Hypothermic stress leads to activation of Ras-Erk signaling

E Y Chan, S L Stang, D A Bottorff, J C Stone

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)


The small GTPase Ras is converted to the active, GTP-bound state during exposure of vertebrate cells to hypothermic stress. This activation occurs more rapidly than can be accounted for by spontaneous nucleotide exchange. Ras-guanyl nucleotide exchange factors and Ras GTPase-activating proteins have significant activity at 0 degrees C in vitro, leading to the hypothesis that normal Ras regulators influence the relative amounts of Ras-GTP and Ras-GDP at low temperatures in vivo. When hypothermic cells are warmed to 37 degrees C, the Raf-Mek-Erk protein kinase cascade is activated. After prolonged hypothermic stress, followed by warming to physiologic temperature, cultured fibroblasts assume a rounded morphology, detach from the substratum, and die. All of these biologic responses are attenuated by pharmacologic inhibition of Mek. Previously, it had been found that low temperature blocks acute growth factor signaling to Erk. In the present study, we found that this block occurs at the level of Raf activation. Temperature regulation of Ras signaling could help animal cells respond appropriately to hypothermic stress, and Ras-Erk signaling can be manipulated to improve the survival of cells in cold storage.

Original languageEnglish
Pages (from-to)1337-44
Number of pages8
JournalJournal of Clinical Investigation
Issue number9
Publication statusPublished - May 1999


  • animals
  • calcium-calmodulin-dependent protein kinases
  • cell line
  • cell survival
  • dogs
  • enzyme activation
  • enzyme inhibitors
  • epidermal growth factor
  • fibroblasts
  • guanosine triphosphate
  • humans
  • hydrolysis
  • hypothermia
  • rats
  • signal transduction
  • ras proteins


Dive into the research topics of 'Hypothermic stress leads to activation of Ras-Erk signaling'. Together they form a unique fingerprint.

Cite this