title: Differential requirement of protein tyrosine kinase and protein kinase C in the generation of IL-2-induced LAK cell and alpha CD3-induced CD3-AK cell responses.
abstract: This study examined the role of protein tyrosine kinase (PTK) and protein kinase C (PKC) in the signal transduction pathways for lymphocyte activation through IL-2R to generate LAK cells and through TCR-CD3 to generate CD3-AK cells. Two PTK inhibitors [herbimycin A and genistein (PTK-I)] and two PKC inhibitors [calphositin C and staurosporine (PKC-I)] were used in the experiments. It was found that the primary activation pathway through IL-2R was PTK-dependent; that is, generation of both the IL-2-induced proliferative and the cytotoxic responses was completely abrogated by PTK-I and not by PKC-I. Quite different results were obtained with the alpha CD3-induced CD3-AK cell response. First, the alpha CD3-induced proliferation was only partially inhibited by PTK-I or PKC-I alone. Second, generation of CD3-AK cytotoxic response was primarily PKC-dependent; that is, only PKC-I induced significant inhibition. Genistein was found to reduce protein tyrosine phosphorylation in both LAK cells and CD3-AK cells, indicating that CD3-AK cells were also susceptible to PTK-I treatment. Further studies showed that PTK-I and not PKC-I suppressed perforin mRNA expression and N-2-benzyoxycarbonyl-L-lysine thiobeneylester esterase production in LAK cells, and the opposite was true for CD3-AK cells. These results indicate that different pathways were employed in lymphocyte activation through IL-2R and TCR-CD3. The former pathway is primarily PTK-dependent. Activation through TCR-CD3 is a more complex event.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Division of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Ting
authors.forename: M E
authors.initials: ME
authors.lastname: Hargrove
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: A D
authors.initials: AD
authors.lastname: Patel
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D016227:Benzoquinones; D005260:Female; D019833:Genistein; D007376:Interleukin-2 / Q000494:pharmacology*; D007529:Isoflavones / Q000494:pharmacology; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects / Q000201:enzymology*; D047029:Lactams, Macrocyclic; D008213:Lymphocyte Activation / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes; D054353:Perforin; D011083:Polycyclic Compounds / Q000494:pharmacology; D052899:Pore Forming Cytotoxic Proteins; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction; D019311:Staurosporine
chemical_list: D000470:Alkaloids; D016227:Benzoquinones; D007376:Interleukin-2; D007529:Isoflavones; D047029:Lactams, Macrocyclic; D008562:Membrane Glycoproteins; D009281:Naphthalenes; D011083:Polycyclic Compounds; D052899:Pore Forming Cytotoxic Proteins; D011809:Quinones; D012333:RNA, Messenger; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D054353:Perforin; D017828:Rifabutin; C020754:herbimycin; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D019311:Staurosporine; C058819:calphostin C