specimens, PLC-γ1 and PLC-γ2. PLC-γ2 PLC-γ2 plays a major role in BCR signal transduction. Absence of this enzyme in knockout specimens severely inhibits the development of B cells because the same signaling pathways necessary for antigen mediated B cell activation are necessary for B cell development from CLPs. In B cell signaling, PI 3-kinase is recruited to the BCR early in the signal transduction pathway. PI-3K phosphorylates PIP2 (Phosphatidylinositol 4,5-bisphosphate) into PIP3 (Phosphatidylinositol 3,4,5-trisphosphate). The increase in concentration of PIP3 recruits PLC-γ2 to the BCR complex which binds to BLNK on the BCR scaffold and membrane PIP3. PLC-γ2 is then phosphorylated by Syk on one site and Btk on two sites. PLC-γ2 then competes with PI-3K for PIP2 which it hydrolyzes into IP3 (inositol 1,4,5-trisphosphate), which ultimately raises intercellular calcium, and diacylglycerol (DAG), which activates portions of the PKC family. Because PLC-γ2 competes for PIP2 with the original signaling molecule PI3K, it serves as a negative feedback mechanism. PLC-δ The PLC-δ subfamily consists of three family members, δ1, 2, and 3. PLC-δ1 (85kDa) is the most well understood of the three. The enzyme is activated by high calcium levels generated by other PLC family members, and therefore functions as a calcium amplifier within the cell. Binding of its substrate PIP2 to the N-terminal PH domain is highly specific and functions to promote activation of the catalytic core. In addition, this specificity helps tether the enzyme tightly to the plasma membrane in order to access substrate through ionic interactions between the phosphate groups of PIP2 and charged residues in the PH domain. While the catalytic core does possess a weak affinity for PIP2, the C2 domain has been shown to mediate calcium-dependent phospholipid binding as well. In this model, the PH and C2 domains operate in concert as a "tether and fix" apparatus necessary for processive catalysis by the enzyme. PLC-δ1 also possesses a classical leucine-rich nuclear export signal (NES) in its EF hand motif, as well as a Nuclear localization signal within its linker region. These two elements combined allow PLC-δ1 to actively translocate into and out of the nucleus. However, its function in the nucleus remains unclear. The widely expressed PLC-δ1 isoform is the best-characterized phospholipase family member, as it was the first to have high-resolution X-ray crystal structures available for analysis. In terms of domain architecture, all of the enzymes are built upon a common PLC-δ backbone, wherein