Non-receptor type protein tyrosine kinase (PTK) Syk is essential for the signaling via the B cell antigen receptor (BCR). Upon BCR crosslinking, Syk is recruited via its tandem SH2 domains to tyrosine-phosphorylated Ig-alpha/Ig-beta constituting components of BCR, and is then activated. The interdomain A lying between the two SH2 domains is highly conserved among different species of Syk and between Syk and ZAP-70. The mutant Syk carrying a deletion in the interdomain A (Delta 140-159) became phosphorylated regardless of BCR ligation and did not induce Ca2+ mobilization upon crosslinking of BCR. Furthermore, in vitro binding assay revealed that deletion of a part of the interdomain A abolished its binding activity to phosphorylated Ig-alpha/Ig-beta. These results indicate that the interdomain A of Syk is required for activation of Syk by binding to the phosphorylated Ig-alpha/Ig-beta upon BCR ligation and inhibition of spontaneous activation at the resting state. (C) 2007 Elsevier Inc. All rights reserved.