Characterization of Phospholipase Cγ Enzymes with Gain-of-Function Mutations

Everett, Katy L.; Bunney, Tom D.; Yoon, Yonghan; Rodrigues‐Lima, Fernando; Harris, Richard; Driscoll, Paul C.; Abe, Koichiro; Fuchs, Helmut; Angelis, Martin Hrabé de; Yu, Philipp; Cho, Wohnwa; Katan, Matilda

doi:10.1074/jbc.m109.019265

Cited by 58 publications

(79 citation statements)

References 38 publications

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“…This distribution resembles those of cutaneous granulomatous lesions in PLAID patients [19]. We therefore compared the effect of cool temperatures on the activity of the mutants PLC ) as described before [17]. Importantly, however, the three mutants displayed A more comprehensive comparison of the effects of the various constituents of the SH2n-SH2c-SH3-spPHc region, alone or in combination, on PLC 2 constitutive activity and sensitivity to cool temperatures is shown in Fig.…”

Section: The Mouse Plc 2 Mutant Ali5 Is Also Sensitive To Activationmentioning

confidence: 94%

“…In transfected COS-7 cells, the corresponding PLC 2 mutants, PLC 2 Ali5 and PLC 2 Ali14 displayed only slightly enhanced basal activity at 37 o C, whereas the compound mutant, PLC 2 Ali5/Ali14 clearly showed constitutively enhanced activity [17]. In Ali5 mice, autoinflammatory dermatitis commenced in the superficial layers of the paws and ears, i.e.…”

Section: The Mouse Plc 2 Mutant Ali5 Is Also Sensitive To Activationmentioning

confidence: 99%

“…Inositol phospholipids were extracted from transfected cells and analyzed as before [17]. COS-7 cells were grown and radiolabeled in 6-well plates.…”

Section: Inositol Phospholipid Analysismentioning

confidence: 99%

“…C, respectively [15][16][17]. The Ali5 mutation also gives rise to platelet hyperreactivity and a prothrombotic phenotype in mice [18].…”

mentioning

confidence: 99%

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Cool-temperature-mediated activation of phospholipase C-γ 2 in the human hereditary disease PLAID

Schade

Walliser

Wist

et al. 2016

Cellular Signalling

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Section: The Mouse Plc 2 Mutant Ali5 Is Also Sensitive To Activationmentioning

confidence: 94%

Section: The Mouse Plc 2 Mutant Ali5 Is Also Sensitive To Activationmentioning

confidence: 99%

See 2 more Smart Citations

Cool-temperature-mediated activation of phospholipase C-γ 2 in the human hereditary disease PLAID

Schade

Walliser

Wist

et al. 2016

Cellular Signalling

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“…To examine EGF-mediated PLC␥ 2 stimulation, COS-7 cells were radiolabeled for 24 h in serum-free DMEM as described previously (45). Briefly, cells were washed twice with 0.3 ml/well DMEM containing the above supplements except serum and then incubated for 24 h in 0.2 ml/well of the same medium supplemented with 0.25% fatty-acid-free bovine serum albumin (catalog no.…”

Section: Journal Of Biological Chemistry 22145mentioning

confidence: 99%

The Phospholipase Cγ2 Mutants R665W and L845F Identified in Ibrutinib-resistant Chronic Lymphocytic Leukemia Patients Are Hypersensitive to the Rho GTPase Rac2 Protein

Walliser

Hermkes

Schade

et al. 2016

Journal of Biological Chemistry

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Mutations in the gene encoding phospholipase C-␥ 2 (PLC␥ 2 ) have been shown to be associated with resistance to targeted therapy of chronic lymphocytic leukemia (CLL) with the Bruton's tyrosine kinase inhibitor ibrutinib. The fact that two of these mutations, R665W and L845F, imparted upon PLC␥ 2 an ϳ2-3-fold ibrutinib-insensitive increase in the concentration of cytosolic Ca 2؉ following ligation of the B cell antigen receptor (BCR) led to the assumption that the two mutants exhibit constitutively enhanced intrinsic activity. Here, we show that the two PLC␥ 2 mutants are strikingly hypersensitive to activation by Rac2 such that even wild-type Rac2 suffices to activate the mutant enzymes upon its introduction into intact cells. Enhanced "basal" activity of PLC␥ 2 in intact cells is shown using the pharmacologic Rac inhibitor EHT 1864 and the PLC␥ 2 F897Q mutation mediating Rac resistance to be caused by Rac-stimulated rather than by constitutively enhanced PLC␥ 2 activity. We suggest that R665W and L845F be referred to as allomorphic rather than hypermorphic mutations of PLCG2. Rerouting of the transmembrane signals emanating from BCR and converging on PLC␥ 2 through Rac in ibrutinib-resistant CLL cells may provide novel drug treatment strategies to overcome ibrutinib resistance mediated by PLCG2 mutations or to prevent its development in ibrutinib-treated CLL patients.Inositol-phospholipid-specific phospholipases C (PLCs) 3 regulate many fundamental functions of normal and neoplastic B cells (1, 2). They catalyze the formation of inositol 1,4,5-trisphosphate (InsP 3 ) and diacylglycerol and, at the same time, decrease the local or general plasma membrane abundance of their substrate, phosphatidylinositol 4,5-bisphosphate (PtdInsP 2 ) (3). Three members of the six mammalian PLC subfamilies, ␤, ␥, ␦, ⑀, , and , play important roles in B cells as follows: PLC␤ 2 , PLC␤ 3 , and PLC␥ 2 . PLC␤ 2 and PLC␤ 3 are important in mediating B cell responses to G-protein-coupled chemokine receptors (4). PLC␥ 2 serves as a key component of the B cell receptor (BCR) signalosome by interacting with cell surface receptor activation, e.g. by antigens (5), cleavage fragments of the third complement component (6), and bacterial, viral, or autoimmunity host DNA (7), and even certain chemokines (8). PLC␥ 2 activation results in InsP 3 -mediated increases in the concentration of free Ca 2ϩ , diacylglycerol-mediated activation of protein kinases C, and changes in transmembrane signaling directly mediated by PtdInsP 2 (9).Several lines of evidence point to an important contribution of enhanced BCR signaling in the pathogenesis, progression, and/or maintenance of B cell leukemias and lymphomas. For example, leukemic B cells of patients with chronic lymphocytic leukemia (CLL) specifically express a restricted immunoglobulin heavy variable (IGHV) gene repertoire, suggesting that CLL development represents an antigen-superantigen-driven process (10). Furthermore, the presence or absence of somatic mutations in rearranged IGHV genes determin...

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A novel N‐ethyl‐N‐nitrosourea–induced mutation in phospholipase Cγ2 causes inflammatory arthritis, metabolic defects, and male infertility in vitro in a murine model

Abe¹,

Fuchs²,

Boersma³

et al. 2011

Arthritis & Rheumatism

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138

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Objective. It is difficult to identify a single causative factor for inflammatory arthritis because of the multifactorial nature of the disease. This study was undertaken to dissect the molecular complexity of systemic inflammatory disease, utilizing a combined approach of mutagenesis and systematic phenotype screening in a murine model.Methods. In a large-scale N-ethyl-N-nitrosourea mutagenesis project, the Ali14 mutant mouse strain was established because of dominant inheritance of spontaneous swelling and inflammation of the hind paws. Genetic mapping and subsequent candidate gene sequencing were conducted to find the causative gene, and systematic phenotyping of Ali14/؉ mice was performed in the German Mouse Clinic. Results.A novel missense mutation in the phospholipase C␥2 gene (Plcg2) was identified in Ali14/؉ mice. Because of the hyperreactive external entry of calcium observed in cultured B cells and other in vitro experiments, the Ali14 mutation is thought to be a novel gain-of-function allele of Plcg2. Findings from systematic screening of Ali14/؉ mice demonstrated various phenotypic changes: an abnormally high T cell:B cell

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Characterization of Phospholipase Cγ Enzymes with Gain-of-Function Mutations

Cited by 58 publications

References 38 publications

Cool-temperature-mediated activation of phospholipase C-γ 2 in the human hereditary disease PLAID

Cool-temperature-mediated activation of phospholipase C-γ 2 in the human hereditary disease PLAID

The Phospholipase Cγ2 Mutants R665W and L845F Identified in Ibrutinib-resistant Chronic Lymphocytic Leukemia Patients Are Hypersensitive to the Rho GTPase Rac2 Protein

A novel N‐ethyl‐N‐nitrosourea–induced mutation in phospholipase Cγ2 causes inflammatory arthritis, metabolic defects, and male infertility in vitro in a murine model

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