Upstream events in BCR signaling. (A) BCR signaling in the absence of antigen binding provides a tonic survival signal dependent on PI3K. In this model, the Ras GTPAse TC21 binds to nonphosphorylated tyrosine motifs (black boxes) in Iga and Igß and activates PI3K-dependent survival signals. PI3Ka and PI3Kd assume redundant functions in this pathway. (B) BCR signaling in response to antigen binding induces LYN- and SYK-dependent phosphorylation (phosphorylation denoted by “P” in orange circle) of tyrosine motifs (red boxes) on CD79A and CD79B. A number of protein kinases (red symbols) and the lipid kinase PI3Kd (blue symbol) transmit survival, cell growth, and proliferation signals and regulate cell migration. The transcription factors NF-?B and NFAT are important regulators of BCR-induced gene expression changes. Small-molecule inhibitors of select kinases in the BCR pathway that have demonstrated significant clinical activity are indicated.