STIMULATION OF THE T-CELL ANTIGEN RECEPTOR-CD3 COMPLEX SIGNALING PATHWAY BY THE TYROSINE PHOSPHATASE INHIBITOR PERVANADATE IS MEDIATED BY INHIBITION OF CD45 - EVIDENCE FOR 2 INTERCONNECTED LCK FYN-DEPENDENT ORZAP-70-DEPENDENT SIGNALING PATHWAYS/

The tyrosine phosphatase specific inhibitor pervanadate is a potent ac tivator of T lymphocytes through induction of tyrosine phosphorylation and downstream events of the activation cascade. Using CD45- or CD3-n egative variants of the Jurkat leukemic T-cell line rue show that the different biochemical events induced by pervanadate appeared to be dep endent on the presence at the cell surface of either CD45 or CD3. CD45 -dependent events such as tyrosine phosphorylation of Shc, activation of nuclear factor-kappa B (NF-kappa B), activator protein 1 (AP-1), tr anscription factors, and stimulation of interleukin-2 (IL-2) promoter and of CD69 and CD25 surface expression paralleled activation of the t yrosine kinases lck and fyn. By contrast, stimulation of calcium influ x, a CD3-dependent event, paralleled zap-70 activation. The data demon strate that the T-cell antigen receptor-CD3 (TcR-CD3) complex is funct ionally linked to two different protein tyrosine kinase (PTK) modules with separate specific functions and that CD45 may bean important regu lator of this coupling. (C) 1996 Wiley-Liss, Inc.