The serine protease inhibitors, tosylphenylalanine chloromethyl ketone and tosyllysine chloromethyl ketone, potently inhibit pp70s6k activation.
pp70(s6k) is a mitogen-regulated serine/threonine kinase involved in the G1 to S phase transition of the cell cycle. We have analyzed its regulation in several cell lines by a variety of agonists and have found that pp70(s6k) activation by all stimuli tested is completely blocked by the serine protease inhibitors tosylphenylalanine chloromethyl ketone (TPCK) and tosyllysine chloromethyl ketone (TLCK). TPCK inhibition of the pp70(s6k) signaling pathway resembles that of the immunosuppressant rapamycin; however, we demonstrate that their methods of inhibition differ. We find that TPCK and TLCK are not general signaling inhibitors since the activation of the mitogen-activated protein kinase pathway is not abrogated. The demonstration that these protease inhibitors prevent signaling via the pp70(s6k) pathway will help in understanding the variety of physiological processes that TPCK and TLCK have been shown to effect.
Grammer
T C
TC
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Blenis
J
J
D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D051379:Mice; D011090:Polyenes / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus; D014107:Tosyllysine Chloromethyl Ketone / Q000494:pharmacology*; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology*
D011090:Polyenes; D015842:Serine Proteinase Inhibitors; D014107:Tosyllysine Chloromethyl Ketone; D014108:Tosylphenylalanyl Chloromethyl Ketone; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus