The role of PLCγ2 in immunological disorders, cancer and neurodegeneration

Jackson, JT; Mulazzani, E; Nutt, SL; Masters, SL

Author(s): Jackson, JT; Mulazzani, E; Nutt, SL; Masters, SL;
Details: Publication Year 2021-06-19,Volume 297,Issue #2,Page 100905
Journal Title: Journal of Biological Chemistry
Abstract: PLCγ2 is a critical signalling molecule activated downstream from a variety of cell surface receptors that contain an intracellular immunoreceptor tyrosine-based activation motif (ITAM). These receptors recruit kinases such as Syk, BTK and BLNK to phosphorylate and activate PLCγ2, which then generates 1D-myo-inositol 1,4,5-trisphosphate (IP(3)) and diacylglycerol (DAG). These well known second messengers are required for diverse membrane functionality including cellular proliferation, endocytosis and calcium flux. As a result, PLCγ2 dysfunction is associated with a variety of diseases including cancer, neurodegeneration and immune disorders. The diverse pathologies associated with PLCγ2 are exemplified by distinct genetic variants. Inherited mutations at this locus cause PLCγ2-associated antibody deficiency and immune dysregulation (PLAID), in some cases with autoinflammation (APLAID). Acquired mutations at this locus, which often arise as a result of BTK inhibition to treat chronic lymphocytic leukaemia (CLL), result in constitutive downstream signalling and lymphocyte proliferation. Finally, a third group of PLCγ2 variants actually have a protective effect in a variety of neurodegenerative disorders, presumably by increased uptake and degradation of deleterious neurological aggregates. Therefore, manipulating PLCγ2 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 realised. Here, we review the signalling roles of PLCγ2 in haematopoietic 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.
Publisher: Elsevier
Keywords: Phospholipase C; cancer; immunodeficiency; inflammation; neurodegeneration
Research Division(s): Immunology; Inflammation
PubMed ID: 34157287
Publisher's Version: https://doi.org/10.1016/j.jbc.2021.100905
Open Access at Publisher's Site: https://doi.org/10.1016/j.jbc.2021.100905
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2021-06-25 01:41:43

Last Modified: 2022-06-21 11:42:17