Review Article

Does B Cell Receptor Signaling in Chronic Lymphocytic Leukaemia Cells Differ from That in Other B Cell Types?

Figure 1

Induction of proximal BCR signaling. Illustration of the most proximal signals initiated during BCR engagement. (a) Antigen engagement of the BCR induces Lyn-mediated phosphorylation of CD79 on tyrosine residues within and outside the ITAM motif. This attracts adaptor molecules such as LAB, Nck, BCAP, and BLNK, as well as the tyrosine kinase Syk. (b) Syk binding to tyrosine phosphorylated CD79 induces its activation, and it phosphorylates BLNK, BCAP, and LAB. Phospho-BCAP attracts and activates PI3Kδ and converts PIP2 to PIP3. The presence of PIP3 on the plasma membrane attracts PDK1 and Akt; PDK1 phosphorylates and activates Akt, and this is followed by a second phosphorylation event by mTorc2. PIP3 on the plasma membrane also attracts Btk, which then binds to phospho-BLNK and exposes a phosphorylation site for Syk leading to autophosphorylation and full activation of Btk [17]. Phospho-BLNK also acts as a scaffold for PLCγ2. (c) Active Btk phosphorylates and activates PLCγ2 and catalyzes the conversion of PIP2 to DAG and IP3 (which acts on ER to release intracellular Ca2+). DAG and Ca2+ then act to activate PKCβ. (d) Phospho-BLNK and phospho-LAB serve as scaffolds for Vav, which is also attracted to the plasma membrane by the presence of PIP3. Syk is then able to phosphorylate and activate Vav, which then acts as a guanine exchange factor to convert GDP-Rac1/2 to GTP-Rac1/2. This results in cytoskeletal changes and induction of BCR internalization.
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