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

Schade, Anja; Walliser, Claudia; Wist, Martin; Haas, Jennifer; Vatter, Petra; Kraus, Johann M.; Filingeri, Davide; Havenith, George; Kestler, Hans A.; Milner, Joshua D.; Gierschik, Peter

doi:10.1016/j.cellsig.2016.05.010

Cited by 27 publications

(34 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

See 1 more Smart Citation

Functional characterization of phospholipase C-γ2 mutant protein causing both somatic ibrutinib resistance and a germline monogenic autoinflammatory disorder

et al. 2018

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional characterization of phospholipase C-γ2 mutant protein causing both somatic ibrutinib resistance and a germline monogenic autoinflammatory disorder

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…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%

A PIP ₂ -derived amplification loop fuels the sustained initiation of B cell activation

Xie

Guo

et al. 2017

Sci. Immunol.

View full text Add to dashboard Cite

Lymphocytes have evolved sophisticated signaling amplification mechanisms to efficiently activate downstream signaling after detection of rare ligands in their microenvironment. B cell receptor microscopic clusters (BCR microclusters) are assembled on the plasma membrane and recruit signaling molecules for the initiation of lymphocyte signaling after antigen binding. We identified a signaling amplification loop derived from phosphatidylinositol 4,5-biphosphate (PIP) for the sustained B cell activation. Upon antigen recognition, PIP was depleted by phospholipase C-γ2 (PLC-γ2) within the BCR microclusters and was regenerated by phosphatidic acid-dependent type I phosphatidylinositol 4-phosphate 5-kinase outside the BCR microclusters. The hydrolysis of PIP inside the BCR microclusters induced a positive feedback mechanism for its synthesis outside the BCR microclusters. The falling gradient of PIP across the boundary of BCR microclusters was important for the efficient formation of BCR microclusters. Our results identified a PIP-derived amplification loop that fuels the sustained initiation of B cell activation.

show abstract

“…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%

A PI(4,5)P2‐derived “gasoline engine model” for the sustained B cell receptor activation

Wan

Shaheen

et al. 2019

Immunological Reviews

View full text Add to dashboard Cite

To efficiently initiate activation responses against rare ligands in the microenvironment, lymphocytes employ sophisticated mechanisms involving signaling amplification. Recently, a signaling amplification mechanism initiated from phosphatidylinositol (PI) 4, 5‐biphosphate [PI(4,5)P2] hydrolysis and synthesis for sustained B cell activation has been reported. Antigen and B cell receptor (BCR) recognition triggered the prompt reduction of PI(4,5)P2 density within the BCR microclusters, which led to the positive feedback for the synthesis of PI(4,5)P2 outside of the BCR microclusters. At single molecule level, the diffusion of PI(4,5)P2 was slow, allowing for the maintenance of a PI(4,5)P2 density gradient between the inside and outside of the BCR microclusters and the persistent supply of PI(4,5)P2 from outside to inside of the BCR microclusters. Here, we review studies that have contributed to uncovering the molecular mechanisms of PI(4,5)P2‐derived signaling amplification model. Based on these studies, we proposed a “gasoline engine model” in which the activation of B cell signaling inside the microclusters is similar to the working principle of burning gasoline within the engine chamber of a gasoline engine. We also discuss the evidences showing the potential universality of this model and future prospects.

show abstract

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

Cited by 27 publications

References 61 publications

Functional characterization of phospholipase C-γ2 mutant protein causing both somatic ibrutinib resistance and a germline monogenic autoinflammatory disorder

Functional characterization of phospholipase C-γ2 mutant protein causing both somatic ibrutinib resistance and a germline monogenic autoinflammatory disorder

A PIP ₂ -derived amplification loop fuels the sustained initiation of B cell activation

A PI(4,5)P2‐derived “gasoline engine model” for the sustained B cell receptor activation

Contact Info

Product

Resources

About

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

Cited by 27 publications

References 61 publications

Functional characterization of phospholipase C-γ2 mutant protein causing both somatic ibrutinib resistance and a germline monogenic autoinflammatory disorder

Functional characterization of phospholipase C-γ2 mutant protein causing both somatic ibrutinib resistance and a germline monogenic autoinflammatory disorder

A PIP 2 -derived amplification loop fuels the sustained initiation of B cell activation

A PI(4,5)P2‐derived “gasoline engine model” for the sustained B cell receptor activation

Contact Info

Product

Resources

About

A PIP ₂ -derived amplification loop fuels the sustained initiation of B cell activation