2016
DOI: 10.1016/j.cellsig.2016.05.010
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Cool-temperature-mediated activation of phospholipase C-γ 2 in the human hereditary disease PLAID

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Cited by 27 publications
(34 citation statements)
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“…Next, we compared the effects of PLCG2 mutations observed in ibrutinib-resistant CLL patients to a PLCG2 deletion, ΔSH, effectively removing the entire autoinhibitory nSH2-cSH2-SH3 region of the encoded protein and previously characterized as one of the most active deletion mutant of PLCγ [ 16 , 25 ]. Figure 9C shows that the disease-related PLCγ 2 point mutants showed marked differences in their activities, but that none of them reached the high activity of PLCγ 2 ΔSH, which was still 4.2-fold higher (based on the amounts of cDNA required for half-maximal inositol phosphate formation) than the activity of PLCγ 2 R665W|L845F|S707Y, the most active of the point mutants mediating ibrutinib resistance in CLL patients.…”
Section: Resultsmentioning
confidence: 99%
See 1 more Smart Citation
“…Next, we compared the effects of PLCG2 mutations observed in ibrutinib-resistant CLL patients to a PLCG2 deletion, ΔSH, effectively removing the entire autoinhibitory nSH2-cSH2-SH3 region of the encoded protein and previously characterized as one of the most active deletion mutant of PLCγ [ 16 , 25 ]. Figure 9C shows that the disease-related PLCγ 2 point mutants showed marked differences in their activities, but that none of them reached the high activity of PLCγ 2 ΔSH, which was still 4.2-fold higher (based on the amounts of cDNA required for half-maximal inositol phosphate formation) than the activity of PLCγ 2 R665W|L845F|S707Y, the most active of the point mutants mediating ibrutinib resistance in CLL patients.…”
Section: Resultsmentioning
confidence: 99%
“…We have previously shown that the two PLAID PLCγ 2 mutants, PLCγ 2 Δ19 and PLCγ 2 Δ20-22, are strongly (>100-fold), rapidly, and reversibly activated by cooling to temperatures only a few degrees below 37° C. We found that the mechanism(s) underlying PLCγ 2 PLAID mutant activation by cool temperatures is distinct from a mere loss of SH-region-mediated autoinhibition and is dependent on both the integrity and the pliability of the spPH domain [ 16 ]. Subsequently, we showed that the first two PLCγ 2 point mutants to be described to mediate ibrutinib resistance in CLL, R665W and L845F, are strikingly hypersensitive to activation by Rac [ 17 ].…”
Section: Introductionmentioning
confidence: 99%
“…7B). The hyperenzyme activity exhibited by the Δ19 mutant at 20°C accelerated PIP 2 hydrolysis, leading to the significantly increased PIP 2 density outside the BCR microclusters (39). The number of BCR microclusters ( Fig.…”
Section: The Pip 2 -Derived Amplification Loop Accounts For the Enhanmentioning
confidence: 95%
“…B cells expressing PLC-2 mutants from PLAID patients exhibit much higher BCR activation compared with healthy controls (38). These phenomena only occur at low temperatures (20° to 30°C) but not at physiological temperature (37°C) (38,39). Because this report showed that the PIP 2 -derived amplification loop is required for highly efficient activation of B cells, we investigated the contribution of PIP 2derived amplification loop to the phenotype of PLAID-associated PLC-2 by guest on July 5, 2020 http://immunology.sciencemag.org/ Downloaded from mutants.…”
Section: The Pip 2 -Derived Amplification Loop Accounts For the Enhanmentioning
confidence: 99%
“…The answer to this question is somehow can be related to the fact that PI(4,5)P2‐derived signaling amplification might have changed in some diseases. For example, two PLCγ2 mutants from PLAID patients, Δ19 and Δ20‐22, were hyper‐activated at low temperature (20‐30°C), leading to increased PI(4,5)P2 generation, which enhanced the formation of BCR microclusters in B cells with these mutants expression . Therefore, the increased amount of PI(4,5)P2 produced by the enhanced activity of PLCγ2 mutants may induce a hyper‐feedback for BCR microcluster formation, resulting in abnormal activation of BCR signaling under low temperature.…”
Section: The Future Directionsmentioning
confidence: 99%