Signaling Pathways Activated by the B-Cell Receptor in Chronic Lymphocytic Leukemia

Maria Teresa Scupoli; Giovanni Pizzolo

Expert Rev Hematol. 2012;5(3):341-348.

Negative Regulation

The duration and intensity of the BCR signalosome signaling is tightly governed by a dynamic equilibrium between activating (mediated by ITAM) and inhibitory mechanisms. Negative regulation of BCR signaling involves transmembrane receptors such as CD22, CD5, CD72 and FcγRIIB. Their inhibitory function resides on a cytoplasmic domain referred to as the immunoreceptor tyrosine-based inhibition motif (ITIM), which is phosphorylated by LYN upon BCR stimulation. Phosphorylated ITIMs recruit phosphatases, such as Src homology 2 (SH2) domain-containing phosphatase-1 (SHP-1) or SH2 domain-containing inositol phosphatase (SHIP), thus arresting BCR signaling. Therefore, LYN is responsible for both positive and negative regulation of BCR signaling. Recently, a new immunoregulatory function has been ascribed to ITIMs, which can propagate inhibitory signals under specific configurations termed inhibitory ITAM (ITAMi).^[28]

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