Figure 6.

A proposed model for Btk activation by PI 3-kinase-γ and Src family kinases. PI 3-kinase-γ (p101 and p110γ) is activated by dissociated G protein β, γ subunits as a result of ligand binding to G protein-coupled receptors (GPCR). P85/PI 3-kinase is activated by BCR. The product of p85/PI 3-kinase and PI 3-kinase-γ, PI(3,4,5)P₃, then binds the Btk PH domain directing BTK localization to the membrane. Alternatively, one or several unknown kinases dependent on PI(3,4,5)P₃ may activate Btk by transphosphorylation. In both cases, Btk becomes available for the activation by Src family kinases (SFK) associated with the BCR. Src family kinases then transphosphorylate Btk on Tyr-551 to induce Btk activation. Btk subsequently autophosphorylates Tyr-223 within its SH3 domain and effects a downstream signal. Both PI 3-kinase and Src family kinases are required for the efficient activation of Btk and induction of Btk downstream signaling.