Dysfunction of phospholipase Cγ in immune disorders and cancer

Candidate driver genes involved in genome maintenance and DNA repair in Sézary syndrome

“…This mutation is predicted to impair the auto-inhibitory function of PLCG1, which limits TCR signaling downstream of receptor ligation. 6,63 In addition, a further recurrent variant (PLCG1 D342N ) has been shown to increase inositol phosphate production in COS-7 cells. 38 It is not yet clear whether the other recurrent PLCG1 variants identified affect this same catalytic function and whether these variants are sufficient alone to enable constitutive TCR signaling without costimulatory signals, but recent studies in SS and ATLL have detected activating CD28 mutations and CTLA4-CD28 and ICOS-CD28 gene fusions.…”

Phospholipase Cγ1 (PLCγ1) Controls Osteoclast Numbers via Colony-stimulating Factor 1 (CSF-1)-dependent Diacylglycerol/β-Catenin/CyclinD1 Pathway

“…PLC␥1 enzymatic activity leads to increased calcium levels and DAG production (2). Because calcium is known to modulate NFATc1 and shPLC␥1 cells have normal NFATc1 levels, we hypothesized that reduced DAG production may be responsible for impaired ␤-catenin/cyclinD1 expression in PLC␥1-deficient cells.…”

“…Phospholipase C␥ (PLC␥) 4 family members PLC␥1 and PLC␥2 are critical regulators of signaling pathways downstream of growth factor receptors, integrins, and immune complexes and modulate a variety of signaling pathways involved in cell differentiation, motility, and adhesion to name a few (1)(2)(3). The main function of the PLC␥ family is to cleave phosphatidylinositol 4,5-bisphosphate (PIP 2 ) into two secondary messengers, inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol (DAG).…”

“…The main function of the PLC␥ family is to cleave phosphatidylinositol 4,5-bisphosphate (PIP 2 ) into two secondary messengers, inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol (DAG). IP 3 , in turn, increases intracellular calcium levels via binding to the IP 3 receptors on the endoplasmic reticulum, whereas DAG serves as an endogenous activator of protein kinase C (2,4).…”

“…By contrast, global PLC␥2 knockout mice are viable but have a variety of immunological defects, including impaired inflammatory responses in models of arthritis or infections (8 -10), developmental defects in the lymphatic system (11), and high bone mass due to defective osteoclastogenesis (12). Structure analysis of the two enzymes indicates over 90% homology in the catalytic domain, which mediates the conversion of PIP 2 into IP 3 and DAG, whereas 50 -60% homology is observed within the SH2 and SH3 adaptive motifs (2). Interestingly, however, the different phenotype of the two null mice suggests distinct, non-overlapping specific roles for each enzyme (5).…”