A critical role for p59(fyn) in CD2-based signal transduction

TCR- but not CD2-triggered IL-2 production is p56(lck) dependent. To test t he hypothesis that p59(fyn), a second src-family protein tyrosine kinase (P TK) expressed in T lymphocytes, might be an essential upstream component of the CD2 signaling pathway, we generated human (h) CD2 transgenic (tg) fyn( +/+) and fyn(-/-) mice. Clustering of hCD2 molecules on resting peripheral T lymphocytes results in Ca2+ mobilization, activation of MARK and cellular proliferation. In contrast, in the absence of p59(fyn), these CD2-initiate d activities are markedly reduced, while TCR-triggered proliferation is una ffected. Several CD2 pathway components regulated by p59(fyn) have been ide ntified including phospholipase C-gamma1 (PLC-gamma1), Vav, protein kinase C-theta isoform (PKC-theta), docking protein (Dok), focal adhesion kinase ( FAK) and Pyk2. Decreased inducible PKC-theta catalytic activity and Vav pho sphorylation likely account for diminished p38 and JNK activation in hCD2tg fyn(-/-) mice. Moreover, deficiency in fyn-dependent PLC-gamma1 catalytic activity may contribute to reduced PKC-alpha -dependent ERK activation. Of note, CD2-dependent Dok but not linker from activated T cells (LAT) tyrosin e phosphorylation requires p59(fyn). Furthermore, that FAK and Pyk2 are tar get substrates implies that p59(fyn) may be an important regulator of T cel l adhesion as well. Collectively, these data identify p59(fyn) as a key PTK in CD2-mediated activation of mature T lymphocytes.