Components of the pre-BCR and pre-BCR signaling pathways disrupted in B-lineage immunodeficiencies.

The left side shows the assembly of the structural components of the pre-BCR: μHC, ψLC, and the Igα/Igβ heterodimer. For simplicity, only the formation of a Fab is shown. As discussed in the text, the mechanism of pre-BCR cross-linking is unknown. By whatever mechanism, pre-BCR cross-linking activates protein tyrosine kinases (PTKs) such as Lyn, followed by a complex series of events (see Benschop et al31 and Rawlings138 for detailed reviews) culminating in initial activation of PLC-γ. Concomitant activation of PI-3 kinase leads to production of PI (3,4,5) P3, which recruits BTK to the membrane where it is phosphorylated by Lyn. BTK then phosphorylates PLC-γ, leading to sustained Ca⁺⁺ flux and enhancement of growth. The assembly (solid arrows) or signaling pathways (dashed arrows) disrupted in antibody-deficiency diseases are shown by an X and a number (1 indicates mutation in Igα that would impair pre-BCR assembly; 2 indicates mutation in ψLC that would impair pre-BCR assembly; 3 indicates mutation in μHC that would impair pre-BCR assembly; 4 indicates BTK mutation in pleckstrin homology domain that would compromise binding to PI (3,4,5) P3; and 5 indicates BTKmutation in catalytic site that would compromise tyrosine phosphorylation of PCL-γ).