Cbl-mediated regulation of T cell receptor-induced AP1 activation. Implications for activation via the Ras signaling pathway.
The functional role of Cbl in regulating T cell receptor (TCR)-mediated signal transduction pathways is unknown. This study uses Cbl overexpression in conjunction with a Ras-sensitive AP1 reporter construct to examine its role in regulating TCR-mediated activation of the Ras pathway. Cbl overexpression in Jurkat T cells inhibited AP1 activity after TCR ligation. However, AP1 induction by 4beta-phorbol 12-myristate 13-acetate, which up-regulates Ras activity in a protein kinase C-dependent, TCR/tyrosine kinase-independent manner, was not affected by Cbl overexpression. Cbl overexpression also did not affect AP1 induction by an activated Ras protein or a membrane-bound form of the guanine nucleotide exchange factor Sos. In addition, activation of the mitogen-activated protein kinase Erk2 was decreased by Cbl overexpression. Therefore, Cbl regulates events that are required for full TCR-mediated Ras activation, and data are presented to support a model whereby Cbl regulates events required for Ras activation via its association with Grb2.
Rellahan
B L
BL
Laboratory of Immunobiology, Division of Monoclonal Antibodies, Office of Therapeutics Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA. rellahan@a1.cber.fda.gov
Graham
L J
LJ
Stoica
B
B
DeBell
K E
KE
Bonvini
E
E
D048868:Adaptor Proteins, Signal Transducing; D029721:Drosophila Proteins; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein; D017930:Genes, Reporter; D006801:Humans; D019169:Jurkat Cells; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D018631:ras Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D029721:Drosophila Proteins; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D018808:Transcription Factor AP-1; D050721:Proto-Oncogene Proteins c-cbl; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D018631:ras Proteins; C106411:Cbl protein, Drosophila; D013755:Tetradecanoylphorbol Acetate