Interleukin 2 stimulation of p70 S6 kinase activity is inhibited by the immunosuppressant rapamycin.
Binding of interleukin 2 (IL-2) to its receptor generates intracellular signals, including the activation of tyrosine and serine/threonine kinases. In this study the activation of the serine/threonine-specific ribosomal protein S6 kinases in response to IL-2 was analyzed in the murine T-cell line CTLL-20, a model system of IL-2-dependent proliferation. Two major classes of S6 kinases have been characterized: the 90-kDa (rsk) family and the 70-kDa family. In response to the addition of recombinant IL-2, total S6 kinase activity was increased. This S6 kinase activity could not be immunoprecipitated by an antiserum specific for S6 kinases of the 90-kDa family, exhibited a chromatographic behavior characteristic of 70-kDa S6 kinases, and was recognized by a 70-kDa S6 kinase-specific antiserum. Thus, IL-2 binding to its receptor induces specific activation of the 70-kDa family of S6 kinases. Rapamycin, a macrolide immunosuppressant that inhibits IL-2-dependent proliferation, inhibited IL-2-stimulated 70-kDa S6 kinase activity subsequent to early increases in tyrosine kinase activity. These findings imply that the targets of rapamycin include molecules involved in the activation of 70-kDa S6 kinases. These observations further suggest that S6 kinases of the 70-kDa family participate in signal transmission pathways subsequent to IL-2 binding to its receptor.
Calvo
V
V
Division of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.
Crews
C M
CM
Vik
T A
TA
Bierer
B E
BE
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002460:Cell Line; D002852:Chromatography, Ion Exchange; D015151:Immunoblotting; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D008970:Molecular Weight; D010750:Phosphoproteins / Q000302:isolation & purification / Q000378:metabolism; D019000:Phosphotyrosine; D011090:Polyenes / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000302:isolation & purification / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus; D016559:Tacrolimus / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D010750:Phosphoproteins; D011090:Polyenes; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D019000:Phosphotyrosine; D014443:Tyrosine; D011494:Protein Kinases; D019893:Ribosomal Protein S6 Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D013755:Tetradecanoylphorbol Acetate; D020123:Sirolimus; D016559:Tacrolimus