Activated BCR signaling or its oncogenic mimics activate SRC family kinases such as LYN, resulting in phosphorylation of CD19-Y482/513 and IFITM3-Y20. Phosphorylated tyrosine residues on CD19, which provide docking sites for the SH2 domains of the PI3K regulatory subunit p85, facilitates localization and activation of PI3K to the lipid raft on plasma membrane. Transiently synthesized PIP3 by the PI3K catalytic subunit p110 stably accumulated by IFITM3 at the BCR signalosome. IFITM3, therefore, stabilizes the BCR signalosome, supports PIP3-mediated recruitment of downstream effector molecules such as BTK and ATK, enhances BCR signaling or BCR-mimicking oncogenic signaling. The effect of the amphipathic helix of IFITM3-mediated cholesterol accumulation at lipid raft on BCR signaling has not yet been investigated.
