The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration

Phosphatidylinositol-specific phospholipase C gamma 2 (PLC gamma 2) is a critical signaling molecule activated downstream from a variety of cell surface receptors that contain an intracellular immunoreceptor tyrosine-based activation motif. These receptors recruit kinases such as Syk, BTK, and BLNK to phosphorylate and activate PLC gamma 2, which then generates 1Dmyo-inositol 1,4,5-trisphosphate and diacylglycerol. These well-known second messengers are required for diverse membrane functionality including cellular proliferation, endocytosis, and calcium flux. As a result, PLC gamma 2 dysfunction is associated with a variety of diseases including cancer, neurodegeneration, and immune disorders. The diverse pathologies associated with PLC gamma 2 are exemplified by distinct genetic variants. Inherited mutations at this locus cause PLC gamma 2-associated antibody deficiency and immune dysregulation, in some cases with autoinflammation. Acquired mutations at this locus, which often arise as a result of BTK inhibition to treat chronic lymphocytic leukemia, result in constitutive downstream signaling and lymphocyte proliferation. Finally, a third group of PLC gamma 2 variants actually has a protective effect in a variety of neurodegenerative disorders, presumably by increased uptake and degradation of deleterious neurological aggregates. Therefore, manipulating PLC gamma 2 activity either up or down could have therapeutic benefit; however, we require a better understanding of the signaling pathways propagated by these variants before such clinical utility can be realized. Here, we review the signaling roles of PLC gamma 2 in hematopoietic cells to help understand the effect of mutations driving immune disorders and cancer and extrapolate from this to roles which may relate to protection against neurodegeneration.

Automated summary

PLC gamma 2 is a crucial signaling molecule downstream from cell surface receptors, its dysfunction associated with various diseases. Variants in PLC gamma 2 exhibit diverse pathologies, offering potential for therapeutic manipulation.