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• W2892935322 abstract "Depending on its occurrence in the germline or somatic context, a single point mutation, S707Y, of phospholipase C-γ2 (PLCγ2) gives rise to two distinct human disease states: acquired resistance of chronic lymphocytic leukemia cells (CLL) to inhibitors of Brutons´s tyrosine kinase (Btk) and dominantly inherited autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation, APLAID, respectively. The functional relationships of the PLCγ2S707Y mutation to other PLCG2 mutations causing (i) Btk inhibitor resistance of CLL cells and (ii) the APLAID-related human disease PLCγ2-associated antibody deficiency and immune dysregulation, PLAID, revealing different clinical characteristics including cold-induced urticaria, respectively, are currently incompletely understood. Here, we show that PLCγ2S707 point mutants displayed much higher activities at 37° C than the CLL Btk inhibitor resistance mutants R665W and L845F and the two PLAID mutants, PLCγ2Δ19 and PLCγ2Δ20-22. Combinations of CLL Btk inhibitor resistance mutations synergized to enhance PLCγ2 activity, with distinct functional consequences for different temporal orders of the individual mutations. Enhanced activity of PLCγ2S707Y was not observed in a cell-free system, suggesting that PLCγ2 activation in intact cells is dependent on regulatory rather than mutant-enzyme-inherent influences. Unlike the two PLAID mutants, PLCγ2S707Y was insensitive to activation by cooling and retained marked hyperresponsiveness to activated Rac upon cooling. In contrast to the PLAID mutants, which are insensitive to activation by endogenously expressed EGF receptors, the S707Y mutation markedly enhanced the stimulatory effect of EGF, explaining some of the pathophysiological discrepancies between immune cells of PLAID and APLAID patients in response to receptor-tyrosine-kinase activation." @default.
• W2892935322 created "2018-10-05" @default.
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• W2892935322 date "2018-09-28" @default.
• W2892935322 modified "2023-10-12" @default.
• W2892935322 title "Functional characterization of phospholipase C-γ2 mutant protein causing both somatic ibrutinib resistance and a germline monogenic autoinflammatory disorder" @default.
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• W2892935322 doi "https://doi.org/10.18632/oncotarget.26173" @default.
• W2892935322 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6188132" @default.
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