Abstract
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
Substances
-
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