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)-mediate d signal transduction pathways is unknown. This study uses Cbl overexp ression in conjunction with a Ras-sensitive AP1 reporter construct to examine its role in regulating TCR mediated activation of the Ras path way, Cbl overexpression in Jurkat T cells inhibited AP1 activity after TCR ligation, However, AP1 induction by 4 beta-phorbol 12-myristate 1 3-acetate, which up-regulates Ras activity in a protein kinase C-depen dent, TCR/tyrosine kinase-independent manner was not affected by Cbl o verexpression. Cbl overexpression also did not affect AP1 induction by an activated Ras protein or a membrane bound form of the guanine nucl eotide exchange factor Sos. In addition, activation of the mitogen-act ivated protein kinase Erk2 was decreased by Cbl overexpression. Theref ore, Cbl regulates events that are required for full TCR-mediated Ras activation, and data are presented to support a model whereby Cbl regu lates events required for Ras activation via its association with Grb2 .