Tyrosine kinase activation is an immediate and essential step in hypotonic cell swelling-induced ERK activation and c-fos gene expression in cardiac myocytes

Junichi Sadoshima, Zhihua Qiu, James P. Morgan, Seigo Izumo

Research output: Contribution to journalArticlepeer-review

136 Scopus citations

Abstract

Hypotonic stress causes rapid cell swelling and initiates various cellular adaptive processes. However, it is unknown how cells initially sense low osmolarity and convert it into intracellular signals. We investigated the signal transduction mechanism initiated by hypotonic cell swelling in cardiac myocytes using c-fos expression as a nuclear marker. Treatment of myocytes with hypotonic culture media rapidly induced c-fos expression, whereas hypertonic stress had no effect. Transfection of c-fos reporter gene constructs suggested that the hypotonic stress response element maps to the serum response element of the c-fos promoter. Hypotonic stress immediately (within 5 s) activated tyrosine kinase activity, while activation of ERK1/2 peaked at 5 min. Stress-activated kinase (JNK1) was modestly activated at 15 min, whereas HOG1 like kinase (p38) was not activated by hypotonic stress. Extensive pharmacological studies indicated that only tyrosine kinase inhibitors suppressed the hypotonic swelling-induced c-fos expression. The effect of hypotonic stress was mimicked by chlorpromazine, which is known to cause membrane deformation. These results suggest that the signaling mechanism of hypotonic stress is distinct from that of hyperosmolar stress in mammalian cells. Tyrosine kinase activation is the earliest detectable cell response and plays an essential role in hypotonic swelling-induced ERK1/2 activation and c-fos expression.

Original languageEnglish (US)
Pages (from-to)5535-5546
Number of pages12
JournalEMBO Journal
Volume15
Issue number20
DOIs
StatePublished - Oct 15 1996
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Neuroscience
  • Molecular Biology
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

Keywords

  • Hypotonic
  • MAP kinase
  • Stretch
  • Tyrosine kinase
  • c-fos

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