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The stress-activated protein kinase subfamily of c-Jun kinases

J M Kyriakis1, P Banerjee, E Nikolakaki

  • 1Diabetes Research Laboratory, Medical Services, Massachusetts General Hospital East, Charlestown 02129.

Nature
|May 12, 1994
PubMed

Insights

Stress-activated protein kinases (SAPKs) are a new class of MAP kinases. These kinases are activated by cellular stress and tumor necrosis factor-alpha, regulating c-Jun activity.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Biochemistry

Background:

  • Mitogen-activated protein (MAP) kinases Erk-1 and Erk-2 are proline-directed kinases activated by tyrosine and threonine phosphorylation.
  • The kinase p54, similar to Erks-1/2, is proline-directed and requires Tyr and Ser/Thr phosphorylation for activity.
  • p54 exhibits distinct substrate specificity, phosphorylating the c-Jun transactivation domain more actively than pp90rsk.

Purpose of the Study:

  • To characterize the kinase p54 and its subfamily of extracellularly regulated kinases.
  • To investigate the activation mechanisms and signaling pathways involving p54.
  • To establish the role of p54 in cellular stress responses and TNF-alpha signaling.

Main Methods:

  • Molecular cloning of p54.
  • Analysis of kinase activity and substrate specificity.
  • Investigation of activation by mitogens, phorbol esters, cellular stress, and tumor necrosis factor (TNF)-alpha.

Main Results:

  • Molecular cloning revealed p54 belongs to a unique subfamily of extracellularly regulated kinases, designated stress-activated protein kinases (SAPKs).
  • SAPKs are 40-45% identical to Erks-1/2 but are poorly activated by mitogens or phorbol esters.
  • SAPKs are the principal c-Jun N-terminal kinases activated by cellular stress and TNF-alpha, and also by sphingomyelinase.

Conclusions:

  • SAPKs define a novel signaling pathway activated by TNF-alpha and cellular stress.
  • This pathway may be initiated by sphingomyelin-based second messengers.
  • SAPKs play a crucial role in regulating the activity of c-Jun in response to stress and TNF-alpha.

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