References 1. Wang R (2010) Hydrogen sulfide: the third gasotransmitter in biology and medicine. Antioxid Redox Signal 12: 1061–1064. 2. Gadalla MM, Snyder SH (2010) Hydrogen sulfide as a gasotransmitter. J Neurochem 113: 14–26. 3. Wagner F, Asfar P, Calzia E, Radermacher P, Szabo C (2009) Bench-to-bedside review: Hydrogen sulfide–the third gaseous transmitter: applications for critical care. Crit Care 13: 213. 4. Kimura H (2010) Hydrogen sulfide: its production, release and functions. Amino Acids. 5. Shibuya N, Mikami Y, Kimura Y, Nagahara N, Kimura H (2009) Vascular endothelium expresses 3-mercaptopyruvate sulfurtransferase and produces hydrogen sulfide. J Biochem 146: 623–626. 6. Shibuya N, Tanaka M, Yoshida M, Ogasawara Y, Togawa T, et al. (2009) 3- Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain. Antioxid Redox Signal 11: 703–714. 7. Lefer DJ (2007) A new gaseous signaling molecule emerges: cardioprotective role of hydrogen sulfide. Proc Natl Acad Sci U S A 104: 17907–17908. 8. Abe K, Kimura H (1996) The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci 16: 1066–1071. 9. Zhao W, Zhang J, Lu Y, Wang R (2001) The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener. EMBO J 20: 6008–6016. 10. Zhao W, Wang R (2002) H(2)S-induced vasorelaxation and underlying cellular and molecular mechanisms. Am J Physiol Heart Circ Physiol 283: H474–480. 11. Yang G, Wu L, Jiang B, Yang W, Qi J, et al. (2008) H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science 322: 587–590. 12. Elrod JW, Calvert JW, Morrison J, Doeller JE, Kraus DW, et al. (2007) Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preser- vation of mitochondrial function. Proc Natl Acad Sci U S A 104: 15560–15565. 13. Yao LL, Huang XW, Wang YG, Cao YX, Zhang CC, et al. (2010) Hydrogen sulfide protects cardiomyocytes from hypoxia/reoxygenation-induced apoptosis by preventing GSK-3beta-dependent opening of mPTP. Am J Physiol Heart Circ Physiol 298: H1310–1319. 14. Yang G, Tang G, Zhang L, Wu L, Wang R (2011) The Pathogenic Role of Cystathionine gamma-Lyase/Hydrogen Sulfide in Streptozotocin-Induced Di- abetes in Mice. Am J Pathol. 15. Yang W, Yang G, Jia X, Wu L, Wang R (2005) Activation of KATP channels by H2S in rat insulin-secreting cells and the underlying mechanisms. J Physiol 569: 519–531. 16. Hegde A, Bhatia M (2011) Hydrogen sulfide in inflammation: friend or foe? Inflamm Allergy Drug Targets 10: 118–122. 17. Zanardo RC, Brancaleone V, Distrutti E, Fiorucci S, Cirino G, et al. (2006) Hydrogen sulfide is an endogenous modulator of leukocyte-mediated in- flammation. FASEB J 20: 2118–2120. 18. Cai WJ, Wang MJ, Moore PK, Jin HM, Yao T, et al. (2007) The novel proangiogenic effect of hydrogen sulfide is dependent on Akt phosphorylation. Cardiovasc Res 76: 29–40. 19. Wang MJ, Cai WJ, Li N, Ding YJ, Chen Y, et al. (2010) The hydrogen sulfide donor NaHS promotes angiogenesis in a rat model of hind limb ischemia. Antioxid Redox Signal 12: 1065–1077. 20. Papapetropoulos A, Pyriochou A, Altaany Z, Yang G, Marazioti A, et al. (2009) Hydrogen sulfide is an endogenous stimulator of angiogenesis. Proc Natl Acad Sci U S A 106: 21972–21977. 21. Ridley AJ, Schwartz MA, Burridge K, Firtel RA, Ginsberg MH, et al. (2003) Cell migration: integrating signals from front to back. Science 302: 1704–1709. 22. Vicente-Manzanares M, Webb DJ, Horwitz AR (2005) Cell migration at a glance. J Cell Sci 118: 4917–4919. 23. Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420: 629–635. 24. Sun M, Wang G, Paciga JE, Feldman RI, Yuan ZQ, et al. (2001) AKT1/ PKBalpha kinase is frequently elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells. Am J Pathol 159: 431–437. H2S Signals through VEGFR-PI3K-Rac1-Cofilin 25. Lauffenburger DA, Horwitz AF (1996) Cell migration: a physically integrated molecular process. Cell 84: 359–369. 26. Le Clainche C, Carlier MF (2008) Regulation of actin assembly associated with protrusion and adhesion in cell migration. Physiol Rev 88: 489–513. 27. Ridley AJ (2001) Rho GTPases and cell migration. J Cell Sci 114: 2713–2722. 28. Mustafa AK, Gadalla MM, Sen N, Kim S, Mu W, et al. (2009) H2S signals through protein S-sulfhydration. Sci Signal 2: ra72. 29. Jimenez C, Portela RA, Mellado M, Rodriguez-Frade JM, Collard J, et al. (2000) Role of the PI3K regulatory subunit in the control of actin organization and cell migration. J Cell Biol 151: 249–262. 30. Pan J, Kao YL, Joshi S, Jeetendran S, Dipette D, et al. (2005) Activation of Rac1 by phosphatidylinositol 3-kinase in vivo: role in activation of mitogen-activated protein kinase (MAPK) pathways and retinoic acid-induced neuronal differen- tiation of SH-SY5Y cells. J Neurochem 93: 571–583. 31. Toker A (2002) Phosphoinositides and signal transduction. Cell Mol Life Sci 59: 761–779. 32. Hawkins PT, Anderson KE, Davidson K, Stephens LR (2006) Signalling through Class I PI3Ks in mammalian cells. Biochem Soc Trans 34: 647–662. 33. Graupera M, Guillermet-Guibert J, Foukas LC, Phng LK, Cain RJ, et al. (2008) Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature 453: 662–666. 34. Cain RJ, Vanhaesebroeck B, Ridley AJ (2010) The PI3K p110alpha isoform regulates endothelial adherens junctions via Pyk2 and Rac1. J Cell Biol 188: 863–876. 35. Viala E, Pouyssegur J (2004) Regulation of tumor cell motility by ERK mitogen- activated protein kinases. Ann N Y Acad Sci 1030: 208–218. 36. Ray RM, Vaidya RJ, Johnson LR (2007) MEK/ERK regulates adherens junctions and migration through Rac1. Cell Motil Cytoskeleton 64: 143–156. 37. Arber S, Barbayannis FA, Hanser H, Schneider C, Stanyon CA, et al. (1998) Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature 393: 805–809. 38. Delorme V, Machacek M, DerMardirossian C, Anderson KL, Wittmann T, et al. (2007) Cofilin activity downstream of Pak1 regulates cell protrusion efficiency by organizing lamellipodium and lamella actin networks. Dev Cell 13: 646–662. 39. Rousseau S, Houle F, Landry J, Huot J (1997) p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells. Oncogene 15: 2169–2177. 40. Hedges JC, Dechert MA, Yamboliev IA, Martin JL, Hickey E, et al. (1999) A role for p38(MAPK)/HSP27 pathway in smooth muscle cell migration. J Biol Chem 274: 24211–24219. 41. Nguyen DH, Catling AD, Webb DJ, Sankovic M, Walker LA, et al. (1999) Myosin light chain kinase functions downstream of Ras/ERK to promote migration of urokinase-type plasminogen activator-stimulated cells in an integrin-selective manner. J Cell Biol 146: 149–164. 42. Liu ZX, Yu CF, Nickel C, Thomas S, Cantley LG (2002) Hepatocyte growth factor induces ERK-dependent paxillin phosphorylation and regulates paxillin- focal adhesion kinase association. J Biol Chem 277: 10452–10458. 43. Hunger-Glaser I, Salazar EP, Sinnett-Smith J, Rozengurt E (2003) Bombesin, lysophosphatidic acid, and epidermal growth factor rapidly stimulate focal adhesion kinase phosphorylation at Ser-910: requirement for ERK activation. J Biol Chem 278: 22631–22643. 44. Huang C, Rajfur Z, Borchers C, Schaller MD, Jacobson K (2003) JNK phosphorylates paxillin and regulates cell migration. Nature 424: 219–223. 45. Cheng C, Kong X, Wang H, Gan H, Hao Y, et al. (2009) Trihydrophobin 1 Interacts with PAK1 and Regulates ERK/MAPK Activation and Cell Migration. J Biol Chem 284: 8786–8796. 46. Klemke RL, Cai S, Giannini AL, Gallagher PJ, de Lanerolle P, et al. (1997) Regulation of cell motility by mitogen-activated protein kinase. J Cell Biol 137: 481–492. 47. Mitra SK, Hanson DA, Schlaepfer DD (2005) Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol 6: 56–68. PLOS ONE | www.plosone.org 13 September 2012 | Volume 7 | Issue 9 | e44590