title: Role of protein kinase C in T-cell antigen receptor regulation of p21ras: evidence that two p21ras regulatory pathways coexist in T cells.
abstract: T-lymphocyte activation via the antigen receptor complex (TCR) results in accumulation of p21ras in the active GTP-bound state. Stimulation of protein kinase C (PKC) can also activate p21ras, and it has been proposed that the TCR effect on p21ras occurs as a consequence of TCR regulation of PKC. To test the role of PKC in TCR regulation of p21ras, a permeabilized cell system was used to examine TCR regulation of p21ras under conditions in which TCR activation of PKC was blocked, first by using a PKC pseudosubstrate peptide inhibitor and second by using ionic conditions that prevent phosphatidyl inositol hydrolysis and hence diacylglycerol production and PKC stimulation. The data show that TCR-induced p21ras activation is not mediated exclusively by PKC. Thus, in the absence of PKC stimulation, the TCR was still able to induce accumulation of p21ras-GTP complexes, and this stimulation correlated with an inactivation of p21ras GTPase-activating proteins. The protein tyrosine kinase inhibitor herbimycin could prevent the non-PKC-mediated, TCR-induced stimulation of p21ras. These data indicate that two mechanisms for p21ras regulation coexist in T cells: one PKC mediated and one not. The TCR can apparently couple to p21ras via a non-PKC-controlled route that may involve tyrosine kinases.
authors.affiliation: Lymphocyte Activation Laboratory, I.C.R.F. Laboratories, London, United Kingdom.
authors.forename: M
authors.initials: M
authors.lastname: Izquierdo
authors.forename: J
authors.initials: J
authors.lastname: Downward
authors.forename: J D
authors.initials: JD
authors.lastname: Graves
authors.forename: D A
authors.initials: DA
authors.lastname: Cantrell
mesh_terms: D000595:Amino Acid Sequence; D016227:Benzoquinones; D002463:Cell Membrane Permeability; D004075:Diglycerides / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D010716:Phosphatidylinositols / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology; D011946:Receptors, Antigen / Q000378:metabolism*; D017828:Rifabutin / Q000031:analogs & derivatives; D013601:T-Lymphocytes / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D016227:Benzoquinones; D004075:Diglycerides; D047029:Lactams, Macrocyclic; D010716:Phosphatidylinositols; D011809:Quinones; D011946:Receptors, Antigen; D017828:Rifabutin; C020754:herbimycin; D006160:Guanosine Triphosphate; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)