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2015;10 (3): e0116938.

H-Ras mediates the inhibitory effect of epidermal growth factor on the epithelial Na+ channel.

Il-Ha Lee, Sung-Hee Song, David I Cook, Anuwat Dinudom
Author Information
  1. Il-Ha Lee: Discipline of Physiology, The Bosch Institute, School of Medical Sciences, The University of Sydney, New South Wales, 2006, Australia.
  2. Sung-Hee Song: Discipline of Physiology, The Bosch Institute, School of Medical Sciences, The University of Sydney, New South Wales, 2006, Australia.
  3. David I Cook: Discipline of Physiology, The Bosch Institute, School of Medical Sciences, The University of Sydney, New South Wales, 2006, Australia.
  4. Anuwat Dinudom: Discipline of Physiology, The Bosch Institute, School of Medical Sciences, The University of Sydney, New South Wales, 2006, Australia.
PMID: 25774517 DOI: 10.1371/journal.pone.0116938

Abstract

The present study investigates the role of small G-proteins of the Ras family in the epidermal growth factor (EGF)-activated cellular signalling pathway that downregulates activity of the epithelial Na+ channel (ENaC). We found that H-Ras is a key component of this EGF-activated cellular signalling mechanism in M1 mouse collecting duct cells. Expression of a constitutively active H-Ras mutant inhibited the amiloride-sensitive current. The H-Ras-mediated signalling pathway that inhibits activity of ENaC involves c-Raf, and that the inhibitory effect of H-Ras on ENaC is abolished by the MEK1/2 inhibitor, PD98059. The inhibitory effect of H-Ras is not mediated by Nedd4-2, a ubiquitin protein ligase that regulates the abundance of ENaC at the cell surface membrane, or by a negative effect of H-Ras on proteolytic activation of the channel. The inhibitory effects of EGF and H-Ras on ENaC, however, were not observed in cells in which expression of caveolin-1 (Cav-1) had been knocked down by siRNA. These findings suggest that the inhibitory effect of EGF on ENaC-dependent Na+ absorption is mediated via the H-Ras/c-Raf, MEK/ERK signalling pathway, and that Cav-1 is an essential component of this EGF-activated signalling mechanism. Taken together with reports that mice expressing a constitutive mutant of H-Ras develop renal cysts, our findings suggest that H-Ras may play a key role in the regulation of renal ion transport and renal development.

References

  1. Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1732-7 [PMID: 9990093]
  2. Am J Physiol Cell Physiol. 2013 Jan 1;304(1):C102-11 [PMID: 23135700]
  3. J Biol Chem. 2002 Apr 19;277(16):13539-47 [PMID: 11805112]
  4. J Biol Chem. 2004 Sep 3;279(36):37771-8 [PMID: 15215250]
  5. J Biol Chem. 1998 Mar 6;273(10):5419-22 [PMID: 9488658]
  6. Am J Physiol. 1999 Mar;276(3 Pt 1):G567-71 [PMID: 10070030]
  7. J Membr Biol. 2001 Dec 1;184(3):313-9 [PMID: 11891557]
  8. J Biol Chem. 2002 Apr 5;277(14):12158-63 [PMID: 11809752]
  9. Cell Mol Life Sci. 2007 Oct;64(19-20):2575-89 [PMID: 17628742]
  10. Am J Physiol Renal Physiol. 2003 Jan;284(1):F57-64 [PMID: 12388407]
  11. Am J Physiol Heart Circ Physiol. 2004 Jan;286(1):H91-8 [PMID: 12969891]
  12. Pflugers Arch. 1997 Jul;434(3):323-31 [PMID: 9178633]
  13. J Biol Chem. 1998 Nov 13;273(46):30770-6 [PMID: 9804854]
  14. J Biol Chem. 2007 Jul 13;282(28):20207-12 [PMID: 17502380]
  15. Am J Physiol. 1991 Nov;261(5 Pt 2):F896-903 [PMID: 1659225]
  16. J Biol Chem. 1996 May 17;271(20):11930-5 [PMID: 8662667]
  17. Physiol Rev. 1991 Apr;71(2):429-45 [PMID: 1706528]
  18. J Biol Chem. 2004 Apr 30;279(18):18111-4 [PMID: 15007080]
  19. J Biol Chem. 2008 Sep 12;283(37):25290-5 [PMID: 18650438]
  20. Am J Physiol Renal Physiol. 2005 Mar;288(3):F474-82 [PMID: 15522985]
  21. Annu Rev Physiol. 1999;61:627-61 [PMID: 10099704]
  22. Cancer Biol Ther. 2009 Aug;8(15):1470-7 [PMID: 19483462]
  23. Nephrol Dial Transplant. 2003 Nov;18(11):2284-92 [PMID: 14551355]
  24. J Biol Chem. 2005 Nov 18;280(46):38264-70 [PMID: 16172119]
  25. J Biol Chem. 2002 Sep 13;277(37):33541-4 [PMID: 12167633]
  26. Mol Cell. 1998 Sep;2(3):397-403 [PMID: 9774978]
  27. J Biol Chem. 2009 May 8;284(19):12663-9 [PMID: 19304660]
  28. Kidney Int. 1991 Jun;39(6):1168-75 [PMID: 1654478]
  29. Kidney Int. 1996 Mar;49(3):656-65 [PMID: 8648906]
  30. EMBO J. 1998 Nov 16;17(22):6633-48 [PMID: 9822607]
  31. Am J Physiol Renal Physiol. 2005 Jan;288(1):F150-61 [PMID: 15454394]
  32. Kidney Int. 2004 Jun;65(6):2441-2 [PMID: 15149358]
  33. Pflugers Arch. 2010 Feb;459(3):451-63 [PMID: 19823867]
  34. J Biol Chem. 1999 Dec 10;274(50):35449-54 [PMID: 10585415]
  35. Biochem Biophys Res Commun. 2005 Jun 3;331(2):503-11 [PMID: 15850788]
  36. Nat Rev Mol Cell Biol. 2008 Jul;9(7):517-31 [PMID: 18568040]
  37. Nature. 1984 Nov 1-7;312(5989):71-5 [PMID: 6092966]
  38. Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37 [PMID: 11252954]
  39. Int J Cancer. 1997 Nov 27;73(5):749-56 [PMID: 9398057]
  40. Kidney Int. 2000 Jan;57(1):33-40 [PMID: 10620185]
  41. EMBO J. 1994 Feb 1;13(3):511-21 [PMID: 8313896]
  42. Biochim Biophys Acta. 2005 May 20;1669(2):108-15 [PMID: 15893513]
  43. Cell. 2002 Sep 20;110(6):669-72 [PMID: 12297041]
  44. Genes Cancer. 2011 Mar;2(3):216-31 [PMID: 21779495]
  45. Oncogene. 2008 Apr 24;27(19):2754-62 [PMID: 17998936]
  46. J Biol Chem. 1998 Sep 11;273(37):24052-6 [PMID: 9727023]
  47. Mol Cell Biol. 1988 Aug;8(8):3235-43 [PMID: 3145408]
  48. Int J Biochem Cell Biol. 2008;40(12):2707-19 [PMID: 18562239]
  49. J Membr Biol. 2002 Nov 15;190(2):83-92 [PMID: 12474073]
  50. J Biol Chem. 2004 Feb 6;279(6):5042-6 [PMID: 14645220]
  51. J Cell Physiol. 2010 Apr;223(1):252-9 [PMID: 20049896]
  52. Am J Physiol Renal Physiol. 2009 Jun;296(6):F1417-27 [PMID: 19297452]
  53. Am J Physiol Cell Physiol. 2005 May;288(5):C1003-11 [PMID: 15634742]
  54. J Gen Physiol. 2007 Sep;130(3):313-28 [PMID: 17724164]
  55. Am J Physiol. 1999 May;276(5 Pt 1):C1154-61 [PMID: 10329965]
  56. Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11710-5 [PMID: 9326675]
  57. Int Rev Cytol Suppl. 1979;(10):163-72 [PMID: 391743]
  58. Biochemistry. 2010 Mar 9;49(9):1970-4 [PMID: 20131908]
  59. Am J Physiol Cell Physiol. 2009 Oct;297(4):C935-44 [PMID: 19625610]
  60. Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):20120-5 [PMID: 18077438]
  61. Physiol Rev. 2001 Jan;81(1):153-208 [PMID: 11152757]
  62. J Biol Chem. 2011 Jun 3;286(22):19259-69 [PMID: 21464134]
  63. Am J Physiol. 1991 Feb;260(2 Pt 2):F163-9 [PMID: 1996668]
  64. J Biol Chem. 2003 Sep 26;278(39):37073-82 [PMID: 12871941]
  65. Am J Physiol Renal Physiol. 2004 Jun;286(6):F1226-31 [PMID: 14749256]
  66. Exp Cell Res. 2009 Feb 15;315(4):602-10 [PMID: 18761338]
  67. J Biol Chem. 2007 Oct 12;282(41):29866-73 [PMID: 17715136]
  68. Cell. 1995 Dec 15;83(6):969-78 [PMID: 8521520]
  69. Am J Physiol Renal Physiol. 2005 Jun;288(6):F1201-12 [PMID: 15671346]
  70. J Biol Chem. 2005 Jul 22;280(29):26796-804 [PMID: 15917253]
  71. Mol Biol Cell. 2002 Sep;13(9):3042-54 [PMID: 12221114]
  72. Biochim Biophys Acta. 2011 Oct;1812(10):1301-13 [PMID: 20959142]
  73. J Biol Chem. 2008 Mar 7;283(10):6033-9 [PMID: 18174164]
  74. Eur J Neurosci. 1992;4(4):361-368 [PMID: 12106362]
  75. EMBO J. 2002 Oct 1;21(19):5109-17 [PMID: 12356727]

MeSH Term

Animals
Down-Regulation
Epidermal Growth Factor
Epithelial Sodium Channel Blockers
Epithelial Sodium Channels
HEK293 Cells
Humans
MAP Kinase Kinase 1
MAP Kinase Signaling System
Mice
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Mutation
Oncogene Proteins
Proto-Oncogene Proteins c-raf
Rats
ras Proteins

Chemicals

Epithelial Sodium Channel Blockers
Epithelial Sodium Channels
Hras protein, rat
Oncogene Proteins
Epidermal Growth Factor
Proto-Oncogene Proteins c-raf
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
MAP Kinase Kinase 1
ras Proteins
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 1

Word Cloud

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