Antigen aggregation of receptors composed of membrane Ig (mIg) and transducers CD79a and CD79b leads to tyrosine phosphorylation of CD79 immunoreceptor tyrosine-based activation motifs (ITAMs) (green) by Lyn/Fyn Src family tyrosine kinases. Participation of Src family kinases in this signaling pathway is negatively regulated by CSK-mediated phosphorylation of their C-terminal tyrosines. Phosphorylation of conserved ITAM motif tyrosines leads to recruitment of SH2 domain–containing effectors, including Syk, Lyn, and Fyn, and further activation of these effectors, initiating downstream pathways leading to cell activating (green arrows) and opposing regulatory signaling (red arrows). Among these proximally acting kinases, Lyn uniquely initiates both activating and regulatory circuitry by phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) embedded in cytoplasmic tails of membrane proteins, including FCRLs, CD72, CD22, FcγRIIB, and other molecules. These phosphorylated motifs propagate inhibitory signals via activation of SHP and SHIP phosphatases. Lyn may also act through other intermediaries, e.g., monophosphorylated antigen receptor ITAMs, casein kinase 2, and components of the BLK/BANK1/InsP3 receptor complex on ER membranes, to trigger regulatory circuitry. Shown in red lettering are molecules in which certain allelic forms have been shown to increase risk of development of SLE.