CrossRefPubMedGoogle Scholar
  36. 36.
    Sells MA, Boyd JT, Chernoff J (1999) p21-activated kinase 1 (Pak1) regulates cell motility in mammalian fibroblasts. J Cell Biol 145(4):837–849CrossRefPubMedGoogle Scholar
  37. 37.
    Sells MA, Knaus UG, Bagrodia S, Ambrose DM, Bokoch GM, Chernoff J (1997) Human p21-activated kinase 1 (Pak1) regulates actin organization in mammalian cells. Curr Biol 7(3):202–217CrossRefPubMedGoogle Scholar
  38. 38.
    Sander EE, ten Klooster JP, van Delft S, van der Kammen RA, Collard JG (1999) Rac downregulates Rho activity: reciprocal balance between both GTPases determines cellular morphology and migratory behavior. J Cell Biol 147(5):1009–1021CrossRefPubMedGoogle Scholar
  39. 39.
    Nimnual AS, Yatsula BA, Bar-Sagi D (2003) Redox-dependent downregulation of Rho by Rac. Nat Cell Biol 5:236–241CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  1. 1.Department of PhysiologyCornell University Weill Medical CollegeNew YorkUSA

Personalised recommendations