ABSTRACT
Tyrosine phosphorylation is essential for lymphocyte activation (2,3). Cellular tyrosine phosphorylation is induced by the concerted action of specific protein tyrosine kinases
CD45 CD3/TCR
CD45
w
o
ERK's
Activation of Adaptor and Effector Molecules
PLCy Grb2-Sos p36 PI-3K GAP She V a v
cbl
Activation
—- | j Inhibitory Action « M ITAM
CUD SH2 Domain
Figure 1, Antigen receptor signaling in lymphocytes. (From Schieven GL, in Oxidative Stress and Signal Transduction, Cadenas E and Forman HJ, eds. New York: Chapman & Hall.)
Activation of Lymphocyte Signal Pathways 37
(PTK) and phosphotyrosine phosphatases (PTP). The Src-family tyrosine kinases are activated first, followed by the Syk-family kinases (see Ref. 7 for review). In T cells, the T cell receptor (TCR) binds a peptide antigen presented by major histocompatibility complex (MHC). CD4 binds to MHC II, stabilizing the interaction between the TCR and MHC II, whereas CD8 performs a similar function in binding to MHC I. Lck is associated with CD4 and CD8. These binding events lead to the activation of the Srcfamily kinases Lck and Fyn (Figure 1). These kinases then act to phosphorylate the £, 8, e, and 7 chains of the TCR at dual tyrosines present in ITAM (immunoreceptor tyrosine activation motif) sequences. The Syk-family kinases Syk and ZAP-70 then bind to the phosphorylated ITAM sequences via their SH2 domains (Figure 1). SH2 domains bind phosphotyrosine in the context of specific amino acid sequences and are responsible for the phosphotyrosine-dependent assembly of multiprotein signaling complexes (see Ref. 8 for review). Although both Syk and ZAP-70 are present in T cells; ZAP-70 is essential for productive T cell receptor signaling (9). Syk is primarily involved in B cell and myeloid cell signaling. Lck activates ZAP-70 by phosphorylating it on Tyr-493 after ZAP-70 has bound via its SH2 domains to tyrosine phosphorylated I chain (7). When ZAP-70 and Syk are activated, they phosphorylate themselves at multiple additional sites, so that they become scaffolds for the assembly of signaling complexes of proteins through SH2 interactions (10,11).
