Hypertonic shock inhibits growth factor receptor signaling, induces caspase-3 activation, and causes reversible fragmentation of the mitochondrial network

Jeremy Copp, Sandra Wiley, Manus W. Ward, Peter Van Der Geer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Hyperosmotic stress can be encountered by the kidney and the skin, as well as during treatment of acute brain damage. It can lead to cell cycle arrest or apoptosis. Exactly how mammalian cells detect hyperosmolarity and how the cell chooses between cell cycle arrest or death remains to be established. It has been proposed that hyperosmolarity is detected directly by growth factor receptor protein tyrosine kinases. To investigate this, we tested whether growth factors and osmotic stress cooperate in the activation of signaling pathways. Receptors responded normally to the presence of growth factors, and we observed normal levels of GTP-bound Ras under hyperosmotic conditions. In contrast, activation of Raf, Akt, ERK1, ERK2, and c-Jun NH2-terminal kinase was strongly reduced. These observations suggest that hyperosmotic conditions block signaling directly downstream of active Ras. It is thought that apoptotic cell death due to environmental stress is initiated by cytochrome c release from the mitochondria. Visualization of cytochrome c using immunofluorescence showed that hypertonic conditions result in a breakup of the mitochondrial network, which is reestablished within 1 h after hypertonic medium is replaced with isotonic medium. When we carried out live imaging, we observed that the mitochondrial membrane potential disappeared immediately after the onset of hyperosmotic shock. Our observations provide new insights into the hypertonic stress response pathway. In addition, they show that signaling downstream of Ras and mitochondrial dynamics can easily be manipulated by the exposure of cells to hyperosmotic conditions.

Original languageEnglish (US)
Pages (from-to)C403-C415
JournalAmerican Journal of Physiology - Cell Physiology
Volume288
Issue number2 57-2
DOIs
StatePublished - Feb 2005
Externally publishedYes

Keywords

  • Hyperosmotic shock
  • Mitogen-activated protein kinase
  • Protein tyrosine kinases
  • Ras

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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