The Na+/H+ Exchanger, NHE1, Differentially Regulates Mitogen-Activated Protein Kinase Subfamilies after Osmotic Shrinkage in Ehrlich Lettre Ascites Cells (original) (raw)

2007, Cellular Physiology and Biochemistry

Abstract

Osmotic stress modulates mitogen activated protein kinase (MAPK) activities, leading to altered gene transcription and cell death/survival balance, however, the mechanisms involved are incompletely elucidated. Here, we show, using a combination of biochemical and molecular biology approaches, that three MAPKs exhibit unique interrelationships with the Na + /H + exchanger, NHE1, after osmotic cell shrinkage: Extracellular Signal Regulated Kinase (ERK1/2) is inhibited in an NHE1-dependent, pH i -independent manner, c-Jun N-terminal kinase (JNK1/2) is stimulated, in part through NHE1-mediated intracellular alkalinization, and p38 MAPK is activated in an NHE1independent manner, and contributes to NHE1 activation and ERK inhibition. Shrinkage-induced ERK1/2 inhibition was attenuated in Ehrlich Lettre Ascites cells by NHE1 inhibitors (EIPA, cariporide) or removal of extracellular Na + , and mimicked by human (h) NHE1 expression in cells lacking endogenous NHE1 activity. The effect of NHE1 on ERK1/2 was pH i -independent and upstream of MEK1/2. Shrinkageactivation of JNK1/2 was attenuated by EIPA, augmented by hNHE1 expression, and abolished in the presence of HCO 3 -. Basal JNK activity was augmented at alkaline pH i . Shrinkage-activation of p38 MAPK was NHE1-independent, and p38 MAPK inhibition (SB203580) attenuated NHE1 activation and ERK1/2 inhibition. Long-term shrinkage elicited caspase-3 activation and a loss of cell viability, which was augmented by ERK1/2 or JNK1/2 inhibition, and attenuated by p38 MAPK inhibition.

Loading...

Loading Preview

Sorry, preview is currently unavailable. You can download the paper by clicking the button above.

References (55)

  1. Lang F, Busch GL, Ritter M, Volkl H, Waldegger S, Gulbins E, Haussinger D: Functional significance of cell volume regu- latory mechanisms. Physiol Rev 1998;78:247-306.
  2. Ciano-Oliveira C, Thirone AC, Szaszi K, Kapus A: Osmotic stress and the cytoskeleton: the R(h)ole of Rho GTPases. Acta Physiol (Oxf) 2006;187:257-272.
  3. Hoffmann EK, Pedersen SF: Sensors and signal transduction pathways in vertebrate cell volume regulation. Contrib Nephrol 2006;152:54-104.
  4. Nylandsted J, Jaattela M, Hoffmann EK, Pedersen SF: Heat shock protein 70 inhib- its shrinkage-induced programmed cell death via mechanisms independent of ef- fects on cell volume-regulatory membrane transport proteins. Pflugers Arch 2004;449:175-185.
  5. Friis MB, Friborg CR, Schneider L, Nielsen MB, Lambert IH, Christensen ST, Hoffmann EK: Cell shrinkage as a signal to apoptosis in NIH 3T3 fibroblasts. J Physiol 2005;567:427-443.
  6. Pedersen SF: The Na + /H + exchanger NHE1 in stress-induced signal transduction: implications for cell proliferation and cell death. Pflugers Arch 2006;452:249-259.
  7. Baumgartner M, Patel H, Barber DL: Na + / H + exchanger NHE1 as plasma membrane scaffold in the assembly of signaling com- plexes. Am J Physiol Cell Physiol 2004;287:C844-C850.
  8. Rich IN, Worthington-White D, Garden OA, Musk P: Apoptosis of leukemic cells accompanies reduction in intracellular pH after targeted inhibition of the Na+/H+ exchanger. Blood 2000;95:1427-1434.
  9. 9 Sheikh-Hamad D, Gustin MC: MAP kinases and the adaptive response to hypertonicity: functional preservation from yeast to mammals. Am J Physiol Renal Physiol 2004;287:F1102-F1110.
  10. 10 Malek AM, Goss GG. Jiang L, Izumo S, Alper SL: Mannitol at clinical concentrations activates multiple signaling pathways and induces apoptosis in endothelial cells. Stroke 1998;29:2631- 2640.
  11. Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME: Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science1995; 270:1326-1331.
  12. Liu J, Minemoto Y, Lin A: c-Jun N-terminal protein kinase 1 (JNK1), but not JNK2, is essential for tumor necrosis factor alpha- induced c-Jun kinase activation and apoptosis. Mol Cell Biol 2004;24:10844- 10856.
  13. Lee JS, Lee JJ, Seo JS: HSP70 deficiency results in activation of c-Jun N-terminal Kinase, extracellular signal-regulated ki- nase, and caspase-3 in hyperosmolarity-in- duced apoptosis. J Biol Chem 2005;280:6634-6641.
  14. 14 Uhlik MT, Abell AN, Johnson NL, Sun W, Cuevas BD, Lobel-Rice KE, Horne EA, Dell'Acqua ML, Johnson GL: Rac- MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock. NatCell Biol 2003;5:1104-1110.
  15. Padda R, Wamsley-Davis A, Gustin MC, Ross R, Yu C, Sheikh-Hamad D: MEKK3- mediated signaling to p38 kinase and TonE in hypertonically stressed kidney cells. Am J Physiol Renal Physiol 2006;291:F874- F881.
  16. Kyriakis, J. M. and Avruch, J. (2001). Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev. 81, 807-869.
  17. 17 Uhlik MT, Abell AN, Cuevas BD, Nakamura K, Johnson GL: Wiring diagrams of MAPK regulation by MEKK1, 2, and 3. BiochemCell Biol 2004;82:658-663.
  18. Kolch W: Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol 2005;6:827-837.
  19. 19 Zhang H, Shi X, Hampong M, Blanis L, Pelech S: Stress-induced inhibition of ERK1 and ERK2 by direct interaction with p38 MAP kinase. J Biol Chem 2001;276:6905-6908.
  20. 20 Goss GG, Jiang L, Vandorpe DH, Kieller D, Chernova MN, Robertson M, Alper SL: Role of JNK in hypertonic activation of Cl - -dependent Na + /H + exchange in Xenopus oocytes. Am J Physiol Cell Physiol 2001;281:C1978-C1990.
  21. Pedersen SF, Varming C, Christensen ST, Hoffmann EK: Mechanisms of activation of NHE by cell shrinkage and by calyculin A in Ehrlich ascites tumor cells. J Membr Biol 2002;189:67-81.
  22. 22 Gillis D, Shrode LD, Krump E, Howard CM, Rubie EA, Tibbles LA, Woodgett J, Grinstein S: Osmotic stimulation of the Na + / H + exchanger NHE1: relationship to the activation of three MAPK pathways. J Membr Biol 2001;181:205-214.
  23. 23 Mukhin YV, Garnovskaya MN, Ullian ME, Raymond JR: ERK is regulated by sodium- proton exchanger in rat aortic vascular smooth muscle cells. J Biol Chem 2004;279:1845-1852.
  24. Yamazaki T, Komuro I, Kudoh S, Zou Y, Nagai R, Aikawa R, Uozumi H, Yazaki Y: (1998). Role of ion channels and exchangers in mechanical stretch-induced cardiomyocyte hypertrophy. Circ Res 1998;82:430-437.
  25. Aker S, Snabaitis AK, Konietzka I, Van De SA, Bongler K, Avkiran M, Heusch G, Schulz R: Inhibition of the Na + /H + exchanger attenuates the deterioration of ventricular function during pacing-induced heart failure in rabbits. Cardiovasc Res 2004;63:273-282.
  26. Rentsch ML, Ossum CG, Hoffmann EK, Pedersen SF: Roles of Na + /H + exchange in regulation of p38 mitogen-activated protein kinase activity and cell death after chemi- cal anoxia in NIH3T3 fibroblasts. Pflugers Arch 2007.
  27. Javadov S, Baetz D, Rajapurohitam V, Zeidan A, Kirshenbaum LA. Karmazyn M: Antihypertrophic effect of Na + /H + exchanger isoform 1 inhibition is mediated by reduced mitogen-activated protein kinase activation secondary to improved mitochondrial integrity and decreased generation of mitochondrial-derived reactive oxygen species. J Pharmacol Exp Ther 2006;317:1036-1043.
  28. Pedersen SF, Darborg BV, Rentsch ML, Rasmussen M: Regulation of mitogen- activated protein kinase pathways by the plasma membrane Na + /H + exchanger, NHE1. Arch Biochem.Biophys 2006.
  29. Darborg B, Hoffmann EK, Pedersen SF: Causal relationship between NHE1, NKCC1, MAPKs and ERM proteins after osmotic shrinkage in Ehrlich Lettre mouse ascites tumor cells. FASEB J 2005;19(5 Part 2 Suppl. S):A1155.
  30. Rotin D, Grinstein S: Impaired cell volume regulation in Na + /H + exchange-deficient mutants. Am J Physiol 1989;257:C1158- C1165.
  31. Rasmussen M, Alexander RT, Darborg B, Hoffmann EK, Kapus A, Pedersen SF: Osmotic cell shrinkage activates ezrin/ radixin/moesin (ERM) proteins: Activation mechanisms and physiological implications. Am J Physiol, Cell Physiol. submitted 2006.
  32. Boyarsky G, Ganz MB, Sterzel RB, Boron WF: pH regulation in single glomerular mesangial cells. I. Acid extrusion in absence and presence of HCO3-. Am J Physiol 1988;255:C844-C856.
  33. Pedersen SF, Kramhoft B, Jorgensen NK, Hoffmann EK: Shrinkage-induced activa- tion of the Na + /H + exchanger in Ehrlich as- cites tumor cells: mechanisms involved in the activation and a role for the exchanger in cell volume regulation. J Membr Biol 1996;149:141-159.
  34. Pedersen SF, Cala PM: Comparative biol- ogy of the ubiquitous Na + /H + exchanger, NHE1: Lessons from erythrocytes. J Exp Zoolog Part A Comp Exp Biol 2004;301:569-578.
  35. NHE1 Regulates MAPKs After Osmotic Cell Shrinkage Cell Physiol Biochem 2007;20:735-750
  36. Klausen TK, Hougaard C, Hoffmann EK, Pedersen SF: Cholesterol modulates the vol- ume regulated anion current in Ehrlich Lettre Ascites cells via effects on Rho and F-actin. Am J Physiol Cell Physiol submit- ted 2006.
  37. Khanna C, Wan X, Bose S, Cassaday R, Olomu O, Mendoza A, Yeung C, Gorlick R, Hewitt SM, Helman L J: The membrane- cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med 2004;10:182-186.
  38. Piechotta K, Garbarini N, England R, Delpire E: Characterization of the interaction of the stress kinase SPAK with the Na + -K + -2Cl-cotransporter in the nervous system: evidence for a scaffolding role of the kinase. J Biol Chem 2003;278:52848-52856.
  39. Schliess F, Haussinger D: Osmosensing and signaling in the regulation of liver function. Contrib Nephrol 2006;152:198-209.
  40. 39 Bortner CD, Cidlowski JA: Absence of volume regulatory mechanisms contributes to the rapid activation of apoptosis in thymocytes. Am J Physiol 1996;271:C950- C961.
  41. Haworth RS, McCann C, Snabaitis AK, Roberts NA, Avkiran M: Stimulation of the plasma membrane Na + /H + exchanger NHE1 by sustained intracellular acidosis. Evidence for a novel mechanism mediated by the ERK pathway. J Biol Chem 2003;278:31676-31684.
  42. Denker SP, Barber DL: Cell migration re- quires both ion translocation and cytoskeletal anchoring by the Na-H ex- changer NHE1. J Cell Biol 2002;159:1087- 1096.
  43. Denker SP, Huang DC, Orlowski J, Furthmayr H, Barber DL: Direct binding of the Na-H exchanger NHE1 to ERM proteins regulates the cortical cytoskeleton and cell shape independently of H + translocation. Mol Cell 2000;6:1425-1436.
  44. Bourguignon LY, Singleton PA, Diedrich F, Stern R, Gilad E: CD44 interaction with Na + /H + exchanger (NHE1) creates acidic microenvironments leading to hyaluronidase-2 and cathepsin B activation and breast tumor cell invasion. J Biol Chem 2004;279:26991-27007.
  45. Hamilton SR, Fard SF, Paiwand FF, Tolg C, Veiseh M, Wang C, McCarthy JB, Bissell MJ, Koropatnick J, Turley EA: The Hyaluronan Receptors CD44 and Rhamm (CD168) Form Complexes with ERK1,2 That Sustain High Basal Motility in Breast Cancer Cells. J Biol Chem 2007;282:16667-16680.
  46. Lewis A, Di Ciano C, Rotstein OD, Kapus A: Osmotic stress activates Rac and Cdc42 in neutrophils: role in hypertonicity-induced actin polymerization. Am.J Physiol Cell Physiol 2002;282:C271-C279.
  47. Wesselborg S, Bauer MK, Vogt M, Schmitz ML, Schulze-Osthoff K: Activation of tran- scription factor NF-kappaB and p38 mi- togen-activated protein kinase is mediated by distinct and separate stress effector path- ways. J Biol Chem 1997;272:12422-12429.
  48. 47 Bode JG, Gatsios P, Ludwig S, Rapp UR, Haussinger D, Heinrich PC, Graeve L: The mitogen-activated protein (MAP) kinase p38 and its upstream activator MAP kinase kinase 6 are involved in the activation of signal transducer and activator of transcription by hyperosmolarity. J Biol Chem 1999;274:30222-30227.
  49. Shrode LD, Rubie EA, Woodgett JR, Grinstein S: Cytosolic alkalinization increases stress-activated protein kinase/c- Jun NH2-terminal kinase (SAPK/JNK) activity and p38 mitogen-activated protein kinase activity by a calcium-independent mechanism. J Biol Chem 1997;272:13653- 13659.
  50. McLean LA, Roscoe J, Jorgensen NK, Gorin FA, Cala PM: Malignant gliomas display altered pH regulation by NHE1 compared with nontransformed astrocytes. Am J Physiol Cell Physiol 2000;278:C676- C688.
  51. Cardone RA, Casavola V, Reshkin SJ: The role of disturbed pH dynamics and the Na + / H + exchanger in metastasis. Nat Rev Can- cer 2005;5:786-795.
  52. 51 Kennedy NJ, Davis RJ: Role of JNK in tumor development. Cell Cycle 2003;2:199- 201.
  53. Terada Y, Inoshita S, Hanada S, Shimamura H, Kuwahara M, Ogawa W, Kasuga M, Sasaki S, Marumo F: Hyperosmolality activates Akt and regulates apoptosis in renal tubular cells. Kidney Int 2001;60:553- 567.
  54. Xie Z, Askari A: Na + /K + -ATPase as a signal transducer. Eur J Biochem 2002;269:2434- 2439.
  55. Hegle AP, Marble DD, Wilson GF: A voltage-driven switch for ion-independent signaling by ether-a-go-go K + channels. Proc Natl Acad Sci U S A 2006;103:2886- 2891.