Regulation of BCR signaling and Bcl-2 family protein expression by p66Shc. BCR cross-linking by antigen induces recruitment and activation of Syk, which could be facilitated by the adaptor protein p52Shc. Syk then activates Akt and ERK, which transduce the antiapoptotic BCR signal. p66Shc competitively inhibits recruitment of p52Shc, resulting in less efficient activation of Syk, Akt, and ERK and an alteration in the balance between antiapoptotic and proapoptotic BCR signals in favor of the latter. In parallel, p66Shc can enhance production of reactive oxygen species (ROS) by mitochondria, which could be responsible for the induced changes in the expression of antiapoptotic (Bcl-2, Bcl-xL) and proapoptotic (Bak, Bax) Bcl-2 family members. Phosphorylated proteins are depicted with a “P.” Professional illustration by Marie Dauenheimer.