Characterization of Phospholipase Cγ Enzymes with Gain-of-Function Mutations
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Phospholipase C gamma isozymes (PLC gamma 1 and PLC gamma 2) have a crucial role in the regulation of a variety of cellular functions. Both enzymes have also been implicated in signaling events underlying aberrant cellular responses. Using N-ethyl-N-nitrosourea (ENU) mutagenesis, we have recently identified single point mutations in murine PLC gamma 2 that lead to spontaneous inflammation and autoimmunity. Here we describe further, mechanistic characterization of two gain-of-function mutations, D993G and Y495C, designated as ALI5 and ALI14. The residue Asp-993, mutated in ALI5, is a conserved residue in the catalytic domain of PLC enzymes. Analysis of PLC gamma 1 and PLC gamma 2 with point mutations of this residue showed that removal of the negative charge enhanced PLC activity in response to EGF stimulation or activation by Rac. Measurements of PLC activity in vitro and analysis of membrane binding have suggested that ALI5-type mutations facilitate membrane interactions without compromising substrate binding and hydrolysis. The residue mutated in ALI14 (Tyr-495) is within the spPH domain. Replacement of this residue had no effect on folding of the domain and enhanced Rac activation of PLC gamma 2 without increasing Rac binding. Importantly, the activation of the ALI14-PLC gamma 2 and corresponding PLC gamma 1 variants was enhanced in response to EGF stimulation and bypassed the requirement for phosphorylation of critical tyrosine residues. ALI5- and ALI14-type mutations aff…
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The majority of hypermorphic variants (S707Y, Y495C, D993G) have been identified in the context of APLAID disorders, and in some mouse models with autoinflammatory phenotypes.
“the majority of hypermorphic variants (S707Y, Y495C, D993G) have been identified in the context of APLAID disorders, and in some mouse models with autoinflammatory phenotypes [3, 109, 110]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [110]
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- Authors
- Everett, K. L., Bunney, T. D., Yoon, Y., Rodrigues-Lima, F., Harris, R., Driscoll, P. C., Abe, K., Fuchs, H., Hrabé de Angelis, M., Yu, P., Cho, W., & Katan, M.
- Affiliations
- Institute of Cancer Research (GB)
- University of Illinois Chicago (US)
- Institute of Structural and Molecular Biology (GB)
- Tokai University (JP)
- Helmholtz Munich (DE)
- Philipps University of Marburg (DE)
- Corresponding author
- Katan, Matilda
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-08
- Volume
- 284
- Issue
- 34
- Pages
- 23083-23093
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2755714
- OpenAlex
- W2132419558
- Cited by
- 63
- References
- 38
- Citations by year
- 2026: 1 · 2025: 3 · 2023: 3 · 2022: 3 · 2021: 7 · 2020: 6 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 5 · 2015: 3 · 2014: 7 · 2013: 3 · 2012: 3
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
- Site cant be reached (submittedVersion)
- Funders
- Cancer Research UK
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- PLCγ2, phospholipase C-gamma1, gain-of-function mutations, autoinhibition, membrane binding, Rac activation, EGF stimulation, tyrosine phosphorylation, autoimmunity, N-ethyl-N-nitrosourea mutagenesis
- MeSH terms
- Alkylating Agents, Amino Acid Sequence, Animals, Calorimetry, Cell Line, Chlorocebus aethiops, Drosophila, Ethylnitrosourea, Isoenzymes, Molecular Sequence Data, Mutation, Magnetic Resonance Spectroscopy, Structure-Activity Relationship, Sequence Homology, Amino Acid, Protein Structure, Secondary, Protein Structure, Tertiary, COS Cells, Catalytic Domain, Surface Plasmon Resonance, Mice, Phospholipase C gamma
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