Reconstitution of Syk function by the ZAP-70 protein tyrosine kinase

AbstractZAP-70 and Syk are PTKs required for TCR and BCR function, respectively. Loss of the Syk PTK results in a nonfunctional BCR. We provide evidence here that ZAP-70 and Syk are functionally homologous in antigen receptor signaling by demonstrating that expression of ZAP-70 in Syk− B cells reconstitutes SCR function. Reconstitution required the presence of functional Src homology 2 (SH2) and catalytic domains of ZAP-70. Thus, drug targeting of a single SH2 domain within ZAP-70 should be sufficient to Inhibit hematopoletic antigen receptor function. In addition, we demonstrate that both ZAP-70 and Syk can bind directly to the phosphorylated Igα and Igβ subunits with affinities comparable to their binding to the TCR CD3ε subunit. These data suggest that ZAP-70 and Syk are comparable in their abilities to mediate hematopoletic antigen receptor signaling