Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 297, Issue 2, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.jbc.2021.100905
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Funding
- German Research Foundation (DFG) [SCHU 3126/3-1]
- National Health and Medical Research Council [1155342, 2003159]
- Sylvia and Charles Viertel Foundation
- Howard Hughes Medical Institute-Wellcome International Research Scholarship
- National Health and Medical Research Council of Australia [1155342, 2003159] Funding Source: NHMRC
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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.
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.
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