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

Nature. 1994 May 12;369(6476):156-60. doi: 10.1038/369156a0.


The mitogen-activated protein (MAP) kinases Erk-1 and Erk-2 are proline-directed kinases that are themselves activated through concomitant phosphorylation of tyrosine and threonine residues. The kinase p54 (M(r) 54,000), which was first isolated from cycloheximide-treated rats, is proline-directed like Erks-1/2, and requires both Tyr and Ser/Thr phosphorylation for activity. p54 is, however, distinct from Erks-1/2 in its substrate specificity, being unable to phosphorylate pp90rsk but more active in phosphorylating the c-Jun transactivation domain. Molecular cloning of p54 reveals a unique subfamily of extracellularly regulated kinases. Although they are 40-45% identical in sequence to Erks-1/2, unlike Erks-1/2 the p54s are only poorly activated in most cells by mitogens or phorbol esters. However, p54s are the principal c-Jun N-terminal kinases activated by cellular stress and tumour necrosis factor (TNF)-alpha, hence they are designated stress-activated protein kinases, or SAPKs. SAPKs are also activated by sphingomyelinase, which elicits a subset of cellular responses to TNF-alpha (ref. 9). SAPKs therefore define a new TNF-alpha and stress-activated signalling pathway, possibly initiated by sphingomyelin-based second messengers, which regulates the activity of c-Jun.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / classification
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Line
  • Cloning, Molecular
  • Cycloheximide / pharmacology
  • Enzyme Activation / drug effects
  • Hot Temperature
  • Mice
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase 9
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Kinases / classification
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Protein Serine-Threonine Kinases
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-jun / classification
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Rats
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Sphingomyelin Phosphodiesterase / pharmacology
  • Swine
  • Tumor Necrosis Factor-alpha / pharmacology


  • Proto-Oncogene Proteins c-jun
  • Tumor Necrosis Factor-alpha
  • Cycloheximide
  • Protein Kinases
  • Mitogen-Activated Protein Kinase 9
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Sphingomyelin Phosphodiesterase

Associated data

  • GENBANK/L27111
  • GENBANK/L27112
  • GENBANK/L27128
  • GENBANK/L27129