title: The Jak/STAT signaling pathway is downregulated at febrile temperatures.
abstract: BACKGROUND
  The Janus family of kinases (JAKs), Jak1, Jak2, Jak3, and Tyk2, constitute a subgroup of non-receptor protein tyrosine kinases. Upon cytokine binding, the receptor-associated kinases are activated and phosphorylate tyrosine residues in their cognate cytokine receptors. Their activities are controlled at several levels and include cellular concentration, auto-activation, and degradation.
  
  
  RESULTS
  Our findings show that elevated temperatures in the fever range irreversibly aggregate Jak2 and considerably reduce functional Jak2 protein levels. Jak2 synthesis remains unaltered. We observed that also the protein level of the signal transducer and activator of transcription, STAT5b, is transiently decreased at temperatures above 37°C. Consequently, the signaling response, e.g. via the growth hormone receptor, is reduced.
  
  
  CONCLUSIONS
  These findings predict that elevated body temperatures lower the responsiveness of cytokine receptors.
authors.affiliation: Department of Cell Biology and Institute of Biomembranes, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Tobias
authors.initials: T
authors.lastname: Nespital
authors.forename: Ger J
authors.initials: GJ
authors.lastname: Strous
mesh_terms: D000818:Animals; D001831:Body Temperature; D002458:Cell Fractionation; D006224:Cricetinae; D003412:Cricetulus; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D057809:HEK293 Cells; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism; D018613:Microscopy, Confocal; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D017931:DNA Primers; D053612:Janus Kinases